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There has been significant controversy regarding the effects of pre‐hospitalization use of renin‐angiotensin system (RAS) inhibitors on the prognosis of hypertensive COVID‐19 patients.,We retrospectively assessed 2,297 hospitalized COVID‐19 patients at Tongji Hospital in Wuhan, China, from January 10th to March 30th, 2020; and identified 1,182 patients with known hypertension on pre‐hospitalization therapy.,We compared the baseline characteristics and in‐hospital mortality between hypertensive patients taking RAS inhibitors (N=355) versus non‐RAS inhibitors (N=827).,Of the 1,182 hypertensive patients (median age 68 years, 49.1% male), 12/355 (3.4%) patients died in the RAS inhibitors group vs.,95/827 (11.5%) patients in the non‐RAS inhibitors group (p<0.0001).,Adjusted hazard ratio for mortality was 0.28 (95% CI 0.15‐0.52, p<0.0001) at 45 days in the RAS inhibitors group compared with non‐RAS inhibitors group.,Similar findings were observed when patients taking angiotensin receptor blockers (N=289) or angiotensin converting enzyme inhibitors (N=66) were separately compared with non‐RAS inhibitors group.,The RAS inhibitors group compared with non‐RAS inhibitors group had lower levels of C‐reactive protein (median 13.5 vs.,24.4 pg/mL; p=0.007) and interleukin‐6 (median 6.0 vs.,8.5 pg/mL; p=0.026) on admission.,The protective effect of RAS inhibitors on mortality was confirmed in a meta‐analysis of published data when our data were added to previous studies (odd ratio 0.44, 95% CI 0.29-0.65, p<0.0001).,In a large single center retrospective analysis we observed a protective effect of pre‐hospitalization use of RAS inhibitors on mortality in hypertensive COVID‐19 patients; which might be associated with reduced inflammatory response.
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The dysfunction of the renin-angiotensin system (RAS) has been observed in coronavirus infection disease (COVID-19) patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs), are associated with clinical outcomes remains unknown.,COVID-19 patients with hypertension were enrolled to evaluate the effect of RAS inhibitors.,We observed that patients receiving ACEI or ARB therapy had a lower rate of severe diseases and a trend toward a lower level of IL-6 in peripheral blood.,In addition, ACEI or ARB therapy increased CD3 and CD8 T cell counts in peripheral blood and decreased the peak viral load compared to other antihypertensive drugs.,This evidence supports the benefit of using ACEIs or ARBs to potentially contribute to the improvement of clinical outcomes of COVID-19 patients with hypertension.
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Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE.,This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE.,A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19.,MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion.,Validated evaluation tools were used to grade the level of evidence to support each recommendation.,When evidence did not exist, guidance was developed based on consensus using the modified Delphi process.,The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements.,Very little evidence exists in the COVID-19 population.,The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements.,The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving.
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Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis.,In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy.,Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease.,Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.,•COVID-19 may predispose patients to arterial and venous thrombosis.,•Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,•Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,•The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic.,COVID-19 may predispose patients to arterial and venous thrombosis.,Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic.
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There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2).,We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive.,Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class.,A difference of at least 10 percentage points was prespecified as a substantial difference.,Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness.,A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness.,There was no association between any single medication class and an increased likelihood of a positive test.,None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.,We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.
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Angiotensin converting enzyme-2 (ACE2) receptors mediate the entry into the cell of three strains of coronavirus: SARS-CoV, NL63 and SARS-CoV-2.,ACE2 receptors are ubiquitous and widely expressed in the heart, vessels, gut, lung (particularly in type 2 pneumocytes and macrophages), kidney, testis and brain.,ACE2 is mostly bound to cell membranes and only scarcely present in the circulation in a soluble form.,An important salutary function of membrane-bound and soluble ACE2 is the degradation of angiotensin II to angiotensin1-7.,Consequently, ACE2 receptors limit several detrimental effects resulting from binding of angiotensin II to AT1 receptors, which include vasoconstriction, enhanced inflammation and thrombosis.,The increased generation of angiotensin1-7 also triggers counter-regulatory protective effects through binding to G-protein coupled Mas receptors.,Unfortunately, the entry of SARS-CoV2 into the cells through membrane fusion markedly down-regulates ACE2 receptors, with loss of the catalytic effect of these receptors at the external site of the membrane.,Increased pulmonary inflammation and coagulation have been reported as unwanted effects of enhanced and unopposed angiotensin II effects via the ACE→Angiotensin II→AT1 receptor axis.,Clinical reports of patients infected with SARS-CoV-2 show that several features associated with infection and severity of the disease (i.e., older age, hypertension, diabetes, cardiovascular disease) share a variable degree of ACE2 deficiency.,We suggest that ACE2 down-regulation induced by viral invasion may be especially detrimental in people with baseline ACE2 deficiency associated with the above conditions.,The additional ACE2 deficiency after viral invasion might amplify the dysregulation between the ‘adverse’ ACE→Angiotensin II→AT1 receptor axis and the ‘protective’ ACE2→Angiotensin1-7→Mas receptor axis.,In the lungs, such dysregulation would favor the progression of inflammatory and thrombotic processes triggered by local angiotensin II hyperactivity unopposed by angiotensin1-7.,In this setting, recombinant ACE2, angiotensin1-7 and angiotensin II type 1 receptor blockers could be promising therapeutic approaches in patients with SARS-CoV-2 infection.
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Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease.,In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis.,Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated.,Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19.,Further, we review other agents, including immunomodulators, that may have antithrombotic properties.,It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.
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Coronavirus disease 2019 (COVID-19) has caused a global pandemic in just a few months, causing millions infected.,Nearly 20% of COVID-19 patients present severe coagulation abnormalities, which may occur in almost all of the severe and critical ill COVID-19 cases.,Concomitant venous thromboembolism (VTE), a potential cause of unexplained deaths, has been frequently reported in COVID-19 cases, but its management is still challenging due to the complexity between antithrombotic therapy and coagulation disorders.,Based on frontline practical experience and comprehensive literature review, here a panel of experts and physicians from China and Europe developed an evidence and opinion-based consensus on the prophylaxis and management of VTE associated with COVID-19.,This statement aims for clinicians treating COVID-19 and provides practical recommendations in detailed situations, for example, how to choose thromboprophylactic measures for patients with diverse severity of disease and bleeding risk, or which kind of anticoagulant should be prescribed.,With limited experience on COVID19-associated VTE, this expert consensus statement should be helpful for clinicians worldwide with specific suggestions.
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Greinacher et al report a detailed characterization of a potential mechanism underlying the pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT).,They propose that the pathogenesis of VITT involves a 2-step mechanism, initiated by binding of platelet factor 4 to components of the ChadOX1 nCov-19 adenoviral vaccine followed by a prothrombotic antibody response similar to autoimmune heparin-induced thrombocytopenia.,This work helps explain the clinical observations and also suggests modifications to future vaccine production to reduce the risk of VITT.,ChAdOx1 nCoV-19 vaccine contains human TRex HEK293 cell-derived proteins and EDTA.Vaccine components and PF4 form complexes on platelet surfaces to which VITT patient antibodies bind.,ChAdOx1 nCoV-19 vaccine contains human TRex HEK293 cell-derived proteins and EDTA.,Vaccine components and PF4 form complexes on platelet surfaces to which VITT patient antibodies bind.,SARS-CoV-2 vaccine ChAdOx1 nCoV-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT).,Using biophysical techniques, mouse models, and analysis of VITT patient samples, we identified determinants of this vaccine-induced adverse reaction.,Super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound.,PF4/vaccine complex formation was charge-driven and increased by addition of DNA.,Proteomics identified substantial amounts of virus production-derived T-REx HEK293 proteins in the ethylenediaminetetraacetic acid (EDTA)-containing vaccine.,Injected vaccine increased vascular leakage in mice, leading to systemic dissemination of vaccine components known to stimulate immune responses.,Together, PF4/vaccine complex formation and the vaccine-stimulated proinflammatory milieu trigger a pronounced B-cell response that results in the formation of high-avidity anti-PF4 antibodies in VITT patients.,The resulting high-titer anti-PF4 antibodies potently activated platelets in the presence of PF4 or DNA and polyphosphate polyanions.,Anti-PF4 VITT patient antibodies also stimulated neutrophils to release neutrophil extracellular traps (NETs) in a platelet PF4-dependent manner.,Biomarkers of procoagulant NETs were elevated in VITT patient serum, and NETs were visualized in abundance by immunohistochemistry in cerebral vein thrombi obtained from VITT patients.,Together, vaccine-induced PF4/adenovirus aggregates and proinflammatory reactions stimulate pathologic anti-PF4 antibody production that drives thrombosis in VITT.,The data support a 2-step mechanism underlying VITT that resembles the pathogenesis of (autoimmune) heparin-induced thrombocytopenia.
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Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca).,More data were needed on the pathogenesis of this unusual clotting disorder.,We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19.,We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions.,Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.,Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49).,Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage.,Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died.,Five patients had disseminated intravascular coagulation.,None of the patients had received heparin before symptom onset.,All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin.,Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter).,Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.,Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia.,(Funded by the German Research Foundation.)
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COVID-19 has rapidly impacted on mortality worldwide.1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets.,Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor.,Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths.,COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions.,Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively).,We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date.,OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.
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This study evaluated cardiac involvement in patients recovered from coronavirus disease-2019 (COVID-19) using cardiac magnetic resonance (CMR).,Myocardial injury caused by COVID-19 was previously reported in hospitalized patients.,It is unknown if there is sustained cardiac involvement after patients’ recovery from COVID-19.,Twenty-six patients recovered from COVID-19 who reported cardiac symptoms and underwent CMR examinations were retrospectively included.,CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping).,Edema ratio and LGE were assessed in post-COVID-19 patients.,Cardiac function, native T1/T2, and ECV were quantitatively evaluated and compared with controls.,Fifteen patients (58%) had abnormal CMR findings on conventional CMR sequences: myocardial edema was found in 14 (54%) patients and LGE was found in 8 (31%) patients.,Decreased right ventricle functional parameters including ejection fraction, cardiac index, and stroke volume/body surface area were found in patients with positive conventional CMR findings.,Using quantitative mapping, global native T1, T2, and ECV were all found to be significantly elevated in patients with positive conventional CMR findings, compared with patients without positive findings and controls (median [interquartile range]: native T1 1,271 ms [1,243 to 1,298 ms] vs. 1,237 ms [1,216 to 1,262 ms] vs. 1,224 ms [1,217 to 1,245 ms]; mean ± SD: T2 42.7 ± 3.1 ms vs.,38.1 ms ± 2.4 vs.,39.1 ms ± 3.1; median [interquartile range]: 28.2% [24.8% to 36.2%] vs.,24.8% [23.1% to 25.4%] vs.,23.7% [22.2% to 25.2%]; p = 0.002; p < 0.001, and p = 0.002, respectively).,Cardiac involvement was found in a proportion of patients recovered from COVID-19.,CMR manifestation included myocardial edema, fibrosis, and impaired right ventricle function.,Attention should be paid to the possible myocardial involvement in patients recovered from COVID-19 with cardiac symptoms.
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African-Americans/Blacks have suffered higher morbidity and mortality from COVID-19 than all other racial groups.,This study aims to identify the causes of this health disparity, determine prognostic indicators, and assess efficacy of treatment interventions.,We performed a retrospective cohort study of clinical features and laboratory data of COVID-19 patients admitted over a 52-day period at the height of the pandemic in the United States.,This study was performed at an urban academic medical center in New York City, declared a COVID-only facility, serving a majority Black population.,Of the 1103 consecutive patients who tested positive for COVID-19, 529 required hospitalization and were included in the study. 88% of patients were Black; and a majority (52%) were 61-80 years old with a mean body mass index in the “obese” range. 98% had one or more comorbidities.,Hypertension was the most common (79%) pre-existing condition followed by diabetes mellitus (56%) and chronic kidney disease (17%).,Patients with chronic kidney disease who received hemodialysis were found to have lower mortality, than those who did not receive it, suggesting benefit from hemodialysis Age > 60 years and coronary artery disease were independent predictors of mortality in multivariate analysis.,Cox proportional hazards modeling for time to death demonstrated a significantly high ratio for COPD/Asthma, and favorable effects on outcomes for pre-admission ACE inhibitors and ARBs.,CRP (180, 283 mg/L), LDH (551, 638 U/L), glucose (182, 163 mg/dL), procalcitonin (1.03, 1.68 ng/mL), and neutrophil:lymphocyte ratio (8.3:10.0) were predictive of mortality on admission and at 48-96 h.,Of the 529 inpatients 48% died, and one third of them died within the first 3 days of admission. 159/529patients received invasive mechanical ventilation, of which 86% died and of the remaining 370 patients, 30% died.,COVID-19 patients in our predominantly Black neighborhood had higher in-hospital mortality, likely due to higher prevalence of comorbidities.,Early dialysis and pre-admission intake of ACE inhibitors/ARBs improved patient outcomes.,Early escalation of care based on comorbidities and key laboratory indicators is critical for improving outcomes in African-American patients.,The online version contains supplementary material available at 10.1186/s12879-021-05782-9.
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Coronavirus disease (COVID-19) has been designated a global pandemic by the World Health Organization.,It is unclear whether previous treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) affects the prognosis of COVID-19 patients.,The aim of this study was to evaluate the clinical implications of previous treatment with ACEI/ARB on the prognosis of patients with COVID-19 infection.,Single-center, retrospective, observational cohort study based on all the inhabitants of our health area.,Analyses of main outcomes (mortality, heart failure, hospitalization, intensive care unit [ICU] admission, and major acute cardiovascular events [a composite of mortality and heart failure]) were adjusted by multivariate logistic regression and propensity score matching models.,Of the total population, 447 979 inhabitants, 965 patients (0.22%) were diagnosed with COVID-19 infection, and 210 (21.8%) were under ACEI or ARB treatment at the time of diagnosis.,Treatment with ACEI/ARB (combined and individually) had no effect on mortality (OR, 0.62; 95%CI, 0.17-2.26; P = .486), heart failure (OR, 1.37; 95%CI, 0.39-4.77; P = .622), hospitalization rate (OR, 0.85; 95%CI, 0.45-1.64; P = .638), ICU admission (OR, 0.87; 95%CI, 0.30-2.50; P = .798), or major acute cardiovascular events (OR, 1.06; 95%CI, 0.39-2.83; P = .915).,This neutral effect remained in a subgroup analysis of patients requiring hospitalization.,Previous treatment with ACEI/ARB in patients with COVID-19 had no effect on mortality, heart failure, requirement for hospitalization, or ICU admission.,Withdrawal of ACEI/ARB in patients testing positive for COVID-19 would not be justified, in line with current recommendations of scientific societies and government agencies.
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Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%.,However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring.,Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab.,Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation.,The patient initially presented with intractable nausea with no known gastrointestinal etiology.,High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days.,Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis.,Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis.,Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily.,Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band.,This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy.,This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.
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Immune-mediated myocarditis is an uncommon adverse effect of immune checkpoint inhibition and is associated with a high rate of mortality.,In this reported case, a 64-year-old woman with right temporo-parietal glioblastoma IDH-WT was treated with nivolumab, temozolomide and radiation therapy on a clinical trial.,She developed malignant arrhythmias secondary to histologically confirmed severe immune-mediated myocarditis.,She was treated with equine anti-thymocyte globulin (ATGAM) due to development of malignant arrhythmias refractory to high-dose corticosteroids.,This report describes the only case of immune-mediated myocarditis treated with ATGAM resulting in a favourable outcome.,Use of ATGAM should be considered in cases of steroid-refractory immune-mediated myocarditis and administered in close consultation with a cardiac transplant team experienced in the use of this agent.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children.,A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation.,The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology.,We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C.,We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage.,Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.,•Hyperinflammation in MIS-C differs from that of acute COVID-19•T cell subsets discriminate Kawasaki disease patients from MIS-C•IL-17A drives Kawasaki but not MIS-C hyperinflammation•Global profiling reveals candidate autoantibodies with pathogenic potential,Hyperinflammation in MIS-C differs from that of acute COVID-19,T cell subsets discriminate Kawasaki disease patients from MIS-C,IL-17A drives Kawasaki but not MIS-C hyperinflammation,Global profiling reveals candidate autoantibodies with pathogenic potential,A systems immunology approach describes how multisystem inflammatory syndrome in children (MIS-C) is distinct from Kawasaki disease as well as the cytokine storm associated with severe COVID-19 in terms of its molecular and immune profiles.
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Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome.,We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States.,The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month.,Clinicians abstracted the data onto standardized forms.,We report on 186 patients with MIS-C in 26 states.,The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020.,Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%).,The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died.,Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease-like features were documented in 74 (40%).,Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation.,The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).,Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents.,(Funded by the Centers for Disease Control and Prevention.)
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Supplemental Digital Content is available in the text.,To assess the role of thromboprophylaxis regimens on the occurrence of pulmonary embolism in coronavirus disease 2019 patients.,Retrospective analysis of prospectively collected data on coronavirus disease 2019 patients, included between March 10, and April 30, 2020.,ICU of an University Hospital in Belgium.,Critically ill adult mechanically ventilated coronavirus disease 2019 patients were eligible if they underwent a CT pulmonary angiography, as part of the routine management in case of persistent hypoxemia or respiratory deterioration.,The primary endpoint of this study was the occurrence of pulmonary embolism according to the use of standard thromboprophylaxis (i.e. subcutaneous enoxaparin 4,000 international units once daily) or high regimen thromboprophylaxis (i.e. subcutaneous enoxaparin 4,000 international units bid or therapeutic unfractioned heparin).,Of 49 mechanically ventilated coronavirus disease 2019, 40 underwent CT pulmonary angiography after a median of 7 days (4-8 d) since ICU admission and 12 days (9-16 d) days since the onset of symptoms.,Thirteen patients (33%) were diagnosed of pulmonary embolism, which was bilateral in six patients and localized in the right lung in seven patients.,D-dimers on the day of CT pulmonary angiography had a predictive accuracy of 0.90 (95% CIs: 0.78-1.00) for pulmonary embolism.,The use of high-regimen thromboprophylaxis was associated with a lower occurrence of pulmonary embolism (2/18; 11%) than standard regimen (11/22, 50%-odds ratio 0.13 [0.02-0.69]; p = 0.02); this difference remained significant even after adjustment for confounders.,Six patients with pulmonary embolism (46%) and 14 patients without pulmonary embolism (52%) died at ICU discharge (odds ratio 0.79 [0.24-3.26]; p = 0.99).,In this study, one third of coronavirus disease 2019 mechanically ventilated patients have a pulmonary embolism visible on CT pulmonary angiography.,High regimen thromboprophylaxis may decrease the occurrence of such complication.
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This case series reports a systematic assessment of deep vein thrombosis among patients in an intensive care unit in France with severe coronavirus disease 2019 (COVID-19).
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This is an observational cohort study comparing 156 patients evaluated for acute stroke between March 30 and May 31, 2020 at a comprehensive stroke center with 138 patients evaluated during the corresponding time period in 2019.,During the pandemic, the proportion of COVID-19 positive patients was low (3%), the time from symptom onset to hospital presentation was significantly longer, and a smaller proportion of patients underwent reperfusion therapy.,Among patients directly evaluated at our institution, door-to-needle and door-to-recanalization metrics were significantly longer.,Our findings support concerns that the current pandemic may have a negative impact on the management of acute stroke.
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Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease with serious public health risk and has taken the world off-guard with its rapid spread.,As the COVID-19 pandemic intensifies, overwhelming the healthcare system and the medical community, current practice for the management of acute ischemic stroke (AIS) will require modification, and guidelines should be relaxed while maintaining high standard quality of care.,The aim of these suggestions is to avoid contributing to the rapid spread of COVID-19 as well as to conserve what are likely to be very limited resources (including personnel, intensive care/hospital beds as well as physicians) while maintaining high quality care for patients with AIS.,We present our recommendations for the management of acute stroke during the COVID-19 pandemics.
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Increases in cardiac troponin indicative of myocardial injury are common in patients with coronavirus disease-2019 (COVID-19) and are associated with adverse outcomes such as arrhythmias and death.,These increases are more likely to occur in those with chronic cardiovascular conditions and in those with severe COVID-19 presentations.,The increased inflammatory, prothrombotic, and procoagulant responses following severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection increase the risk for acute nonischemic myocardial injury and acute myocardial infarction, particularly type 2 myocardial infarction, because of respiratory failure with hypoxia and hemodynamic instability in critically ill patients.,Myocarditis, stress cardiomyopathy, acute heart failure, and direct injury from SARS-CoV-2 are important etiologies, but primary noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis, probably cause more of the myocardial injury.,The structured use of serial cardiac troponin has the potential to facilitate risk stratification, help make decisions about when to use imaging, and inform stage categorization and disease phenotyping among hospitalized COVID-19 patients.,•Increases in cardiac troponin indicative of myocardial injury are common and prognostic in COVID-19.,•Increases can be due to chronic injury, acute nonischemic injury, or acute MI.,•Troponin, along with inflammatory and thrombotic markers, may facilitate COVID-19 stage classification and risk stratification.,Increases in cardiac troponin indicative of myocardial injury are common and prognostic in COVID-19.,Increases can be due to chronic injury, acute nonischemic injury, or acute MI.,Troponin, along with inflammatory and thrombotic markers, may facilitate COVID-19 stage classification and risk stratification.
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To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19).,We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years.,Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors.,Risk factors of death and myocardial injury were analysed using multivariable regression models.,A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs.,9.7%; P < 0.001) than survivors.,The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001].,The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively.,In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury.,The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities.
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Clinical characteristics and treatment outcomes of acute type A aortic dissection with D‐dimer elevation have not been clarified.,D‐dimer was measured preoperatively within 24 hours of symptom onset in 262 patients with acute type A aortic dissection.,The median (and interquartile range) admission D‐dimer concentration in our total patient group was 26.7 (8.3-85.9) μg/mL.,Median (interquartile range) D‐dimer concentrations were 5.0 (2.6-18.0) μg/mL for complete false lumen thrombosis (n=33), 60.9 (19.4-160.4) μg/mL for partial thrombosis (n=81), 26.5 (10.0-70.6) μg/mL for a patent false lumen (n=131), and 8.7 (3.2-26.9) μg/mL for ulcerlike projection (n=17) (P<0.01).,With a D‐dimer concentration of ≤8.3 μg/mL representing the lower quartile, we then investigated predictors of a low D‐dimer level.,Multivariate analysis showed dissection limited to the ascending aorta (P<0.01; odds ratio, 9.81) or descending aorta (P<0.01; odds ratio, 7.68), a completely thrombosed false lumen (P<0.01; odds ratio, 4.02), and absence of brain ischemia (P=0.013; odds ratio, 4.74) to be predictors of the lower D‐dimer concentration.,Compared with patients with a low D‐dimer concentration (≤8.3 μg/mL, n=66), patients with a D‐dimer concentration >8.3 μg/mL (n=196) had a reduced preoperative platelet count and increased operation time and transfusion volume.,In‐hospital mortality was elevated in this group (1.5% versus 11.2%; P=0.031), although 7‐year survival did not differ for hospital survivors (lower versus higher, 93.1% versus 79.1%; P=0.21).,D‐dimer concentrations are strongly influenced by the extent of dissection and false lumen status.,Operative risks are increased in patients with a relatively high D‐dimer concentration.
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Fibrin degradation products (FDP) and D-dimer have been considered to be involved in many vascular diseases.,In this study we aimed to explore the diagnostic implication of FDP and D-dimer in aortic dissection patients. 202 aortic dissection patients were collected as the case group, 150 patients with other cardiovascular diseases, including myocardial infarction (MI, n = 45), pulmonary infarction (n = 51) and abdominal aortic aneurysm (n = 54) were collected as non-dissection group, and 27 healthy people were in the blank control group.,The FDP and D-dimer levels were detected with immune nephelometry.,Logist regression analysis was performed to evaluate the influence of FDP and D-dimer for the aortic dissection patients.,ROC curve was used to determine the diagnostic value of FDP and D-dimer.,The FDP and D-dimer levels were significantly higher in aortic dissection patients than in non-dissection patients and the healthy controls.,FDP and D-dimer were both the risk factors for patients with aortic dissection.,From the ROC analysis, diagnostic value of FDP and D-dimer were not high to distinguish aortic dissection patients from the non-dissection patients.,However FDP and D-dimer could be valuable diagnostic marker to differentiate aortic dissection patients and healthy controls with both AUC 0.863.
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MicroRNAs (miRNAs) are non-coding RNAs that function as regulators of gene expression and thereby contribute to the complex disease phenotypes.,Hypertrophic cardiomyopathy (HCM) and Dilated cardiomyopathy (DCM) can cause sudden cardiac death and eventually develop into heart failure.,However, they have different clinical and pathophysiological phenotype and the expressional spectrum of miRNAs in left ventricles of HCM and DCM has never been compared before.,This study selected 30 human left ventricular heart samples belonged to three diagnostic groups (Control, HCM, DCM).,Each group has ten samples.,Based on previous findings, the expression of 13 different microRNAs involving heart failure and hypertrophy (miR-1-3p, miR-10b, miR-21, miR-23a, miR-27a, miR-29a, miR-133a-3p, miR-142-3p, miR-155, miR-199a-3p, miR-199a-5p, miR-214, miR-497) was measured.,17 HCM patients were included as second group to validate the associations.,We found miR-155, miR-10b and miR-23a were highly expressed in both HCM and DCM compared with control.,MiR-214 was downregulated and miR-21 was upregulated in DCM but not in HCM.,We also identified miR-1-3p and miR-27a expressed significantly different between HCM and DCM and both miRNAs downregulated in HCM.,And only miR-1-3p correlated with left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) that reflected the cardiac function in HCM.,A second HCM group also confirmed this correlation.,We then predicted Chloride voltage-gated channel 3 (Clcn3) as a direct target gene of miR-1-3p using bioinformatics tools and confirmed it by Luciferase reporter assay.,Our data demonstrated that different cardiomyopathies had unique miRNA expression pattern.,And the expression levels of miR-1-3p and miR-27a had disease-specificity and sensitivity in HCM, whereas only miR-1-3p was significantly associated with left ventricular function in HCM identifying it as a potential target to improve the cardiac function in end-stage HCM.,We also provide Clcn3 as a direct target of miR-1-3p which sheds light on the mechanism of HCM.,The online version of this article (10.1186/s12967-018-1534-3) contains supplementary material, which is available to authorized users.
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Dysregulation of intracellular trafficking system plays a fundamental role in the progression of cardiovascular disease.,Up-regulation of miR-1 contributes to arrhythmia, we sought to elucidate whether intracellular trafficking contributes to miR-1-driven arrhythmia.,By performing microarray analyses of the transcriptome in the cardiomyocytes-specific over-expression of microRNA-1 (miR-1 Tg) mice and the WT mice, we found that these differentially expressed genes in miR-1 Tg mice were significantly enrichment with the trafficking-related biological processes, such as regulation of calcium ion transport.,Also, the qRT-PCR and western blot results validated that Stx6, Braf, Ube3a, Mapk8ip3, Ap1s1, Ccz1 and Gja1, which are the trafficking-related genes, were significantly down-regulated in the miR-1 Tg mice.,Moreover, we found that Stx6 was decreased in the heart of mice after myocardial infarction and in the hypoxic cardiomyocytes, and further confirmed that Stx6 is a target of miR-1.,Meanwhile, knockdown of Stx6 in cardiomyocytes resulted in the impairments of PLM and L-type calcium channel, which leads to the increased resting ([Ca2+]i).,On the contrary, overexpression of Stx6 attenuated the impairments of miR-1 or hypoxia on PLM and L-type calcium channel.,Thus, our studies reveals that trafficking-related gene Stx6 may regulate intracellular calcium and is involved in the occurrence of cardiac arrhythmia, which provides new insights in that miR-1 participates in arrhythmia by regulating the trafficking-related genes and pathway.
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Insulin resistance has been demonstrated to be involved in the pathogenesis of atherosclerotic cardiovascular diseases (ASCVDs).,This study evaluated the association between the triglyceride-glucose (TyG) index, a novel surrogate indicator of insulin resistance, and the incidence of ASCVDs in people without ASCVDs at baseline by performing a meta-analysis.,Cohort studies reporting the multivariate-adjusted association between the TyG index and the incidence of ASCVDs were obtained by searching the PubMed and Embase databases.,A random-effects model incorporating intra-study heterogeneity was applied to combine the results.,Eight cohort studies comprising 5,731,294 participants were included in this meta-analysis.,The results showed that compared to those with the lowest TyG index category, participants with the highest TyG index category were independently associated with a higher risk of ASCVDs [hazard ratio (HR): 1.61, 95% confidence interval (CI) 1.29-2.01, I2 = 80%, P < 0.001].,This finding was consistent with the meta-analysis results with the TyG index analyzed as a continuous variable (HR per 1-unit increment of the TyG index: 1.39, 95% CI 1.18-1.64, I2 = 89%, P < 0.001).,Subgroup analyses suggested that the age, sex, and diabetic status did not significantly affect the association (for subgroup analyses, all P > 0.05).,Moreover, participants with the highest TyG index category were independently associated with a higher risk of coronary artery disease [(CAD), HR: 1.95, 95% CI 1.47-2.58, I2 = 92%, P < 0.001] and stroke (HR: 1.26, 95% CI 1.23-1.29, I2 = 0%, P < 0.001).,A higher TyG index may be independently associated with a higher incidence of ASCVDs, CAD, and stroke in people without ASCVDs at baseline.
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The triglyceride glucose (TyG) index is an inexpensive clinical surrogate marker for insulin resistance.,However, the relationship between TyG index and atherosclerotic cardiovascular disease (CVD) remains unclear.,We evaluated the relationship between TyG index and CVD using a large-scale population dataset from the National Health Information Database (NHID).,We performed a retrospective observational cohort study of 5,593,134 persons older than 40 years from 2009 to 2017 using the NHID.,We divided the participants into TyG index quartiles.,Outcome variables were stroke, myocardial infarction, and both.,The incidence of outcomes was estimated for each TyG quartile over the total follow-up period.,All outcomes were analyzed by Cox proportional hazards regression analysis while controlling for baseline covariates.,During 8.2 years of mean follow-up, stroke was diagnosed in 89,120 (1.59%), MI in 62,577 (1.12%), and both stroke and MI in 146,744 (2.62%) participants.,Multivariate-adjusted hazard ratios (HRs) for patients in the highest TyG index quartile demonstrated that these patients were at higher risk for stroke (HR = 1.259; 95% confidence interval [CI] 1.233-1.286), for MI (HR = 1.313; 95% CI 1.28-1.346), and for both (HR = 1.282; 95% CI 1.261-1.303) compared with participants in the lowest TyG index quartile.,These effects were independent of age, sex, smoking, alcohol consumption, physical activity, body mass index, systolic blood pressure, and total cholesterol.,In our large population study, TyG index, a simple measure reflecting insulin resistance, was potentially useful in the early identification of individuals at high risk of experiencing a cardiovascular event.,The online version contains supplementary material available at 10.1186/s12916-020-01824-2.
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The vascular endothelium provides the crucial interface between the blood compartment and tissues, and displays a series of remarkable properties that normally maintain homeostasis.,This tightly regulated palette of functions includes control of haemostasis, fibrinolysis, vasomotion, inflammation, oxidative stress, vascular permeability, and structure.,While these functions participate in the moment-to-moment regulation of the circulation and coordinate many host defence mechanisms, they can also contribute to disease when their usually homeostatic and defensive functions over-reach and turn against the host.,SARS-CoV-2, the aetiological agent of COVID-19, causes the current pandemic.,It produces protean manifestations ranging from head to toe, wreaking seemingly indiscriminate havoc on multiple organ systems including the lungs, heart, brain, kidney, and vasculature.,This essay explores the hypothesis that COVID-19, particularly in the later complicated stages, represents an endothelial disease.,Cytokines, protein pro-inflammatory mediators, serve as key danger signals that shift endothelial functions from the homeostatic into the defensive mode.,The endgame of COVID-19 usually involves a cytokine storm, a phlogistic phenomenon fed by well-understood positive feedback loops that govern cytokine production and overwhelm counter-regulatory mechanisms.,The concept of COVID-19 as an endothelial disease provides a unifying pathophysiological picture of this raging infection, and also provides a framework for a rational treatment strategy at a time when we possess an indeed modest evidence base to guide our therapeutic attempts to confront this novel pandemic.
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An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications.,Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy.,To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.,In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital.,Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range.,We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.,We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable.,We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality.,Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.,68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls.,Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014).,VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients.,We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients.,In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).,Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death.,Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.,This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.
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Coagulopathy is a common abnormality in patients with COVID‐19.,However, the exact incidence of venous thromboembolic event is unknown in anticoagulated, severe COVID‐19 patients.,Systematic assessment of venous thromboembolism (VTE) using complete duplex ultrasound (CDU) in anticoagulated COVID‐19 patients.,We performed a retrospective study in 2 French intensive care units (ICU) where CDU is performed as a standard of care.,A CDU from thigh to ankle at selected sites with Doppler waveforms and images was performed early during ICU stay in patients admitted with COVID‐19.,Anticoagulation dose was left to the discretion of the treating physician based on the individual risk of thrombosis.,Patients were classified as treated with prophylactic anticoagulation or therapeutic anticoagulation.,Pulmonary embolism was systematically searched in patients with persistent hypoxemia or secondary deterioration.,From March 19 to April 11, 2020, 26 consecutive patients with severe COVID‐19 were screened for VTE.,Eight patients (31%) were treated with prophylactic anticoagulation, whereas 18 patients (69%) were treated with therapeutic anticoagulation.,The overall rate of VTE in patients was 69%.,The proportion of VTE was significantly higher in patients treated with prophylactic anticoagulation when compared with the other group (100% vs 56%, respectively, P = .03).,Surprisingly, we found a high rate of thromboembolic events in COVID‐19 patients treated with therapeutic anticoagulation, with 56% of VTE and 6 pulmonary embolisms.,Our results suggest considering both systematic screening of VTE and early therapeutic anticoagulation in severe ICU COVID‐19 patients.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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Acute ischemic stroke is a common cause of morbidity and mortality worldwide.,Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke.,However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes.,Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process.,Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death.,Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier.,In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage.,This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.
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Stroke has become a more common disease worldwide.,Despite great efforts to develop treatment, little is known about ischemic stroke.,Cerebral ischemia activates multiple cascades of cell type-specific pathomechanisms.,Ischemic brain injury consists of a complex series of cellular reactions in various cell types within the central nervous system (CNS) including platelets, endothelial cells, astrocytes, neutrophils, microglia/macrophages, and neurons.,Diverse cellular changes after ischemic injury are likely to induce cell death and tissue damage in the brain.,Since cells in the brain exhibit different functional roles at distinct time points after injury (acute/subacute/chronic phases), it is difficult to pinpoint genuine roles of cell types after brain injury.,Many experimental studies have shown the association of apoptosis signal-regulating kinase 1 (ASK1) with cellular pathomechanisms after cerebral ischemia.,Blockade of ASK1, by either pharmacological or genetic manipulation, leads to reduced ischemic brain injury and subsequent neuroprotective effects.,In this review, we present the cell type-specific pathophysiology of the early phase of ischemic stroke, the role of ASK1 suggested by preclinical studies, and the potential use of ASK suppression, either by pharmacologic or genetic suppression, as a promising therapeutic option for ischemic stroke recovery.
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It remains uncertain whether the hypertension (HT) medications angiotensin‐converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) mitigate or exacerbate SARS‐CoV‐2 infection.,We evaluated the association of ACEi and ARB with severe coronavirus disease 19 (COVID‐19) as defined by hospitalization or mortality among individuals diagnosed with COVID‐19.,We investigated whether these associations were modified by age, the simultaneous use of the diuretic thiazide, and the health conditions associated with medication use.,In an observational study utilizing data from a Massachusetts group medical practice, we identified 1449 patients with a COVID‐19 diagnosis.,In our study, pre‐infection comorbidities including HT, cardiovascular disease, and diabetes were associated with increased risk of severe COVID‐19.,Risk was further elevated in patients under age 65 with these comorbidities or cancer.,Twenty percent of those with severe COVID‐19 compared to 9% with less severe COVID‐19 used ACEi, 8% and 4%, respectively, used ARB.,In propensity score‐matched analyses, use of neither ACEi (OR = 1.30, 95% CI 0.93 to 1.81) nor ARB (OR = 0.94, 95% CI 0.57 to 1.55) was associated with increased risk of severe COVID‐19.,Thiazide use did not modify this relationship.,Beta blockers, calcium channel blockers, and anticoagulant medications were not associated with COVID‐19 severity.,In conclusion, cardiovascular‐related comorbidities were associated with severe COVID‐19 outcomes, especially among patients under age 65.,We found no substantial increased risk of severe COVID‐19 among patients taking antihypertensive medications.,Our findings support recommendations against discontinuing use of renin-angiotensin system (RAS) inhibitors to prevent severe COVID‐19.
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Targeting the renin-angiotensin system is proposed to affect mortality due to coronavirus disease 2019 (COVID-19).,We aimed to compare the mortality rates in COVID-19 patients who received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) and those who did not.,In this retrospective cohort study, mortality was considered as the main outcome measure.,All underlying diseases were assessed by the chronic use of medications related to each condition.,We defined two main groups based on the ACEIs/ARBs administration.,A logistic regression model was designed to define independent predictors of mortality as well as a Cox regression analysis.,In total, 2553 patients were included in this study.,The mortality frequency was higher in patients with a history of underlying diseases (22.4% vs 12.7%, P value < 0.001).,The mortality rate in patients who received ACEIs/ARBs were higher than non-receivers (29.3% vs.,19.5%, P value = 0.013, OR = 1.3, 95% CI 1.1, 1.7) in the univariate analysis.,However, the use of ACEIs/ARBs was a protective factor against mortality in the model when adjusted for underlying conditions, length of stay, age, gender, and ICU admission (P value < 0.001, OR = 0.5, 95% CI 0.3, 0.7).,The Kaplan-Meier curve showed an overall survival of approximately 85.7% after a 120-day follow-up.,ACEIs/ARBs are protective factors against mortality in COVID-19 patients with HTN, and these agents can be considered potential therapeutic options in this disease.,The survival probability is higher in ACEIs/ARBs receivers than non-receivers.
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Coronavirus disease 2019 (COVID-19) has resulted in public health measures and health care reconfigurations likely to have impact on chronic disease care.,We aimed to assess the volume and characteristics of patients presenting to hospitals with acute decompensated heart failure (ADHF) during the 2020 COVID-19 pandemic compared with a time-matched 2019 cohort.,Patients presenting to hospitals with ADHF from March 1, to April 19, 2020 and 2019 in an urban hospital were examined.,Multivariable logistic-regression models were used to evaluate the difference in probability of ADHF-related hospitalization between the 2 years.,During the COVID-19 pandemic, a total of 1106 emergency department (ED) visits for dyspnea or peripheral edema were recorded, compared with 800 ED visits in 2019.,A decrease in ADHF-related ED visits of 43.5% (14.8%-79.4%, P = 0.002) and ADHF-related admissions of 39.3% (8.6%-78.5%, P = 0.009) was observed compared with 2019.,Patients with ADHF presenting to hospitals (n = 128) were similar in age, sex, and comorbidities compared with the 2019 cohort (n = 186); however, a higher proportion had recent diagnoses of heart failure.,Upon ED presentation, the relative probability of hospitalization or admission to intensive care was not statistically different.,There was a trend toward higher in-hospital mortality in 2020.,The decline in ADHF-related hospitalizations raises the timely question of how patients with heart failure are managing beyond the acute-care setting and reinforces the need for public education on the availability and safety of emergency services throughout the COVID-19 pandemic.
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COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation.,Reports on the incidence of thrombotic complications are however not available.,We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.,We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020.,All patients received at least standard doses thromboprophylaxis.,The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%).,PE was the most frequent thrombotic complication (n = 25, 81%).,Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.,The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high.,Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.
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Critically ill patients with COVID-19 pneumonia suffered both high thrombotic and bleeding risk.,The effect of SARS-CoV-2 on coagulation and fibrinolysis is not well known.,We conducted a retrospective study of critically ill patients admitted to an intensive care unit (ICU) a cause of severe COVID-19 pneumonia and we evaluated coagulation function using rotational thromboelastometry (ROTEM) on day of admission (T0) and 5 (T5) and 10 (T10) days after admission to ICU.,Coagulation standard parameters were also evaluated.,Forty patients were enrolled into the study.,The ICU and the hospital mortality were 10% and 12.5%, respectively.,On ICU admission, prothrombin time was slightly reduced and it increased significantly at T10 (T0 = 65.1 ± 9.8 vs T10 = 85.7 ± 1.5, p = 0.002), while activated partial thromboplastin time and fibrinogen values were higher at T0 than T10 (32.2 ± 2.9 vs 27.2 ± 2.1, p = 0.017 and 895.1 ± 110 vs 332.5 ± 50, p = 0.002, respectively); moreover, whole blood thromboelastometry profiles were consistent with hypercoagulability characterized by an acceleration of the propagation phase of blood clot formation [i.e., CFT below the lower limit in INTEM 16/40 patients (40%) and EXTEM 20/40 patients (50%)] and significant higher clot strength [MCF above the upper limit in INTEM 20/40 patients (50%), in EXTEM 28/40 patients (70%) and in FIBTEM 29/40 patients (72.5%)]; however, this hypercoagulable state persists in the first five days, but it decreases ten day after, without returning to normal values.,No sign of secondary hyperfibrinolysis or sepsis induced coagulopathy (SIC) were found during the study period.,In six patients (15%) a deep vein thrombosis and in 2 patients (5%) a thromboembolic event, were found; 12 patients (30%) had a catheter-related thrombosis.,ROTEM analysis confirms that patients with severe COVID-19 pneumonia had a hypercoagulation state that persisted over time.
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We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals.,In answering questions raised regarding our study, we updated our database and repeated all analyses.,We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.,We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%).,The median follow-up duration increased from 7 to 14 days.,All patients received pharmacological thromboprophylaxis.,The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%).,The majority of thrombotic events were PE (65/75; 87%).,In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92).,Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12).,Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8).,In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.
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Nowadays, it is well established a link between psoriasis and cardiovascular (CV) diseases.,A series of different overlapping mechanisms including inflammation, homeostasis dysregulation, and genetic susceptibility are thought to underlie this association.,Advances in understanding the molecular patterns involved in the complex scenario of psoriasis have highlighted a tight correlation with atherosclerosis.,Indeed, common profiles are shared in term of inflammatory cytokines and cell types.,In the last decade, the management of psoriasis patients has been revolutionized with the introduction of biological therapies, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12/23, and IL-17 inhibitors.,In clinical setting, the effectiveness of these therapies as well as the incidence of CV events is related to the type of biologics.,In particular, anti-TNF-α agents seem to reduce these events in psoriasis patients whereas anti-IL-12/23 agents related CV events reduction still remain to clarify.,It has to be taken into account that IL-12/23 inhibitors have a shorter post-marketing surveillance period.,An even more restricted observational time is available for anti-IL-17 agents.,IL-17 is associated with psoriasis, vascular disease, and inflammation.,However, IL-17 role in atherosclerosis is still debated, exerting both pro-atherogenic and anti-atherogenic effects depending on the specific context.,In this review, we will discuss the differences between the onset of CV events in psoriasis patients, referred to specific biological therapy and the underlying immunological mechanism.,Given the development of new therapeutic strategies, the investigation of these inhibitors impact on heart failure outcome is extremely important.
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Psoriasis is a common and chronic inflammatory disease of the skin.,It may impair the physical and psychosocial function of patients and lead to decreased quality of life.,Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints.,More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities.,In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke.,In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome.,Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population.,Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk.,Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders.,In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment.
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We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in a 69‐year‐old patient with flu‐like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock.,The patient was successfully treated with venous‐arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation.,Cardiac function fully recovered in 5 days and ECMO was removed.,Endomyocardial biopsy demonstrated low‐grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease.,Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors.,Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses.,Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.,We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort).,Results were validated in 1123 men and 575 women (validation cohort).,The median age was 69 years for men and 75 years for women.,The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively).,In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2.,In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.,In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations.,These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.
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To delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died.,Retrospective case series.,Tongji Hospital in Wuhan, China.,Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed.,Data were collected until 28 February 2020.,Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms.,The median age of deceased patients (68 years) was significantly older than recovered patients (51 years).,Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%).,Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)).,Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)).,The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days.,Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively.,Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients.,Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (72/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (42; 37%), acute kidney injury (28; 25%), and hypoxic encephalopathy (23; 20%).,Patients with cardiovascular comorbidity were more likely to develop cardiac complications.,Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients.,Severe acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk.,Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19.
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To investigate the cardiovascular effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in routine clinical practice.,Cohort study using data from nationwide registers and an active-comparator new-user design.,Denmark, Norway, and Sweden, from April 2013 to December 2016.,20 983 new users of SGLT2 inhibitors and 20 983 new users of dipeptidyl peptidase 4 (DPP4) inhibitors, aged 35-84, matched by age, sex, history of major cardiovascular disease, and propensity score.,Primary outcomes were major cardiovascular events (composite of myocardial infarction, stroke, and cardiovascular death) and heart failure (hospital admission for heart failure or death due to heart failure).,Secondary outcomes were the individual components of the cardiovascular composite and any cause death.,In the primary analyses, patients were defined as exposed from treatment start throughout follow-up (analogous to intention to treat); additional analyses were conducted with an as-treated exposure definition.,Cox regression was used to estimate hazard ratios.,Mean age of the study cohort was 61 years, 60% were men, and 19% had a history of major cardiovascular disease.,Of the total 27 416 person years of follow-up in the SGLT2 inhibitor group, 22 627 (83%) was among patients who initiated dapagliflozin, 4521 (16%) among those who initiated empagliflozin, and 268 (1%) among those who initiated canagliflozin.,During follow-up, 467 SGLT2 inhibitor users (incidence rate 17.0 events per 1000 person years) and 662 DPP4 inhibitor users (18.0) had a major cardiovascular event, whereas 130 (4.7) and 265 (7.1) had a heart failure event, respectively.,Hazard ratios were 0.94 (95% confidence interval 0.84 to 1.06) for major cardiovascular events and 0.66 (0.53 to 0.81) for heart failure.,Hazard ratios were consistent among subgroups of patients with and without history of major cardiovascular disease and with and without history of heart failure.,Hazard ratios for secondary outcomes, comparing SGLT2 inhibitors with DPP4 inhibitors, were 0.99 (0.85 to 1.17) for myocardial infarction, 0.94 (0.77 to 1.15) for stroke, 0.84 (0.65 to 1.08) for cardiovascular death, and 0.80 (0.69 to 0.92) for any cause death.,In the as-treated analyses, hazard ratios were 0.84 (0.72 to 0.98) for major cardiovascular events, 0.55 (0.42 to 0.73) for heart failure, 0.93 (0.76 to 1.14) for myocardial infarction, 0.83 (0.64 to 1.07) for stroke, 0.67 (0.49 to 0.93) for cardiovascular death, and 0.75 (0.61 to 0.91) for any cause death.,In this large Scandinavian cohort, SGLT2 inhibitor use compared with DPP4 inhibitor use was associated with reduced risk of heart failure and any cause death, but not with major cardiovascular events in the primary intention-to-treat analysis.,In the additional as-treated analyses, the magnitude of the association with heart failure and any cause death became larger, and a reduced risk of major cardiovascular events that was largely driven by the cardiovascular death component was observed.,These data help inform patients, practitioners, and authorities regarding the cardiovascular effectiveness of SGLT2 inhibitors in routine clinical practice.
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Supplemental Digital Content is available in the text.,Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose cotransporter 2 inhibitors (SGLT2i).,Trials may have limited ability to address individual end points or safety concerns.,We performed a population-based cohort study among patients with type 2 diabetes mellitus with established cardiovascular disease newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between April 1, 2013, and December 31, 2016.,Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite end point of all-cause mortality and hospitalization for heart failure event, major adverse cardiovascular events (defined as all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke), and individual end points were evaluated using conditional Cox models comparing new SGLT2i users with other antihyperglycemic agents.,The exploratory safety end point was below-knee lower extremity amputation.,Intent-to-treat and on-treatment analyses were performed.,After propensity matching, 25 258 patients were followed for a median of 1.6 years.,Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of all-cause mortality and hospitalization for heart failure (1.73 versus 3.01 events per 100 person-years; HR, 0.57; 95% CI, 0.50-0.65) and major adverse cardiovascular events (2.31 versus 3.45 events per 100 person-years; HR, 0.67; 95% CI, 0.60-0.75).,SGLT2i initiation was also associated with an ≈2-fold higher risk of below-knee lower extremity amputation (0.17 versus 0.09 events per 100 person-years; HR, 1.99; 95% CI, 1.12-3.51).,Because of the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin.,Results were consistent in the on-treatment analysis.,In this high-risk cohort, initiation of SGLT2i was associated with lower risk of all-cause mortality, hospitalization for heart failure, and major adverse cardiovascular events and higher risk of below-knee lower extremity amputation.,Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i.,It remains unclear whether the below-knee lower extremity amputation risk extends across the class of medication, because the study was not powered to make comparisons among individual treatments.
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Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time.,AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria.,Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage.,PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD+), induces further DNA damage and contractile dysfunction.,Accordingly, NAD+ replenishment or PARP1 depletion precludes functional loss.,Moreover, inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila.,Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity.,The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.,Atrial fibrillation (AF) is accompanied by a detrimental loss of functional cardiomyocytes.,Here, Zhang et al. show that AF-induced cardiomyocyte dysfunction is a consequence of DNA damage-mediated PARP1 activation, which leads to depletion of NAD+ and further oxidative stress and DNA damage, and identify PARP1 inhibition as a potential therapeutic strategy in the treatment of AF.
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Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias.,We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway.,Furthermore, we explored the risk factors and the outcomes in LMNA patients.,During 2003-15, genetic testing was performed in patients referred for familial DCM.,LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography.,A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM.,Heart transplantation was recorded and compared with non-ischaemic DCM of other origin.,Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation.,Family screening diagnosed an additional 93 LMNA genotype-positive family members.,We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT.,Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up.,Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT.,Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up.,LMNA mutation prevalence was 6.2% of familial DCM in Norway.,Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up.,Nearly 20% of the LMNA patients required heart transplantation.
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Supplemental Digital Content is available in the text.,Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke.,Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways.,We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries.,To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019.,Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site).,The median National Institute of Health Stroke Scale was 10 (interquartile range [IQR], 4-18).,In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institute of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institute of Health Stroke Scale score).,There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke.,Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge.,In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19.,Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.
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The COVID-19 pandemic is associated with neurological symptoms and complications including stroke.,There is hypercoagulability associated with COVID-19 that is likely a “sepsis-induced coagulopathy” and may predispose to stroke.,The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) present on brain endothelial and smooth muscle cells.,ACE2 is a key part of the renin angiotensin system (RAS) and a counterbalance to angiotensin-converting enzyme 1 (ACE1) and angiotensin II.,Angiotensin II is proinflammatory, is vasoconstrictive, and promotes organ damage.,Depletion of ACE2 by SARS-CoV-2 may tip the balance in favor of the “harmful” ACE1/angiotensin II axis and promote tissue injury including stroke.,There is a rationale to continue to treat with tissue plasminogen activator for COVID-19-related stroke and low molecular weight heparinoids may reduce thrombosis and mortality in sepsis-induced coagulopathy.
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The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide.,We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior).,Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers.,The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers.,The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, −19.7 to −18.7), 11.5% (95%CI, −12.6 to −10.6), and 12.7% (95%CI, −13.6 to −11.8), respectively.,The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers.,High-volume COVID-19 centers (−20.5%) had greater declines in mechanical thrombectomy volumes than mid- (−10.1%) and low-volume (−8.7%) centers (p < 0.0001).,There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations.,SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions.,The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes.,Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.
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•Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,•Some COVID-19 patients have exhibited widespread neurological manifestations including stroke.,•Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19.,•COVID-19-associated coagulopathy is likely caused by inflammation.,•Resultant ACE2 down-regulation causes RAS imbalance, which may lead to stroke.,Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Some COVID-19 patients have exhibited widespread neurological manifestations including stroke.,Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19.,COVID-19-associated coagulopathy is likely caused by inflammation.,Resultant ACE2 down-regulation causes RAS imbalance, which may lead to stroke.,Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat.,Some COVID-19 patients have exhibited widespread neurological manifestations including stroke.,Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19.,COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm.,Recent studies suggest that axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia.,The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes.,ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain.,The aim of this review is to provide insights into the clinical manifestations and pathophysiological mechanisms of stroke in COVID-19 patients.,SARS-CoV-2 can down-regulate ACE2 and, in turn, overactivate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain.,The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.
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The COVID-19 pandemic required a significant redeployment of worldwide healthcare resources.,Fear of infection, national lockdowns and altered healthcare priorities have the potential to impact utilisation of healthcare resources for non-communicable diseases.,To survey health professionals’ views of the impact of the COVID-19 pandemic on the rate and timing of admission of patients with ST-elevation myocardial infarction (STEMI), the European Society of Cardiology (ESC) administered an internet-based questionnaire to cardiologists and cardiovascular nurses across 6 continents.,3101 responses were received from 141 countries across 6 continents.,88.3% responded that their country was in “total lockdown” and 7.1% in partial lockdown.,78.8% responded that the number of patients presenting with STEMI was reduced since the coronavirus outbreak and 65.2% indicated that the reduction in STEMI presentations was >40%.,Approximately 60% of all respondents reported that STEMI patients presented later than usual and 58.5% that >40% of STEMI patients admitted to hospital presented beyond the optimal window for primary percutaneous intervention (PCI) or thrombolysis.,Independent predictors of the reported higher rate of delayed STEMI presentation were a country in total lockdown, >100 COVID-19 cases admitted locally, and the complete restructuring of the local cardiology service.,The survey indicates that the impact of COVID-19 on STEMI presentations is likely to be substantial, with both lower presentations and a higher rate of delayed presentations occurring.,This has potentially important ramifications for future healthcare and policy planning in the event of further waves of this pandemic.
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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ethnic meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program, DIAMANTE, Biobank Japan, and other studies.,We report 568 associations, including 286 autosomal, 7 X chromosomal, and 25 identified in ancestry-specific analyses that were previously unreported.,Transcriptome-wide association analysis detected 3,568 T2D-associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs.,A polygenic risk score was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD), and neuropathy.,We investigated the genetic etiology of T2D-related vascular outcomes in MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease, CKD, PAD, and neuropathy.,These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
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Circulating lipoprotein lipids cause coronary heart disease (CHD).,However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear.,Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD.,We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs).,Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses.,Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I.,The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women.,The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L.,The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively.,The GWAS identified multiple independent SNPs associated at P < 5 × 10−8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440).,Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs.,Almost half (46%) of these SNPs were associated at P < 5 × 10−8 with more than one lipid-related trait.,Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD.,In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker.,Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B.,A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components.,These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.
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Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease.,Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown.,We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype.,Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells.,HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline.,Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway.,Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity.,Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation.,Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.
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Congenital heart disease (CHD) is the leading cause of mortality from birth defects.,Exome sequencing of a single cohort of 2,871 CHD probands including 2,645 parent-offspring trios implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ~11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot.,De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD patients and ~28% with both neurodevelopmental and extra-cardiac congenital anomalies.,Seven genes surpassed thresholds for genome-wide significance and 12 genes not previously implicated in CHD had > 70% probability of being disease-related; DNMs in ~440 genes are inferred to contribute to CHD.,There was striking overlap between genes with damaging DNMs in probands with CHD and autism.
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Supplemental Digital Content is available in the text.,Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood.,In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19.,A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls).,We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well.,We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis.,We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin.,Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity.,Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia.,Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability.,Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19.,Further work is necessary to determine the role of immunothrombosis in COVID-19.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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Multiple myeloma (MM) is an incurable hematologic malignancy with disparities in outcomes noted among racial-ethnic subgroups, likely due to disparities in access to effective treatment modalities.,Clinical trials can provide access to evidence-based medicine but representation of minorities on therapeutic clinical trials has been dismal.,We evaluated the impact of patient race-ethnicity in pooled data from nine large national cooperative group clinical trials in newly diagnosed MM.,Among 2896 patients enrolled over more than two decades, only 18% were non-White and enrollment of minorities actually decreased in most recent years (2002-2011).,African-Americans were younger and had more frequent poor-risk markers, including anemia and increased lactate dehydrogenase.,Hispanics had the smallest proportion of patients on trials utilizing novel therapeutic agents.,While adverse demographic (increased age) and clinical (performance status, stage, anemia, kidney dysfunction) factors were associated with inferior survival, patient race-ethnicity did not have an effect on objective response rates, progression-free, or overall survival.,While there are significant disparities in MM incidence and outcomes among patients of different racial-ethnic groups, this disparity seems to be mitigated by access to appropriate therapeutic options, for example, as offered by clinical trials.,Improved minority accrual in therapeutic clinical trials needs to be a priority.
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Outcomes have improved considerably in multiple myeloma (MM), but disparities among racial‐ethnic groups exist.,Differences in utilization of novel therapeutics are likely contributing factors.,We explored such differences from the SEER‐Medicare database.,A utilization analysis of lenalidomide, thalidomide, bortezomib, and stem cell transplant (SCT) was performed for patients diagnosed with MM between 2007 and 2009, including use over time, use by race, time‐dependent trends for each racial subgroup, and survival analysis.,A total of 5338 MM patients were included with median 2.4‐year follow‐up.,Within the first year of MM diagnosis, utilization of lenalidomide, bortezomib, SCT, and more than one novel agent increased over time while utilization of thalidomide decreased.,There was significantly lower utilization of lenalidomide among African‐Americans (P < 0.01), higher thalidomide use among Hispanics and Asians (P < 0.01), and lower bortezomib use among Asians (P < 0.01).,Hispanics had the highest median number of days to first dose of bortezomib (P = 0.02) and the lowest utilization of SCT (P < 0.01).,Hispanics and Asians were the only groups without notable increases in lenalidomide and bortezomib use, respectively.,SCT utilization increased over time for all except African‐Americans.,SCT use within the first year after diagnosis was associated with better overall survival (HR 0.52; 95% CI: 0.4-0.68), while bortezomib use was associated with inferior survival (HR 1.14; 95% CI 1.02-1.28).,We noted considerable variability in MM therapeutics utilization with seeming inequity for racial‐ethnic minorities.,These trends should be considered to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all races.
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An increased risk of venous thromboembolism (VTE) in patients with COVID-19 pneumonia admitted to intensive care unit (ICU) has been reported.,Whether COVID-19 increases the risk of VTE in non-ICU wards remains unknown.,We aimed to evaluate the burden of asymptomatic deep vein thrombosis (DVT) in COVID-19 patients with elevated D-dimer levels.,In this prospective study consecutive patients hospitalized in non-intensive care units with diagnosis of COVID-19 pneumonia and D-dimer > 1000 ng/ml were screened for asymptomatic DVT with complete compression doppler ultrasound (CCUS).,The study was approved by the Institutional Ethics Committee.,The study comprised 156 patients (65.4% male).,All but three patients received standard doses of thromboprophylaxis.,Median days of hospitalization until CCUS was 9 (IQR 5-17).,CCUS was positive for DVT in 23 patients (14.7%), of whom only one was proximal DVT.,Seven patients (4.5%) had bilateral distal DVT.,Patients with DVT had higher median D-dimer levels: 4527 (IQR 1925-9144) ng/ml vs 2050 (IQR 1428-3235) ng/ml; p < 0.001.,D-dimer levels > 1570 ng/ml were associated with asymptomatic DVT (OR 9.1; CI 95% 1.1-70.1).,D-dimer showed an acceptable discriminative capacity (area under the ROC curve 0.72, 95% CI 0.61-0.84).,In patients admitted with COVID-19 pneumonia and elevated D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series.,Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.,•An increased risk of VTE in patients with COVID-19 pneumonia admitted to intensive care unit has been reported.,•The most consistent hemostatic abnormalities with COVID-19 include mild thrombocytopenia and increased D-dimer levels.,•In COVID-19 patients with high D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series.,•Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.,An increased risk of VTE in patients with COVID-19 pneumonia admitted to intensive care unit has been reported.,The most consistent hemostatic abnormalities with COVID-19 include mild thrombocytopenia and increased D-dimer levels.,In COVID-19 patients with high D-dimer levels, the incidence of asymptomatic DVT is similar to that described in other series.,Higher cut-off levels for D-dimer might be necessary for the diagnosis of DVT in COVID-19 patients.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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There is limited information regarding clinical characteristics and outcomes of patients with SARS-CoV-2 (COVID-19) disease presenting with ST-segment elevation myocardial infarction (STEMI).,In this multicenter retrospective study, we reviewed charts of patients admitted with symptomatic COVID-19 infection and STEMI to a total of 4 hospitals spanning Italy, Lithuania, Spain and Iraq from February 1, 2020 to April 15, 2020.,A total of 78 patients were included in this study, 49 (63%) of whom were men, with a median age of 65 [58, 71] years, and high comorbidity burden.,During hospitalization, 8 (10%) developed acute respiratory distress syndrome, and 14 (18%) required mechanical ventilation. 19 (24%) patients were treated with primary Percutaneous Coronary Intervention (PCI) and 59 (76%) were treated with fibrinolytic therapy. 13 (17%) patients required cardiac resuscitation, and 9 (11%) died.,For the 19 patients treated with primary PCI, 8 (42%) required intubation and 8 (42%) required cardiac resuscitation; stent thrombosis occurred in 4 patients (21%).,A total of 5 patients (26%) died during hospitalization. 50 (85%) of the 59 patients initially treated with fibrinolytic therapy had successful fibrinolysis.,The median time to reperfusion was 27 minutes [20, 34].,Hemorrhagic stroke occurred in 5 patients (9%).,Six patients (10%) required invasive mechanical ventilation; 5 (9%) required cardiac resuscitation, and 4 (7%) died.,In conclusion, this is the largest case series to-date of COVID-19 positive patients presenting with STEMI and spans 4 countries.,We found a high rate of stent thrombosis, indicating a possible need to adapt STEMI management for COVID-19 patients.
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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels.,Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited.,This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation.,Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications.,Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death.,The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8).,The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively.,In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively.,Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death.,Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]).,ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without.,DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations.,Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.,•In addition to thrombotic complications, bleeding is a significant cause of morbidity in patients with COVID-19.,•D-dimer elevation at admission was predictive of bleeding, thrombosis, critical illness, and death in patients with COVID-19.,In addition to thrombotic complications, bleeding is a significant cause of morbidity in patients with COVID-19.,D-dimer elevation at admission was predictive of bleeding, thrombosis, critical illness, and death in patients with COVID-19.
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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied.,We carried out a population-based case-control study in the Lombardy region of Italy.,A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence.,Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use.,Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression.,Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women.,The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile.,Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex.,In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease.,However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
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Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents.,The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐Tpeak (J‐Tpeakc) prolongation would be expected for balanced blockers.,This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐Tpeakc upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively).,Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔQTc and ΔΔJ‐Tpeakc by ≥ 10 ms.,In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced ΔQTc prolongation, but shortened ΔJ‐Tpeakc and prolonged ΔTpeak‐Tend.,Absence of J‐Tpeakc prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.
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To assess the epidemiologic association between Kawasaki disease and common pediatric infectious diseases (PIDs) identified during the coronavirus disease 2019 (COVID-19) pandemic period to confirm whether the infection-triggered theory is a plausible hypothesis for the pathogenesis of Kawasaki disease.,A retrospective epidemiologic study was conducted using datasets obtained from Web-based surveillance of Kawasaki disease and PIDs in Japan.,We compared weekly numbers of patients who developed Kawasaki disease and specific PIDs between 2020 and 2017-2019 and evaluated the association between the percent reduction in the number of patients with these diseases.,A total of 868 patients developed Kawasaki disease in 2020.,During the social distancing period in 2020, the number of patients with Kawasaki disease was approximately 35% lower than in 2017-2019.,Time from the onset of Kawasaki disease until the first hospital visit did not differ significantly among the examined years.,The proportion of older children with Kawasaki disease decreased more than that of infants with Kawasaki disease (age <1 year), resulting in a significant difference in the proportion of infant patients between 2020 and 2017-2019 (24% vs 19%; P < .01).,The number of patients with incomplete Kawasaki disease was unchanged from that of previous years.,The weekly percent reduction in patient numbers differed between Kawasaki disease and PIDs during 2020, with no strong correlation between the 2 diseases.,Our data indicate that parents of patients with Kawasaki disease did not avoid hospital visits during the COVID-19 pandemic period.,The findings indicate the possibility that triggering Kawasaki disease might be associated with presently unidentified respiratory pathogen(s) that potentially might be acquired from both within and outside the household.
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Kawasaki disease (KD) is the commonest medium vessel vasculitis in children.,The etiology of KD remains an enigma despite extensive research.,Infections are considered to be one of the triggers for KD, especially in genetically susceptible hosts.,KD occurring within a short time interval among siblings is an important clinical observation supporting this hypothesis.,In addition, siblings of children with KD are at a higher risk of developing the disease as compared with other children.,Screening for KD in febrile siblings, therefore, seems prudent.,This would help initiate timely therapy and prevent complications.,We briefly review 16 English language reports of KD in siblings diagnosed within 1 month of each other to highlight its etiological and therapeutic implications.Key Points• KD should be suspected in febrile children who have a sibling recently diagnosed with KD.,• Etiological studies should also focus on siblings who develop KD in close temporal proximity.,Key Points,• KD should be suspected in febrile children who have a sibling recently diagnosed with KD.,• Etiological studies should also focus on siblings who develop KD in close temporal proximity.
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Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency.,Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome.,There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV).,Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus.,Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure.,Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms.,Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19.,There is growing literature exploring cardiac involvement in SARS-CoV-2.,Myocardial injury is one of the important pathogenic features of COVID-19.,As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease.,Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients.,The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood.,The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia.,Unlabelled Image
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In this systematic review and meta-analysis, we aimed to explore the association between cardiac injury and mortality, the need for intensive care unit (ICU) care, acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19) in patients with COVID-19 pneumonia.,We performed a comprehensive literature search from several databases.,Definition of cardiac injury follows that of the included studies, which includes highly sensitive cardiac troponin I (hs-cTnl) >99th percentile.The primary outcome was mortality, and the secondary outcomes were ARDS, the need for ICU care, and severe COVID-19.,ARDS and severe COVID-19 were defined per the World Health Organization (WHO) interim guidance of severe acute respiratory infection (SARI) of COVID-19.,There were a total of 2389 patients from 13 studies.,This meta-analysis showed that cardiac injury was associated with higher mortality (RR 7.95 [5.12, 12.34], p < 0.001; I2: 65%).,Cardiac injury was associated with higher need for ICU care (RR 7.94 [1.51, 41.78], p = 0.01; I2: 79%), and severe COVID-19 (RR 13.81 [5.52, 34.52], p < 0.001; I2: 0%).,The cardiac injury was not significant for increased risk of ARDS (RR 2.57 [0.96, 6.85], p = 0.06; I2: 84%).,The level of hs-cTnI was higher in patients with primary + secondary outcome (mean difference 10.38 pg/mL [4.44, 16.32], p = 0.002; I2: 0%).,Cardiac injury is associated with mortality, need for ICU care, and severity of disease in patients with COVID-19.
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The COVID-19 pandemic required a significant redeployment of worldwide healthcare resources.,Fear of infection, national lockdowns and altered healthcare priorities have the potential to impact utilisation of healthcare resources for non-communicable diseases.,To survey health professionals’ views of the impact of the COVID-19 pandemic on the rate and timing of admission of patients with ST-elevation myocardial infarction (STEMI), the European Society of Cardiology (ESC) administered an internet-based questionnaire to cardiologists and cardiovascular nurses across 6 continents.,3101 responses were received from 141 countries across 6 continents.,88.3% responded that their country was in “total lockdown” and 7.1% in partial lockdown.,78.8% responded that the number of patients presenting with STEMI was reduced since the coronavirus outbreak and 65.2% indicated that the reduction in STEMI presentations was >40%.,Approximately 60% of all respondents reported that STEMI patients presented later than usual and 58.5% that >40% of STEMI patients admitted to hospital presented beyond the optimal window for primary percutaneous intervention (PCI) or thrombolysis.,Independent predictors of the reported higher rate of delayed STEMI presentation were a country in total lockdown, >100 COVID-19 cases admitted locally, and the complete restructuring of the local cardiology service.,The survey indicates that the impact of COVID-19 on STEMI presentations is likely to be substantial, with both lower presentations and a higher rate of delayed presentations occurring.,This has potentially important ramifications for future healthcare and policy planning in the event of further waves of this pandemic.
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This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury.
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The death of cardiomyocytes either through apoptosis or necroptosis is the pathological feature of cardiac ischemia-reperfusion (I/R) injury.,Phosphoglycerate mutase 5 (PGAM5), a mitochondrially-localized serine/threonine-protein phosphatase, functions as a novel inducer of necroptosis.,However, intense debate exists regarding the effect of PGAM5 on I/R-related cardiomyocyte death.,Using cardiac-specific PGAM5 knockout (PGAM5CKO) mice, we comprehensively investigated the precise contribution and molecular mechanism of PGAM5 in cardiomyocyte death.,Our data showed that both PGAM5 transcription and expression were upregulated in reperfused myocardium.,Genetic ablation of PGAM5 suppressed I/R-mediated necroptosis but failed to prevent apoptosis activation, a result that went along with improved heart function and decreased inflammation response.,Regardless of PGAM5 status, mitophagy-related cell death was not apparent following I/R.,Under physiological conditions, PGAM5 overexpression in primary cardiomyocytes was sufficient to induce cardiomyocyte necroptosis rather than apoptosis.,At the sub-cellular levels, PGAM5 deficiency increased mitochondrial DNA copy number and transcript levels, normalized mitochondrial respiration, repressed mitochondrial ROS production, and prevented abnormal mPTP opening upon I/R.,Molecular investigation demonstrated that PGAM5 deletion interrupted I/R-mediated DrpS637 dephosphorylation but failed to abolish I/R-induce Drp1S616 phosphorylation, resulting in partial inhibition of mitochondrial fission.,In addition, declining Mfn2 and OPA1 levels were restored in PGAM5CKO cardiomyocytes following I/R.,Nevertheless, PGAM5 depletion did not rescue suppressed mitophagy upon I/R injury.,In conclusion, our results provide an insight into the specific role and working mechanism of PGAM5 in driving cardiomyocyte necroptosis through imposing mitochondrial quality control in cardiac I/R injury.
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Receptor-interacting protein 3 (Ripk3)-mediated necroptosis contributes to cardiac ischaemia-reperfusion (IR) injury through poorly defined mechanisms.,Our results demonstrated that Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2O2.,The higher level of Ripk3 was positively correlated to the infarction area expansion, cardiac dysfunction and augmented cardiomyocytes necroptosis.,Function study further illustrated that upregulated Ripk3 evoked the endoplasmic reticulum (ER) stress, which was accompanied with an increase in intracellular Ca2+ level ([Ca2+]c) and xanthine oxidase (XO) expression.,Activated XO raised cellular reactive oxygen species (ROS) that mediated the mitochondrial permeability transition pore (mPTP) opening and cardiomyocytes necroptosis.,By comparison, genetic ablation of Ripk3 abrogated the ER stress and thus blocked the [Ca2+]c overload-XO-ROS-mPTP pathways, favouring a pro-survival state that ultimately resulted in the inhibition of cardiomyocytes necroptosis in the setting of cardiac IR injury.,In summary, the present study helps to elucidate how necroptosis is mediated by ER stress, via the calcium overload /XO/ROS/mPTP opening axis.,Ripk3 was strongly upregulated in murine hearts subjected to IR injury and cardiomyocytes treated with LPS and H2O2.,The upregulated Ripk3 may evoke the ER stress, which was accompanied with intracellular calcium overload and XO expression.,Activated XO raised cellular reactive oxygen species (ROS) that mediated the mPTP and cardiomyocytes necroptosis.fx1,•ER stress is activated by Ripk3 in cardiac IR injury.,•ER stress induces calcium overload which triggers XO-dependent ROS overproduction.,•ROS outburst promotes mPTP opening that accounts for the necroptosis.,•Inhibiting ER stress favors cardiomyocytes survival and protects cardiac function.,ER stress is activated by Ripk3 in cardiac IR injury.,ER stress induces calcium overload which triggers XO-dependent ROS overproduction.,ROS outburst promotes mPTP opening that accounts for the necroptosis.,Inhibiting ER stress favors cardiomyocytes survival and protects cardiac function.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals.,In answering questions raised regarding our study, we updated our database and repeated all analyses.,We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.,We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%).,The median follow-up duration increased from 7 to 14 days.,All patients received pharmacological thromboprophylaxis.,The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%).,The majority of thrombotic events were PE (65/75; 87%).,In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92).,Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12).,Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8).,In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.
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To describe the cardiac abnormalities in patients with COVID-19 and identify the characteristics of patients who would benefit most from echocardiography.,In a prospective international survey, we captured echocardiography findings in patients with presumed or confirmed COVID-19 between 3 and 20 April 2020.,Patient characteristics, indications, findings, and impact of echocardiography on management were recorded.,Multivariable logistic regression identified predictors of echocardiographic abnormalities.,A total of 1216 patients [62 (52-71) years, 70% male] from 69 countries across six continents were included.,Overall, 667 (55%) patients had an abnormal echocardiogram.,Left and right ventricular abnormalities were reported in 479 (39%) and 397 (33%) patients, respectively, with evidence of new myocardial infarction in 36 (3%), myocarditis in 35 (3%), and takotsubo cardiomyopathy in 19 (2%).,Severe cardiac disease (severe ventricular dysfunction or tamponade) was observed in 182 (15%) patients.,In those without pre-existing cardiac disease (n = 901), the echocardiogram was abnormal in 46%, and 13% had severe disease.,Independent predictors of left and right ventricular abnormalities were distinct, including elevated natriuretic peptides [adjusted odds ratio (OR) 2.96, 95% confidence interval (CI) 1.75-5.05) and cardiac troponin (OR 1.69, 95% CI 1.13-2.53) for the former, and severity of COVID-19 symptoms (OR 3.19, 95% CI 1.73-6.10) for the latter.,Echocardiography changed management in 33% of patients.,In this global survey, cardiac abnormalities were observed in half of all COVID-19 patients undergoing echocardiography.,Abnormalities were often unheralded or severe, and imaging changed management in one-third of patients.
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To describe the characteristics and outcomes of patients with severe COVID-19 and in-hospital cardiac arrest (IHCA) in Wuhan, China.,The outcomes of patients with severe COVID-19 pneumonia after IHCA over a 40-day period were retrospectively evaluated.,Between January 15 and February 25, 2020, data for all cardiopulmonary resuscitation (CPR) attempts for IHCA that occurred in a tertiary teaching hospital in Wuhan, China were collected according to the Utstein style.,The primary outcome was restoration of spontaneous circulation (ROSC), and the secondary outcomes were 30-day survival, and neurological outcome.,Data from 136 patients showed 119 (87.5%) patients had a respiratory cause for their cardiac arrest, and 113 (83.1%) were resuscitated in a general ward.,The initial rhythm was asystole in 89.7%, pulseless electrical activity (PEA) in 4.4%, and shockable in 5.9%.,Most patients with IHCA were monitored (93.4%) and in most resuscitation (89%) was initiated <1 min.,The average length of hospital stay was 7 days and the time from illness onset to hospital admission was 10 days.,The most frequent comorbidity was hypertension (30.2%), and the most frequent symptom was shortness of breath (75%).,Of the patients receiving CPR, ROSC was achieved in 18 (13.2%) patients, 4 (2.9%) patients survived for at least 30 days, and one patient achieved a favourable neurological outcome at 30 days.,Cardiac arrest location and initial rhythm were associated with better outcomes.,Survival of patients with severe COVID-19 pneumonia who had an in-hospital cardiac arrest was poor in Wuhan.
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A remarkably high incidence of venous thromboembolism (VTE) has been reported among critically ill patients with COVID‐19 assisted in the intensive care unit (ICU).,However, VTE burden among non‐ICU patients hospitalized for COVID‐19 that receive guideline‐recommended thromboprophylaxis is unknown.,To determine the incidence of VTE among non‐ICU patients hospitalized for COVID‐19 that receive pharmacological thromboprophylaxis.,We performed a systematic screening for the diagnosis of deep vein thrombosis (DVT) by lower limb vein compression ultrasonography (CUS) in consecutive non‐ICU patients hospitalized for COVID‐19, independent of the presence of signs or symptoms of DVT.,All patients were receiving pharmacological thromboprophylaxis with either enoxaparin or fondaparinux.,The population that we screened consisted of 84 consecutive patients, with a mean age of 67.6 ± 13.5 years and a mean Padua Prediction Score of 5.1 ± 1.6.,Seventy‐two patients (85.7%) had respiratory insufficiency, required oxygen supplementation, and had reduced mobility or were bedridden.,In this cohort, we found 10 cases of DVT, with an incidence of 11.9% (95% confidence interval [CI] 4.98‐18.82).,Of these, 2 were proximal DVT (incidence rate 2.4%, 95% CI −0.87‐5.67) and 8 were distal DVT (incidence rate 9.5%, 95% CI 3.23‐5.77).,Significant differences between subjects with and without DVT were D‐dimer > 3000 µg/L (P < .05), current or previous cancer (P < .05), and need of high flow nasal oxygen therapy and/or non‐invasive ventilation (P < .01).,DVT may occur among non‐ICU patients hospitalized for COVID‐19, despite guideline‐recommended thromboprophylaxis.
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The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients.,First, those with COVID-19 and pre-existing cardiovascular disease have an increased risk of severe disease and death.,Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism.,Third, therapies under investigation for COVID-19 may have cardiovascular side effects.,Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions.,Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become hosts or vectors of virus transmission.,We hereby review the peer-reviewed and pre-print reports pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.,•Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,•CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,•Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,•Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.,Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.
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The current coronavirus disease 2019 (COVID-19) pandemic represents a global public health crisis, disrupting emergency healthcare services.,We determined whether COVID-19 has resulted in delays in stroke presentation and affected the delivery of acute stroke services in a comprehensive stroke center in Hong Kong.,We retrospectively reviewed all patients with transient ischemic attack and stroke admitted via the acute stroke pathway of Queen Mary Hospital, Hong Kong, during the first 60 days since the first diagnosed COVID-19 case in Hong Kong (COVID-19: January 23, 2020-March 24, 2020).,We compared the stroke onset to hospital arrival (onset-to-door) time and timings of inpatient stroke pathways with patients admitted during the same period in 2019 (pre-COVID-19: January 23, 2019-March 24, 2019).,Seventy-three patients in COVID-19 were compared with 89 patients in pre-COVID-19.,There were no significant differences in age, sex, vascular risk factors, nor stroke severity between the 2 groups (P>0.05).,The median stroke onset-to-door time was ≈1-hour longer in COVID-19 compared with pre-COVID-19 (154 versus 95 minutes, P=0.12), and the proportion of individuals with onset-to-door time within 4.5 hours was significantly lower (55% versus 72%, P=0.024).,Significantly fewer cases of transient ischemic attack presented to the hospital during COVID-19 (4% versus 16%, P=0.016), despite no increase in referrals to the transient ischemic attack clinic.,Inpatient stroke pathways and treatment time metrics nevertheless did not differ between the 2 groups (P>0.05 for all comparisons).,During the early containment phase of COVID-19, we noted a prolongation in stroke onset to hospital arrival time and a significant reduction in individuals arriving at the hospital within 4.5 hours and presenting with transient ischemic attack.,Public education about stroke should continue to be reinforced during the COVID-19 pandemic.
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When the coronavirus disease 2019 (COVID-19) outbreak became paramount, medical care for other devastating diseases was negatively impacted.,In this study, we investigated the impact of the COVID-19 outbreak on stroke care across China.,Data from the Big Data Observatory Platform for Stroke of China consisting of 280 hospitals across China demonstrated a significant drop in the number of cases of thrombolysis and thrombectomy.,We designed a survey to investigate the major changes during the COVID-19 outbreak and potential causes of these changes.,The survey was distributed to the leaders of stroke centers in these 280 hospitals.,From the data of Big Data Observatory Platform for Stroke of China, the total number of thrombolysis and thrombectomy cases dropped 26.7% (P<0.0001) and 25.3% (P<0.0001), respectively, in February 2020 as compared with February 2019.,We retrieved 227 valid complete datasets from the 280 stroke centers.,Nearly 50% of these hospitals were designated hospitals for COVID-19.,The capacity for stroke care was reduced in the majority of the hospitals.,Most of the stroke centers stopped or reduced their efforts in stroke education for the public.,Hospital admissions related to stroke dropped ≈40%; thrombolysis and thrombectomy cases dropped ≈25%, which is similar to the results from the Big Data Observatory Platform for Stroke of China as compared with the same period in 2019.,Many factors contributed to the reduced admissions and prehospital delays; lack of stroke knowledge and proper transportation were significant limiting factors.,Patients not coming to the hospital for fear of virus infection was also a likely key factor.,The COVID-19 outbreak impacted stroke care significantly in China, including prehospital and in-hospital care, resulting in a significant drop in admissions, thrombolysis, and thrombectomy.,Although many factors contributed, patients not coming to the hospital was probably the major limiting factor.,Recommendations based on the data are provided.
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Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19).,We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.,In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis.,The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.,This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.,The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met.,Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58).,The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2).,The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort.,Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.,In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.,(ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.)
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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The impact of atrial arrhythmias on coronavirus disease 2019 (COVID‐19)‐associated outcomes are unclear.,We sought to identify prevalence, risk factors and outcomes associated with atrial arrhythmias among patients hospitalized with COVID‐19.,An observational cohort study of 1053 patients with severe acute respiratory syndrome coronavirus 2 infection admitted to a quaternary care hospital and a community hospital was conducted.,Data from electrocardiographic and telemetry were collected to identify atrial fibrillation (AF) or atrial flutter/tachycardia (AFL).,The association between atrial arrhythmias and 30‐day mortality was assessed with multivariable analysis.,Mean age of patients was 62 ± 17 years and 62% were men.,Atrial arrhythmias were identified in 166 (15.8%) patients, with AF in 154 (14.6%) patients and AFL in 40 (3.8%) patients.,Newly detected atrial arrhythmias occurred in 101 (9.6%) patients.,Age, male sex, prior AF, renal disease, and hypoxia on presentation were independently associated with AF/AFL occurrence.,Compared with patients without AF/AFL, patients with AF/AFL had significantly higher levels of troponin, B‐type natriuretic peptide, C‐reactive protein, ferritin and d‐dimer.,Mortality was significantly higher among patients with AF/AFL (39.2%) compared to patients without (13.4%; p < .001).,After adjustment for age and co‐morbidities, AF/AFL (adjusted odds ratio [OR]: 1.93; p = .007) and newly detected AF/AFL (adjusted OR: 2.87; p < .001) were independently associated with 30‐day mortality.,Atrial arrhythmias are common among patients hospitalized with COVID‐19.,The presence of AF/AFL tracked with markers of inflammation and cardiac injury.,Atrial arrhythmias were independently associated with increased mortality.
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A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting-enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied.,We carried out a population-based case-control study in the Lombardy region of Italy.,A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence.,Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use.,Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression.,Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women.,The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile.,Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex.,In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease.,However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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Three months ago, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) broke out in Wuhan, China, and spread rapidly around the world.,Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism (VTE) prevalence is still rarely mentioned.,To determine the incidence of VTE in patients with severe NCP.,In this study, 81 severe NCP patients in the intensive care unit (ICU) of Union Hospital (Wuhan, China) were enrolled.,The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed.,The incidence of VTE in these patients was 25% (20/81), of which 8 patients with VTE events died.,The VTE group was different from the non‐VTE group in age, lymphocyte counts, activated partial thromboplastin time (APTT), D‐dimer, etc.,If 1.5 µg/mL was used as the D‐dimer cut‐off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%.,The incidence of VTE in patients with severe NCP is 25% (20/81), which may be related to poor prognosis.,The significant increase of D‐dimer in severe NCP patients is a good index for identifying high‐risk groups of VTE.
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Despite revascularisation, a large proportion of acute coronary syndrome (ACS) patients continue to experience major adverse cardiovascular events (MACEs), which are worsened by diabetes mellitus (DM).,Fibrinogen (FIB) is a risk factor for MACEs in coronary artery disease and often elevated in DM.,However, the relationships between FIB, glucose metabolism (haemoglobin A1c [HbA1c] and fasting blood glucose [FBG]) and MACEs following percutaneous coronary intervention (PCI) in DM, non-DM or whole patients with ACS remains unknown.,A total of 411 ACS patients undergoing PCI were enrolled in this study.,We compared baseline FIB levels between DM (n = 103) and non-DM (n = 308) patients and divided participants into three groups according to FIB level, i.e.,FIB-L, FIB-M and FIB-H, to compare baseline characteristics and MACEs.,Linear regression analysis of the relationship between glucose metabolism and FIB, Cox regression, survival and landmark analyses of MACEs were also performed over a median of 27.55 months of follow-up.,Patients with DM had higher FIB levels than non-DM patients (3.56 ± 0.99 mg/dL vs.,3.34 ± 0.80 mg/dL, P < 0.05).,HbA1c and FBG were significantly positively correlated with FIB in whole and DM patients but not in non-DM patients (all P < 0.05).,Compared with the FIB-L group, the FIB-M (hazard ratio [HR] 1.797, 95% CI 1.117-2.892, P = 0.016) and FIB-H (HR 1.664, 95% CI 1.002-2.763, P = 0.049) groups were associated with higher MACEs in whole; the FIB-M (HR 7.783, 95% CI 1.012-59.854, P = 0.049) was associated with higher MACEs in DM patients.,FIB was not associated with MACEs in non-DM patients.,During landmark analysis, FIB showed better predictive value for MACEs after PCI in the first 30 months of follow up than in the subsequent period.,In this study from China, FIB was positively associated with glucose metabolism (HbA1c and FBG) in whole and DM populations with ACS.,Moreover, elevated baseline FIB levels may be an important and independent predictor of MACEs following PCI, especially amongst those with DM.,However, as the follow-up period increased, the baseline FIB levels lost their ability to predict MACEs.
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Elevated fibrinogen is associated with short‐term major adverse cardiovascular events (MACE) after percutaneous coronary intervention, but the relation with late MACE is unknown.,Baseline demographics and 2‐year MACE were recorded among subjects undergoing nonemergent percutaneous coronary intervention.,A total of 332 subjects (66.6±19.5 years, 69.9% male, 25.3% acute coronary syndrome) were enrolled.,Two‐year MACE (periprocedural myocardial infarction 9.0%, rehospitalization 6.3%, revascularization 12.7%, non-periprocedural myocardial infarction 4.5%, stent thrombosis 0.9%, stroke 1.8%, and death 0.6%) were associated with higher fibrinogen (352.8±123.4 mg/dL versus 301.6±110.8 mg/dL; P<0.001), longer total stent length (40.1±25.3 mm versus 32.1±19.3 mm; P=0.004), acute coronary syndrome indication (38.7% versus 17.8%; P<0.001), number of bare‐metal stents (0.5±1.1 versus 0.2±0.5; P=0.002), and stent diameter ≤2.5 mm (55.8% versus 38.4%, P=0.003).,No relation between platelet reactivity and 2‐year MACE was observed.,Fibrinogen ≥280 mg/dL (odds ratio [OR] 3.0, confidence interval [CI], 1.6-5.4, P<0.001), total stent length ≥32 mm (OR 2.2, CI, 1.3-3.8, P<0.001), acute coronary syndrome indication (OR 4.1, CI, 2.3-7.5, P<0.001), any bare‐metal stents (OR 3.2, CI, 1.6-6.1, P<0.001), and stent diameter ≤2.5 mm (OR 2.0, CI, 1.2-3.5, P=0.010) were independently associated with 2‐year MACE.,Following a landmark analysis excluding periprocedural myocardial infarction, fibrinogen ≥280 mg/dL remained strongly associated with 2‐year MACE (37.0% versus 17.4%, log‐rank P<0.001).,Elevated baseline fibrinogen level is associated with 2‐year MACE after percutaneous coronary intervention.,Acute coronary syndrome indication for percutaneous coronary intervention, total stent length implanted, and use of bare‐metal stents or smaller‐diameter stents are also independently associated with 2‐year MACE, while measures of on‐thienopyridine platelet reactivity are not.
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Supplemental Digital Content is available in the text.,Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension.,To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.,This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020.,In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03).,In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03).,Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension.,Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers.,While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2).,We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive.,Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class.,A difference of at least 10 percentage points was prespecified as a substantial difference.,Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness.,A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness.,There was no association between any single medication class and an increased likelihood of a positive test.,None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.,We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.
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Although coronavirus disease 2019 (COVID-19) is transmitted via respiratory droplets, there are multiple gastrointestinal and hepatic manifestations of the disease, including abnormal liver-associated enzymes.,However, there are not many published articles on the pathological findings in the liver of patients with COVID-19.,We collected the clinical data from 17 autopsy cases of patients with COVID-19 including age, sex, Body mass index (BMI), liver function test (alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), direct bilirubin, and total bilirubin), D-dimer, and anticoagulation treatment.,We examined histopathologic findings in postmortem hepatic tissue, immunohistochemical (IHC) staining with antibody against COVID-19 spike protein, CD68 and CD61, and electron microscopy.,We counted the number of megakaryocytes in liver sections from these COVID-19-positive cases.,Abnormal liver-associated enzymes were observed in 12 of 17 cases of COVID-19 infection.,With the exception of three cases that had not been tested for D-dimer, all 14 patients’ D-dimer levels were increased, including the cases that received varied doses of anticoagulation treatment.,Microscopically, the major findings were widespread platelet-fibrin microthrombi, steatosis, histiocytic hyperplasia in the portal tract, mild lobular inflammation, ischemic-type hepatic necrosis, and zone 3 hemorrhage.,Rare megakaryocytes were found in sinusoids.,COVID-19 IHC demonstrates positive staining of the histiocytes in the portal tract.,Under electron microscopy, histiocyte proliferation is present in the portal tract containing lipid droplets, lysosomes, dilated ribosomal endoplasmic reticulum, microvesicular bodies, and coronavirus.,The characteristic findings in the liver of patients with COVID-19 include numerous amounts of platelet-fibrin microthrombi, as well as various degrees of steatosis and histiocytic hyperplasia in the portal tract.,Possible mechanisms are also discussed.
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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described.,In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020.,Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors.,We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death.,191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients).,Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission.,Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors.,The longest observed duration of viral shedding in survivors was 37 days.,The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage.,Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.,Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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Acute ischemic stroke may occur in patients with coronavirus disease 2019 (COVID-19), but risk factors, in-hospital events, and outcomes are not well studied in large cohorts.,We identified risk factors, comorbidities, and outcomes in patients with COVID-19 with or without acute ischemic stroke and compared with patients without COVID-19 and acute ischemic stroke.,We analyzed the data from 54 health care facilities using the Cerner deidentified COVID-19 dataset.,The dataset included patients with an emergency department or inpatient encounter with discharge diagnoses codes that could be associated to suspicion of or exposure to COVID-19 or confirmed COVID-19.,A total of 103 (1.3%) patients developed acute ischemic stroke among 8163 patients with COVID-19.,Among all patients with COVID-19, the proportion of patients with hypertension, diabetes, hyperlipidemia, atrial fibrillation, and congestive heart failure was significantly higher among those with acute ischemic stroke.,Acute ischemic stroke was associated with discharge to destination other than home or death (relative risk, 2.1 [95% CI, 1.6-2.4]; P<0.0001) after adjusting for potential confounders.,A total of 199 (1.0%) patients developed acute ischemic stroke among 19 513 patients without COVID-19.,Among all ischemic stroke patients, COVID-19 was associated with discharge to destination other than home or death (relative risk, 1.2 [95% CI, 1.0-1.3]; P=0.03) after adjusting for potential confounders.,Acute ischemic stroke was infrequent in patients with COVID-19 and usually occurs in the presence of other cardiovascular risk factors.,The risk of discharge to destination other than home or death increased 2-fold with occurrence of acute ischemic stroke in patients with COVID-19.
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In order to cope with the exponentially increasing number of patients infected with SARS‐CoV‐2, European countries made enormous efforts to reorganize medical assistance and several diseases, including stroke, were particularly impacted.,We report the experience of stroke neurologists from three European countries (Italy, France and Germany) that faced the pandemic at diverse time points and with different approaches, depending on their resources and healthcare system organization.,Pre‐hospital and in‐hospital acute stroke pathways were reorganized to prioritize COVID‐19 management and, in severely affected regions of Italy and France, stroke care was centralized to a limited number of centers, whereas the remaining stroke units were dedicated to patients with COVID‐19.,Access to acute stroke diagnostics and time‐dependent therapies was limited or delayed because of reduced capacities of emergency services due to the burden of patients with COVID‐19.,A marked reduction in the number of patients presenting with transient ischaemic attack and stroke was noted in the emergency departments of all three countries.,Although we only have preliminary data, these conditions may have affected stroke outcome.,These indirect effects of the COVID‐19 pandemic could negate the efforts of stroke neurologists over the last few years to improve outcome and reduce mortality of stroke patients.,Although the SARS‐CoV‐2 infection rate is slowing down in Europe, the effects of ending lockdown in the next months are unpredictable.,It is important for the European and world stroke community to share what has been learned so far to be plan strategies to ensure stroke care in the future and upcoming challenging times.
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Severe pneumonia is pathological manifestation of Coronavirus Disease 2019 (COVID-19), however complications have been reported in COVID-19 patients with a worst prognosis.,Aim of this study was to evaluate the role of high sensitivity cardiac troponin I (hs-TnI) in patients with SARS-CoV-2 infection.,we retrospectively analysed hs-TnI values measured in 523 patients (median age 64 years, 68% men) admitted to a university hospital in Milan, Italy, and diagnosed COVID-19.,A significant difference in hs-TnI concentrations was found between deceased patients (98 patients) vs discharged (425 patients) [36.05 ng/L IQR 16.5-94.9 vs 6.3 ng/L IQR 2.6-13.9, p < 0.001 respectively].,Hs-TnI measurements were independent predictors of mortality at multivariate analysis adjusted for confounding parameters such as age (HR 1.004 for each 10 point of troponin, 95% CI 1.002-1.006, p < 0.001).,The survival rate, after one week, in patients with hs-TnI values under 6 ng/L was 97.94%, between 6 ng/L and the normal value was 90.87%, between the normal value and 40 ng/L was 86.98, and 59.27% over 40 ng/L.,Increase of hs-TnI associated with elevated mortality in patients with COVID-19.,Troponin shows to be a useful biomarker of disease progression and worse prognosis in COVID-19 patients.
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Cardiac injury has been reported in up to 30% of coronavirus disease 2019 (COVID-19) patients.,However, cardiac injury is defined mainly by troponin elevation without description of associated structural abnormalities and its time course has not been studied.,What are the ECG and echocardiographic abnormalities as well as their time course in critically ill COVID-19 patients?,The cardiac function of 43 consecutive COVID-19 patients admitted to two ICUs was assessed prospectively and repeatedly, combining ECG, cardiac biomarker, and transthoracic echocardiographic analyses from ICU admission to ICU discharge or death or to a maximum follow-up of 14 days.,Cardiac injury was defined by troponin elevation and newly diagnosed ECG or echocardiographic abnormalities, or both.,At baseline, 49% of patients demonstrated a cardiac injury, and 70% of patients experienced cardiac injury within the first 14 days of ICU stay, with a median time of occurrence of 3 days (range, 0-7 days).,The most frequent abnormalities were ECG or echocardiographic signs, or both, of left ventricular (LV) abnormalities (87% of patients with cardiac injury), right ventricular (RV) systolic dysfunction (47%), pericardial effusion (43%), new-onset atrial arrhythmias (33%), LV relaxation impairment (33%), and LV systolic dysfunction (13%).,Between baseline and day 14, the incidence of pericardial effusion and of new-onset atrial arrhythmias increased and the incidence of ECG or echocardiographic signs, or both, of LV abnormalities as well as the incidence of LV relaxation impairment remained stable, whereas the incidence of RV and LV systolic dysfunction decreased.,Cardiac injury is common and early in critically ill COVID-19 patients.,ECG or echocardiographic signs, or both, of LV abnormalities were the most frequent abnormalities, and patients with cardiac injury experienced more RV than LV systolic dysfunction.
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The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades.,We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies.,While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system.,Risk of severe infection and mortality increase with advancing age and male sex.,Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer.,The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC).,Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes.,This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI).,While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis.,Hence, patients should not discontinue their use.,Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19.,Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19.,Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications.,Preventive measures (social distancing and social isolation) also increase cardiovascular risk.,Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
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Many patients with coronavirus disease 2019 (COVID-19) have underlying cardiovascular (CV) disease or develop acute cardiac injury during the course of the illness.,Adequate understanding of the interplay between COVID-19 and CV disease is required for optimum management of these patients.,A literature search was done using PubMed and Google search engines to prepare a narrative review on this topic.,Respiratory illness is the dominant clinical manifestation of COVID-19; CV involvement occurs much less commonly.,Acute cardiac injury, defined as significant elevation of cardiac troponins, is the most commonly reported cardiac abnormality in COVID-19.,It occurs in approximately 8-12% of all patients.,Direct myocardial injury due to viral involvement of cardiomyocytes and the effect of systemic inflammation appear to be the most common mechanisms responsible for cardiac injury.,The information about other CV manifestations in COVID-19 is very limited at present.,Nonetheless, it has been consistently shown that the presence of pre-existing CV disease and/or development of acute cardiac injury are associated with significantly worse outcome in these patients.,Most of the current reports on COVID-19 have only briefly described CV manifestations in these patients.,Given the enormous burden posed by this illness and the significant adverse prognostic impact of cardiac involvement, further research is required to understand the incidence, mechanisms, clinical presentation and outcomes of various CV manifestations in COVID-19 patients.,•COVID-19 is primarily a respiratory illness but cardiovascular involvement can occur through several mechanisms.,•Acute cardiac injury is the most reported cardiovascular abnormality in COVID-19, with average incidence 8-12%•Underlying CVD and/or development of acute cardiac injury are associated with significantly worse outcome in these patients.,•Information about other cardiovascular manifestations is very limited at present.,COVID-19 is primarily a respiratory illness but cardiovascular involvement can occur through several mechanisms.,Acute cardiac injury is the most reported cardiovascular abnormality in COVID-19, with average incidence 8-12%,Underlying CVD and/or development of acute cardiac injury are associated with significantly worse outcome in these patients.,Information about other cardiovascular manifestations is very limited at present.
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Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality.,A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease.,The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy.,Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis.,Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury.,Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum.,Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists.,Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective.,This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment.,From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.
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COronaVirus Disease 2019 (COVID-19) has spread at unprecedented speed and scale into a global pandemic with cardiovascular risk factors and complications emerging as important disease modifiers.,We aim to review available clinical and biomedical literature on cardiovascular risks of COVID-19.,SARS-CoV2, the virus responsible for COVID-19, enters the cell via ACE2 expressed in select organs.,Emerging epidemiological evidence suggest cardiovascular risk factors are associated with increased disease severity and mortality in COVID-19 patients.,Patients with a more severe form of COVID-19 are also more likely to develop cardiac complications such as myocardial injury and arrhythmia.,The true incidence of and mechanism underlying these events remain elusive.,Cardiovascular diseases appear intricately linked with COVID-19, with cardiac complications contributing to the elevated morbidity/mortality of COVID-19.,Robust epidemiologic and biologic studies are urgently needed to better understand the mechanism underlying these associations to develop better therapies.
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Coronavirus disease‐2019 (COVID‐19) has been associated with cardiovascular complications and coagulation disorders.,To explore the coagulopathy and endothelial dysfunction in COVID‐19 patients.,The study analyzed clinical and biological profiles of patients with suspected COVID‐19 infection at admission, including hemostasis tests and quantification of circulating endothelial cells (CECs).,Among 96 consecutive COVID‐19‐suspected patients fulfilling criteria for hospitalization, 66 were tested positive for SARS‐CoV‐2.,COVID‐19‐positive patients were more likely to present with fever (P = .02), cough (P = .03), and pneumonia at computed tomography (CT) scan (P = .002) at admission.,Prevalence of D‐dimer >500 ng/mL was higher in COVID‐19‐positive patients (74.2% versus 43.3%; P = .007).,No sign of disseminated intravascular coagulation were identified.,Adding D‐dimers >500 ng/mL to gender and pneumonia at CT scan in receiver operating characteristic curve analysis significantly increased area under the curve for COVID‐19 diagnosis.,COVID‐19‐positive patients had significantly more CECs at admission (P = .008) than COVID‐19‐negative ones.,COVID‐19‐positive patients treated with curative anticoagulant prior to admission had fewer CECs (P = .02) than those without.,Interestingly, patients treated with curative anticoagulation and angiotensin‐converting‐enzyme inhibitors or angiotensin receptor blockers had even fewer CECs (P = .007).,Curative anticoagulation could prevent COVID‐19‐associated coagulopathy and endothelial lesion.
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Few data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19.,We studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02.2020-10.04.2020).,The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI).,Secondary outcome was overt disseminated intravascular coagulation (DIC).,We included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]).,Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward.,Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%-11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward).,Half of the thromboembolic events were diagnosed within 24 h of hospital admission.,Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%).,Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA).,The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively.,Overt DIC was present in 8 (2.2%) patients.,The high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 h of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.,•COVID-19 is characterized by coagulation activation and endothelial dysfunction.,Few data are available on thromboembolic complications.,•We studied symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02-10.04.2020).,•Venous and arterial thromboembolic events occurred in 8% of hospitalized patients (cumulative rate 21.0%) and 50% of events were diagnosed within 24 h of hospital admission.,•Forty-four (11% of total) patients underwent VTE imaging tests; 16 were positive (36% of tests), suggesting underestimation of thromboembolic complications.,•There is an urgent need to investigate VTE diagnostic strategies and the impact of thromboprophylaxis in ambulatory COVID-19 patients.,COVID-19 is characterized by coagulation activation and endothelial dysfunction.,Few data are available on thromboembolic complications.,We studied symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02-10.04.2020).,Venous and arterial thromboembolic events occurred in 8% of hospitalized patients (cumulative rate 21.0%) and 50% of events were diagnosed within 24 h of hospital admission.,Forty-four (11% of total) patients underwent VTE imaging tests; 16 were positive (36% of tests), suggesting underestimation of thromboembolic complications.,There is an urgent need to investigate VTE diagnostic strategies and the impact of thromboprophylaxis in ambulatory COVID-19 patients.
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Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease.,In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis.,Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated.,Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19.,Further, we review other agents, including immunomodulators, that may have antithrombotic properties.,It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.
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Thirty percent of Covid‐19 patients admitted to intensive care units present with thrombotic complications despite thromboprophylaxis.,Bed rest, obesity, hypoxia, coagulopathy, and acute excessive inflammation are potential mechanisms reported by previous studies.,Better understanding of the underlying mechanisms leading to thrombosis is crucial for developing more appropriate prophylaxis and treatment strategies.,We aimed to assess fibrinolytic activity and thrombin generation in 78 Covid‐19 patients.,Forty‐eight patients admitted to the intensive care unit and 30 patients admitted to the internal medicine department were included in the study.,All patients received thromboprophylaxis.,We measured fibrinolytic parameters (tissue plasminogen activator, PAI‐1, thrombin activatable fibrinolysis inhibitor, alpha2 anti‐plasmin, and tissue plasminogen activator‐modified ROTEM device), thrombin generation, and other coagulation tests (D‐dimer, fibrinogen, factor VIII, antithrombin).,We observed two key findings: a high thrombin generation capacity that remained within normal values despite heparin therapy and a hypofibrinolysis mainly associated with increased PAI‐1 levels.,A modified ROTEM is able to detect both hypercoagulability and hypofibrinolysis simultaneously in Covid‐19 patients with thrombosis.
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Previous studies has shown a significant relationship between baseline triglyceride-glucose (TyG) index and subsequent cardiovascular disease (CVD).,However, the effect of longitudinal changes in TyG index on the risk of CVD remains uncertain.,This study aimed to investigate the association between change in TyG index and the risk of CVD in the general population.,The current study included 62,443 Chinese population who were free of CVD.,The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2], and change in TyG index was defined as the difference between the TyG index in 2010 and that in 2006.,Multivariable-adjusted Cox proportional hazard models and restricted cubic spline analysis were used to examine the association between change in TyG index and the risk of CVD.,During a median follow-up of 7.01 years, 2530 (4.05%) incident CVD occurred, including 2018 (3.23%) incident stroke and 545 (0.87%) incident myocardial infarction (MI).,The risk of developing CVD increased with the quartile of change in TyG index, after adjustment for multiple potential confounders, the hazard ratios for the Q4 group versus the Q1 group were 1.37 (95% confidence interval [CI], 1.21-1.54) for the overall CVD, 1.38 (95% CI, 1.19-1.60) for stroke, and 1.36 (95% CI, 1.05-1.76) for MI.,Restricted cubic spline analysis also showed a cumulative increase in the risk of CVD with increases in the magnitude of change in TyG index.,The addition of change in TyG index to a baseline risk model for CVD improved the C-statistics (P = 0.0097), integrated discrimination improvement value (P < 0.0001), and category-free net reclassification improvement value (P < 0.0001).,Similar results were observed for stroke and MI.,Substantial changes in TyG index independently predict the risk of CVD in the general population.,Monitoring long-term changes in TyG may assist with in the early identification of individuals at high risk of CVD.,The online version contains supplementary material available at 10.1186/s12933-021-01305-7.
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Ischemic heart disease (IHD) without diabetes is considered an important challenge to human health and is associated with a poor prognosis, as well as a lack of health awareness.,We prospectively investigated the relationship between the triglyceride-glucose (TyG) index, a surrogate marker of early insulin resistance, and incident IHD risk in a large cohort of nondiabetic Korean adults using National Health Insurance Service data.,We assessed 16,455 participants (8426 men and 8029 women) without diabetes using data from a health risk assessment study (HERAS) and Korea Health Insurance Review and Assessment (HIRA) data.,The participants were divided into four groups according to TyG index quartiles, calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2].,We prospectively assessed hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD using multivariate Cox proportional-hazards regression models over a 50-month period that followed the baseline survey.,During the follow-up period, 322 (2.0%) participants developed IHD.,HRs of IHD for TyG index quartiles 2-4 were 1.61 (95% CI 1.05-2.48), 1.85 (95% CI 1.21-2.81), and 2.29 (95% CI 1.50-3.51), respectively, after adjusting for age, sex, body mass index, smoking status, alcohol intake, and physical activity.,A higher TyG index precedes and significantly predicts future IHD among nondiabetic Koreans.,Accordingly, the TyG index may be a useful measure in assessing cardiovascular risk for nondiabetic adults in the preclinical stage.
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Although certain risk factors have been associated with increased morbidity and mortality in patients admitted with Coronavirus Disease 2019 (COVID-19), the impact of cardiac injury and high-sensitivity troponin-I (hs-cTnI) concentrations are not well described.,In this large retrospective longitudinal cohort study, we analyzed the cases of 1,044 consecutively admitted patients with COVID-19 from March 9 until April 15.,Cardiac injury was defined by hs-cTnI concentration >99th percentile.,Patient characteristics, laboratory data, and outcomes were described in patients with cardiac injury and different hs-cTnI cut-offs.,The primary outcome was mortality, and the secondary outcomes were length of stay, need for intensive care unit care or mechanical ventilation, and their different composites.,The final analyzed cohort included 1,020 patients.,The median age was 63 years, 511 (50% patients were female, and 403 (40% were white. 390 (38%) patients had cardiac injury on presentation.,These patients were older (median age 70 years), had a higher cardiovascular disease burden, in addition to higher serum concentrations of inflammatory markers.,They also exhibited an increased risk for our primary and secondary outcomes, with the risk increasing with higher hs-cTnI concentrations.,Peak hs-cTnI concentrations continued to be significantly associated with mortality after a multivariate regression controlling for comorbid conditions, inflammatory markers, acute kidney injury, and acute respiratory distress syndrome.,Within the same multivariate regression model, presenting hs-cTnI concentrations were not significantly associated with outcomes, and undetectable hs-cTnI concentrations on presentation did not completely rule out the risk for mechanical ventilation or death.,In conclusion, cardiac injury was common in patients admitted with COVID-19.,The extent of cardiac injury and peak hs-cTnI concentrations were associated with worse outcomes.
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To compare demographic characteristics, clinical presentation, and outcomes of patients with and without concomitant cardiac disease, hospitalized for COVID-19 in Brescia, Lombardy, Italy.,The study population includes 99 consecutive patients with COVID-19 pneumonia admitted to our hospital between 4 March and 25 March 2020.,Fifty-three patients with a history of cardiac disease were compared with 46 without cardiac disease.,Among cardiac patients, 40% had a history of heart failure, 36% had atrial fibrillation, and 30% had coronary artery disease.,Mean age was 67 ± 12 years, and 80 (81%) patients were males.,No differences were found between cardiac and non-cardiac patients except for higher values of serum creatinine, N-terminal probrain natriuretic peptide, and high sensitivity troponin T in cardiac patients.,During hospitalization, 26% patients died, 15% developed thrombo-embolic events, 19% had acute respiratory distress syndrome, and 6% had septic shock.,Mortality was higher in patients with cardiac disease compared with the others (36% vs. 15%, log-rank P = 0.019; relative risk 2.35; 95% confidence interval 1.08-5.09).,The rate of thrombo-embolic events and septic shock during the hospitalization was also higher in cardiac patients (23% vs. 6% and 11% vs. 0%, respectively).,Hospitalized patients with concomitant cardiac disease and COVID-19 have an extremely poor prognosis compared with subjects without a history of cardiac disease, with higher mortality, thrombo-embolic events, and septic shock rates.
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With the spread of coronavirus disease 2019 (COVID-19) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke.,However, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and COVID-19.,We conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between March 15, 2020, and April 19, 2020, within a major health system in New York, the current global epicenter of the pandemic.,We compared the clinical characteristics of stroke patients with a concurrent diagnosis of COVID-19 to stroke patients without COVID-19 (contemporary controls).,In addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between March 15, 2019, and April 15, 2019 (historical controls).,During the study period in 2020, out of 3556 hospitalized patients with diagnosis of COVID-19 infection, 32 patients (0.9%) had imaging proven ischemic stroke.,Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to contemporary controls (30.4%, P=0.003) and historical controls (25.0%, P<0.001).,When compared with contemporary controls, COVID-19 positive patients had higher admission National Institutes of Health Stroke Scale score and higher peak D-dimer levels.,When compared with historical controls, COVID-19 positive patients were more likely to be younger men with elevated troponin, higher admission National Institutes of Health Stroke Scale score, and higher erythrocyte sedimentation rate.,Patients with COVID-19 and stroke had significantly higher mortality than historical and contemporary controls.,We observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with COVID-19.,Most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased.,Studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with COVID-19.
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The COVID-19 pandemic has presented unprecedented challenges to healthcare organizations worldwide.,A steadily rising number of patients requiring intensive care, a large proportion from racial and ethnic minorities, demands creative solutions to provide high-quality care while ensuring healthcare worker safety in the face of limited resources.,Boston Medical Center has been particularly affected due to the underserved patient population we care for and the increased risk of ischemic stroke in patients with COVID-19 infection.,We present protocol modifications developed to manage patients with acute ischemic stroke in a safe and effective manner while prioritizing judicious use of personal protective equipment and intensive care unit resources.,We feel this information will benefit other organizations facing similar obstacles in caring for the most vulnerable patient populations during this ongoing public health crisis.
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Venous thromboembolism (VTE) may complicate the course of Coronavirus Disease 2019 (COVID-19).,To evaluate the incidence of VTE in patients with COVID-19.,MEDLINE, EMBASE, and PubMed were searched up to 24th June 2020 for studies that evaluated the incidence of VTE, including pulmonary embolism (PE) and/or deep vein thrombosis (DVT), in patients with COVID-19.,Pooled proportions with corresponding 95% confidence intervals (CI) and prediction intervals (PI) were calculated by random-effect meta-analysis.,3487 patients from 30 studies were included.,Based on very low-quality evidence due to heterogeneity and risk of bias, the incidence of VTE was 26% (95% PI, 6%-66%).,PE with or without DVT occurred in 12% of patients (95% PI, 2%-46%) and DVT alone in 14% (95% PI, 1%-75%).,Studies using standard algorithms for clinically suspected VTE reported PE in 13% of patients (95% PI, 2%-57%) and DVT in 6% (95% PI, 0%-60%), compared to 11% (95% PI, 2%-46%) and 24% (95% PI, 2%-85%) in studies using other diagnostic strategies or patient sampling.,In patients admitted to intensive care units, VTE occurred in 24% (95% PI, 5%-66%), PE in 19% (95% PI, 6%-47%), and DVT alone in 7% (95% PI, 0%-69%).,Corresponding values in general wards were respectively 9% (95% PI, 0%-94%), 4% (95% PI, 0%-100%), and 7% (95% CI, 1%-49%).,VTE represents a frequent complication in hospitalized COVID-19 patients and often occurs as PE.,The threshold for clinical suspicion should be low to trigger prompt diagnostic testing.,•Incidence of venous thromboembolism (VTE) in Coronavirus Disease-2019 (COVID-19) is unclear.,•A total of 3487 patients with COVID-19 were included in 30 observational studies.,•VTE incidence varied due to differences in diagnostic protocols and hospital setting.,•VTE risk was higher in intensive care units, but seemed also substantial in general wards despite prophylaxis.,Incidence of venous thromboembolism (VTE) in Coronavirus Disease-2019 (COVID-19) is unclear.,A total of 3487 patients with COVID-19 were included in 30 observational studies.,VTE incidence varied due to differences in diagnostic protocols and hospital setting.,VTE risk was higher in intensive care units, but seemed also substantial in general wards despite prophylaxis.
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A remarkably high incidence of venous thromboembolism (VTE) has been reported among critically ill patients with COVID‐19 assisted in the intensive care unit (ICU).,However, VTE burden among non‐ICU patients hospitalized for COVID‐19 that receive guideline‐recommended thromboprophylaxis is unknown.,To determine the incidence of VTE among non‐ICU patients hospitalized for COVID‐19 that receive pharmacological thromboprophylaxis.,We performed a systematic screening for the diagnosis of deep vein thrombosis (DVT) by lower limb vein compression ultrasonography (CUS) in consecutive non‐ICU patients hospitalized for COVID‐19, independent of the presence of signs or symptoms of DVT.,All patients were receiving pharmacological thromboprophylaxis with either enoxaparin or fondaparinux.,The population that we screened consisted of 84 consecutive patients, with a mean age of 67.6 ± 13.5 years and a mean Padua Prediction Score of 5.1 ± 1.6.,Seventy‐two patients (85.7%) had respiratory insufficiency, required oxygen supplementation, and had reduced mobility or were bedridden.,In this cohort, we found 10 cases of DVT, with an incidence of 11.9% (95% confidence interval [CI] 4.98‐18.82).,Of these, 2 were proximal DVT (incidence rate 2.4%, 95% CI −0.87‐5.67) and 8 were distal DVT (incidence rate 9.5%, 95% CI 3.23‐5.77).,Significant differences between subjects with and without DVT were D‐dimer > 3000 µg/L (P < .05), current or previous cancer (P < .05), and need of high flow nasal oxygen therapy and/or non‐invasive ventilation (P < .01).,DVT may occur among non‐ICU patients hospitalized for COVID‐19, despite guideline‐recommended thromboprophylaxis.
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The outbreak of the novel coronavirus in China (SARS‐CoV‐2) that began in December 2019 presents a significant and urgent threat to global health.,This study was conducted to provide the international community with a deeper understanding of this new infectious disease.,Epidemiological, clinical features, laboratory findings, radiological characteristics, treatment, and clinical outcomes of 135 patients in northeast Chongqing were collected and analyzed in this study.,A total of 135 hospitalized patients with COVID‐19 were enrolled.,The median age was 47 years (interquartile range, 36‐55), and there was no significant gender difference (53.3% men).,The majority of patients had contact with people from the Wuhan area.,Forty‐three (31.9%) patients had underlying disease, primarily hypertension (13 [9.6%]), diabetes (12 [8.9%]), cardiovascular disease (7 [5.2%]), and malignancy (4 [3.0%]).,Common symptoms included fever (120 [88.9%]), cough (102 [76.5%]), and fatigue (44 [32.5%]).,Chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs of all the patients.,All patients received antiviral therapy (135 [100%]) (Kaletra and interferon were both used), antibacterial therapy (59 [43.7%]), and corticosteroids (36 [26.7%]).,In addition, many patients received traditional Chinese medicine (TCM) (124 [91.8%]).,It is suggested that patients should receive Kaletra early and should be treated by a combination of Western and Chinese medicines.,Compared to the mild cases, the severe ones had lower lymphocyte counts and higher plasma levels of Pt, APTT, d‐dimer, lactate dehydrogenase, PCT, ALB, C‐reactive protein, and aspartate aminotransferase.,This study demonstrates the clinic features and therapies of 135 COVID‐19 patients.,Kaletra and TCM played an important role in the treatment of the viral pneumonia.,Further studies are required to explore the role of Kaletra and TCM in the treatment of COVID‐19.,83.7% of the patients had contact history in Wuhan or had been to Wuhan or had contact with people from Wuhan.Common symptoms included fever, cough, and fatigue.,Other symptoms include myalgia, fatigue, dyspnea, anorexia, etc.Common complications of the patients include acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, secondary infection and shock.,ICU patients were more likely to have these complications than non‐ICU patients.Compared with non‐ICU patients, ICU patients had lower lymphocyte count, and higher plasma levels of the Pt, APTT, D‐dimer, LDH, PCT, ALB, CRP, AST.All patients received antiviral therapy (kaletra or interferon), antibacterial therapy and corticosteroid and many received traditional chinese medicine.,It was suggested that patients should use kaletra early.,83.7% of the patients had contact history in Wuhan or had been to Wuhan or had contact with people from Wuhan.,Common symptoms included fever, cough, and fatigue.,Other symptoms include myalgia, fatigue, dyspnea, anorexia, etc.,Common complications of the patients include acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, secondary infection and shock.,ICU patients were more likely to have these complications than non‐ICU patients.,Compared with non‐ICU patients, ICU patients had lower lymphocyte count, and higher plasma levels of the Pt, APTT, D‐dimer, LDH, PCT, ALB, CRP, AST.,All patients received antiviral therapy (kaletra or interferon), antibacterial therapy and corticosteroid and many received traditional chinese medicine.,It was suggested that patients should use kaletra early.
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This case series study evaluates the association of underlying cardiovascular disease and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19).,What is the impact of underlying cardiovascular disease (CVD) and myocardial injury on fatal outcomes in patients with coronavirus disease 2019 (COVID-19)?,In this case series study of 187 patients with COVID-19, 27.8% of patients had myocardial injury, which resulted in cardiac dysfunction and arrhythmias.,Myocardial injury has a significant association with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury were relatively favorable.,It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive strategies.,Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents.,Information regarding the impact of cardiovascular complication on fatal outcome is scarce.,To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19.,This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020.,Analysis began February 25, 2020.,Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels.,Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died.,The mean (SD) age was 58.50 (14.66) years.,Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels.,The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs.,Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]).,Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (β = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (β = 0.613, P < .001).,Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16).,During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels.,The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13).,Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable.,Myocardial injury is associated with cardiac dysfunction and arrhythmias.,Inflammation may be a potential mechanism for myocardial injury.,Aggressive treatment may be considered for patients at high risk of myocardial injury.
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The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population.,In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic.,All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic.,Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications.,Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria.,Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.,Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020.,Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both.,The two groups differed in disease incidence (group 1 vs group 2, 0·3 vs ten per month), mean age (3·0 vs 7·5 years), cardiac involvement (two of 19 vs six of ten), KDSS (zero of 19 vs five of ten), MAS (zero of 19 vs five of ten), and need for adjunctive steroid treatment (three of 19 vs eight of ten; all p<0·01).,In the past month we found a 30-fold increased incidence of Kawasaki-like disease.,Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS.,The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease.,A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic.,None.
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Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis.,In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy.,Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease.,Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.,•COVID-19 may predispose patients to arterial and venous thrombosis.,•Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,•Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,•The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic.,COVID-19 may predispose patients to arterial and venous thrombosis.,Initial series suggest the common occurrence of venous thromboembolic disease in patients with severe COVID-19.,The optimal preventive strategy warrants further investigation.,Drug-drug interactions between antiplatelet agents and anticoagulants with investigational COVID-19 therapies should be considered.,The available technology should be used optimally to care for patients without COVID-19 who have thrombotic disease during the pandemic.
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Coronavirus disease 2019 (COVID‐19) can lead to systemic coagulation activation and thrombotic complications.,To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID‐19.,Single‐center cohort study of 198 hospitalized patients with COVID‐19.,Seventy‐five patients (38%) were admitted to the intensive care unit (ICU).,At time of data collection, 16 (8%) were still hospitalized and 19% had died.,During a median follow‐up of 7 days (IQR, 3‐13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis.,The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10‐22), 33% (95% CI, 23‐43) and 42% (95% CI 30‐54) respectively.,For symptomatic VTE, these were 10% (95% CI, 5.8‐16), 21% (95% CI, 14‐30) and 25% (95% CI 16‐36).,VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02‐5.5).,The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17‐37), 47% (95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21) at 7, 14, and 21 days).,The observed risk for VTE in COVID‐19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE.,Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.
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One of the defining features of the novel coronavirus disease 2019 infection has been high rates of venous thromboses.,The present study aimed to describe the prevalence of venous thromboembolism in critically ill patients receiving different regimens of prophylactic anticoagulation.,Single-center retrospective review using data from patients with confirmed severe acute respiratory syndrome coronavirus 2 requiring intubation.,Tertiary-care center in Indianapolis, IN, United States.,Patients hospitalized at international units Health Methodist Hospital with severe acute respiratory syndrome coronavirus 2 requiring intubation between March 23, 2020, and April 8, 2020, who underwent ultrasound evaluation for venous thrombosis.,None.,A total of 45 patients were included.,Nineteen of 45 patients (42.2%) were found to have deep venous thrombosis.,Patients found to have deep venous thrombosis had no difference in time to intubation (p = 0.97) but underwent ultrasound earlier in their hospital course (p = 0.02).,Sequential Organ Failure Assessment scores were similar between the groups on day of intubation and day of ultrasound (p = 0.44 and p = 0.07, respectively). d-dimers were markedly higher in patients with deep venous thrombosis, both for maximum value and value on day of ultrasound (p < 0.01 for both).,Choice of prophylactic regimen was not related to presence of deep venous thrombosis (p = 0.35).,Ultrasound evaluation is recommended if d-dimer is greater than 2,000 ng/mL (sensitivity 95%, specificity 46%) and empiric anticoagulation considered if d-dimer is greater than 5,500 ng/mL (sensitivity 53%, specificity 88%).,Deep venous thrombosis is very common in critically ill patients with coronavirus disease 2019.,There was no difference in incidence of deep venous thrombosis among different pharmacologic prophylaxis regimens, although our analysis is limited by small sample size. d-dimer values are elevated in the majority of these patients, but there may be thresholds at which screening ultrasound or even empiric systemic anticoagulation is indicated.
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Critically ill COVID-19 patients have a clear pattern of inflammation and hypercoagulable state.,The main aim of the study was to evaluate the outcome of severe COVID-19 patients basing on prothrombotic risk factors (i.e.,D-dimer).,We also evaluated the impact of different doses of low molecular weight heparin (LMWH) on the incidence of bleedings.,The data of forty-two patients admitted to the Intensive Care Unit (ICU) were retrospectively analyzed.,On ICU admission, patients with D-dimer < 3000 ng/mL (Group 1) received enoxaparin 4000 UI (6000 UI, if body mass index >35) subcutaneously b.i.d. and patients with D-dimer ≥ 3000 ng/mL (Group 2) received enoxaparin 100 UI/kg every 12 h.,Aspirin was administered to all patients once a day.,Both groups presented a high incidence of perivascular thrombosis (40.9% in Group 1 and 30% in Group 2).,Patients of Group 2 suffered a higher incidence of venous thromboembolism (VTE) than Group 1 (65% vs 13.6%, p = 0.001).,One patient (4.5%) of Group 1 and three patients (15%) of Group 2 suffered from minor bleeding; no patient had major bleeding.,Group 2 had a longer ICU and hospital stay than Group 1 (11.5 ± 5.6 vs 9.0 ± 4.8 and 30 ± 4.9 vs 21 ± 2.3, p < 0.05, respectively) as well as increased ICU mortality (25% vs 9.1%).,More severe critically ill COVID-19 patients have a high incidence of VTE and worse outcome, despite the use of heparin at the therapeutic dose.,However, the use of heparin did not increase the incidence of bleeding complications.,•Risk stratification based on D-dimer values is fundamental in critically ill patients with COVID-19 pneumonia.,•High-risk patients have a higher incidence of thromboembolic events and worse outcome compared with low risk ones.,•The use of heparin in therapeutic doses did not lead to an increase of bleeding risk.,Risk stratification based on D-dimer values is fundamental in critically ill patients with COVID-19 pneumonia.,High-risk patients have a higher incidence of thromboembolic events and worse outcome compared with low risk ones.,The use of heparin in therapeutic doses did not lead to an increase of bleeding risk.
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Severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019 (COVID-19)-induced infection can be associated with a coagulopathy, findings consistent with infection-induced inflammatory changes as observed in patients with disseminated intravascular coagulopathy (DIC).,The lack of prior immunity to COVID-19 has resulted in large numbers of infected patients across the globe and uncertainty regarding management of the complications that arise in the course of this viral illness.,The lungs are the target organ for COVID-19; patients develop acute lung injury that can progress to respiratory failure, although multiorgan failure can also occur.,The initial coagulopathy of COVID-19 presents with prominent elevation of D-dimer and fibrin/fibrinogen-degradation products, whereas abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations.,Coagulation test screening, including the measurement of D-dimer and fibrinogen levels, is suggested.,COVID-19-associated coagulopathy should be managed as it would be for any critically ill patient, following the established practice of using thromboembolic prophylaxis for critically ill hospitalized patients, and standard supportive care measures for those with sepsis-induced coagulopathy or DIC.,Although D-dimer, sepsis physiology, and consumptive coagulopathy are indicators of mortality, current data do not suggest the use of full-intensity anticoagulation doses unless otherwise clinically indicated.,Even though there is an associated coagulopathy with COVID-19, bleeding manifestations, even in those with DIC, have not been reported.,If bleeding does occur, standard guidelines for the management of DIC and bleeding should be followed.
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SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS).,We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19.,ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany.,Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs.,Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days.,Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score.,Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death.,Analyses were done on a modified intention-to-treat basis.,This trial is registered with ClinicalTrials.gov, NCT04353596.,Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition.,Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42).,There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12).,Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023).,At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017).,There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group.,Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery.,The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options.,Austrian Science Fund and German Center for Cardiovascular Research.
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Supplemental Digital Content is available in the text.,After initially hypothesizing a positive relationship between use of renin-angiotensin-aldosterone system inhibitors and risk of coronavirus disease 2019 (COVID-19), more recent evidence suggests negative associations.,We examined whether COVID-19 risk differs according to antihypertensive drug class in patients treated by ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) compared with calcium channel blockers (CCBs).,Three exclusive cohorts of prevalent ACE inhibitors, ARB and CCB users, aged 18 to 80 years, from the French National Health Insurance databases were followed from February 15, 2020 to June 7, 2020.,We excluded patients with a history of diabetes, known cardiovascular disease, chronic renal failure, or chronic respiratory disease during the previous 5 years, to only consider patients treated for uncomplicated hypertension and to limit indication bias.,The primary end point was time to hospitalization for COVID-19.,The secondary end point was time to intubation/death during a hospital stay for COVID-19.,In a population of almost 2 million hypertensive patients (ACE inhibitors: 566 023; ARB: 958 227; CCB: 358 306) followed for 16 weeks, 2338 were hospitalized and 526 died or were intubated for COVID-19.,ACE inhibitors and ARBs were associated with a lower risk of COVID-19 hospitalization compared with CCBs (hazard ratio, 0.74 [95% CI, 0.65-0.83] and 0.84 [0.76-0.93], respectively) and a lower risk of intubation/death.,Risks were slightly lower for ACE inhibitor users than for ARB users.,This large observational study may suggest a lower COVID-19 risk in hypertensive patients treated over a long period with ACE inhibitors or ARBs compared with CCBs.,These results, if confirmed, tend to contradict previous hypotheses and raise new hypotheses.
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Coronavirus disease 2019 (COVID‐19) can lead to systemic coagulation activation and thrombotic complications.,To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID‐19.,Single‐center cohort study of 198 hospitalized patients with COVID‐19.,Seventy‐five patients (38%) were admitted to the intensive care unit (ICU).,At time of data collection, 16 (8%) were still hospitalized and 19% had died.,During a median follow‐up of 7 days (IQR, 3‐13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis.,The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10‐22), 33% (95% CI, 23‐43) and 42% (95% CI 30‐54) respectively.,For symptomatic VTE, these were 10% (95% CI, 5.8‐16), 21% (95% CI, 14‐30) and 25% (95% CI 16‐36).,VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02‐5.5).,The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17‐37), 47% (95% CI, 34‐58), and 59% (95% CI, 42‐72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4‐15), 9.2% (95% CI, 2.6‐21), and 9.2% (2.6‐21) at 7, 14, and 21 days).,The observed risk for VTE in COVID‐19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE.,Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.
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COVID-19 may predispose patients to an increased risk of thrombotic complications through various pathophysiological mechanisms.,Most of the reports on a high incidence of thrombotic complications are in relation to deep vein thrombosis and pulmonary embolism, while the evidence about arterial thrombosis in patients with COVID-19 is limited.,We describe 4 cases of aortic thrombosis and associated ischemic complications in patients with severe SARS-CoV-2 infection.
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Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality.,A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease.,The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy.,Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis.,Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury.,Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum.,Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists.,Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective.,This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment.,From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.
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The aim of this study was to investigate whether right ventricular longitudinal strain (RVLS) was independently predictive of higher mortality in patients with coronavirus disease-2019 (COVID-19).,RVLS obtained from 2-dimensional speckle-tracking echocardiography has been recently demonstrated to be a more accurate and sensitive tool to estimate right ventricular (RV) function.,The prognostic value of RVLS in patients with COVID-19 remains unknown.,One hundred twenty consecutive patients with COVID-19 who underwent echocardiographic examinations were enrolled in our study.,Conventional RV functional parameters, including RV fractional area change, tricuspid annular plane systolic excursion, and tricuspid tissue Doppler annular velocity, were obtained.,RVLS was determined using 2-dimensional speckle-tracking echocardiography.,RV function was categorized in tertiles of RVLS.,Compared with patients in the highest RVLS tertile, those in the lowest tertile were more likely to have higher heart rate; elevated levels of D-dimer and C-reactive protein; more high-flow oxygen and invasive mechanical ventilation therapy; higher incidence of acute heart injury, acute respiratory distress syndrome, and deep vein thrombosis; and higher mortality.,After a median follow-up period of 51 days, 18 patients died.,Compared with survivors, nonsurvivors displayed enlarged right heart chambers, diminished RV function, and elevated pulmonary artery systolic pressure.,Male sex, acute respiratory distress syndrome, RVLS, RV fractional area change, and tricuspid annular plane systolic excursion were significant univariate predictors of higher risk for mortality (p < 0.05 for all).,A Cox model using RVLS (hazard ratio: 1.33; 95% confidence interval [CI]: 1.15 to 1.53; p < 0.001; Akaike information criterion = 129; C-index = 0.89) was found to predict higher mortality more accurately than a model with RV fractional area change (Akaike information criterion = 142, C-index = 0.84) and tricuspid annular plane systolic excursion (Akaike information criterion = 144, C-index = 0.83).,The best cutoff value of RVLS for prediction of outcome was −23% (AUC: 0.87; p < 0.001; sensitivity, 94.4%; specificity, 64.7%).,RVLS is a powerful predictor of higher mortality in patients with COVID-19.,These results support the application of RVLS to identify higher risk patients with COVID-19.
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FGF21 is a critical endogenous regulator in energy homeostasis and systemic glucose and lipid metabolism.,Despite intensive study of the metabolic functions of FGF21, its important role in heart disease needs further exploration.,Apoptosis induced by ox-LDL in vascular endothelial cells is an important step in the progress of atherosclerosis.,The effects of FGF21 treatment on apoptosis induced by ox-LDL were tested in HUVECs.,The role of FGF21 in atherosclerosis was studied by evaluating its function in apolipoprotein E double knockout (apoE−/−) mice.,We found that apoptosis in HUVECs was alleviated by FGF21 treatment.,The effects of FGF21 were independent of the ERK1/2 pathway and were mediated through inhibition of the Fas signaling pathway.,FGF21 suppressed the development of atherosclerosis, and the administration of FGF21 ameliorated Fas-mediated apoptosis in apoE−/− mice.,FGF21 protects against apoptosis in HUVECs by suppressing the expression of Fas; furthermore, FGF21 alleviated atherosclerosis by ameliorating Fas-mediated apoptosis in apoE−/− mice.,The online version of this article (10.1186/s12944-018-0846-x) contains supplementary material, which is available to authorized users.
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Adipose tissue (AT) dysfunction, characterized by loss of its homeostatic functions, is a hallmark of non-communicable diseases.,It is characterized by chronic low-grade inflammation and is observed in obesity, metabolic disorders such as insulin resistance and diabetes.,While classically it has been identified by increased cytokine or chemokine expression, such as increased MCP-1, RANTES, IL-6, interferon (IFN) gamma or TNFα, mechanistically, immune cell infiltration is a prominent feature of the dysfunctional AT.,These immune cells include M1 and M2 macrophages, effector and memory T cells, IL-10 producing FoxP3+ T regulatory cells, natural killer and NKT cells and granulocytes.,Immune composition varies, depending on the stage and the type of pathology.,Infiltrating immune cells not only produce cytokines but also metalloproteinases, reactive oxygen species, and chemokines that participate in tissue remodelling, cell signalling, and regulation of immunity.,The presence of inflammatory cells in AT affects adjacent tissues and organs.,In blood vessels, perivascular AT inflammation leads to vascular remodelling, superoxide production, endothelial dysfunction with loss of nitric oxide (NO) bioavailability, contributing to vascular disease, atherosclerosis, and plaque instability.,Dysfunctional AT also releases adipokines such as leptin, resistin, and visfatin that promote metabolic dysfunction, alter systemic homeostasis, sympathetic outflow, glucose handling, and insulin sensitivity.,Anti-inflammatory and protective adiponectin is reduced.,AT may also serve as an important reservoir and possible site of activation in autoimmune-mediated and inflammatory diseases.,Thus, reciprocal regulation between immune cell infiltration and AT dysfunction is a promising future therapeutic target.
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To assess changes in characteristics and management among ST‐elevation myocardial infarction (STEMI) patients with coronavirus disease (COVID‐19) who underwent primary percutaneous coronary intervention.,Our prospective, monocentric study enrolled all STEMI patients who underwent PPCI during the COVID‐19 outbreak (n = 83).,This cohort was first compared with a previous cohort of STEMI patients (2008-2017, n = 1,552 patients) and was then dichotomized into a non‐COVID‐19 group (n = 72) and COVID‐19 group (n = 11).,In comparison with the pre‐outbreak period, patients during the outbreak period were older (59.6 ± 12.9 vs.,62.6 ± 12.2, p = .03) with a delayed seek to care (mean delay first symptoms‐balloon 3.8 ± 3 vs. .7.4 ± 7.7, p < .001) resulting in a two‐fold higher in‐hospital mortality (non COVID‐19 4.3% vs.,COVID‐19 8.4%, p = .07).,Among the 83 STEMI patients admitted during the outbreak period, 11 patients were infected by COVID‐19.,Higher biological markers of inflammation (C‐reactive protein: 28 ± 39 vs. 98 ± 97 mg/L, p = .04), of fibrinolysis (D‐dimer: 804 ± 1,500 vs. 3,128 ± 2,458 μg/L, p = .02), and antiphospholipid antibodies in four cases were observed in the COVID‐19 group.,In this group, angiographic data also differed: a thrombotic myocardial infarction nonatherosclerotic coronary occlusion (MINOCA) was observed in 11 cases (1.4% vs.,54.5%, p < .001) and associated with higher post‐procedure distal embolization (30.6% vs.,72.7%, p = .007).,The in hospital mortality was significantly higher in the COVID‐19 group (5.6% vs.,27.3%, p = .016).,The COVID‐19 outbreak implies deep changes in the etiopathogenesis and therapeutic management of STEMI patients with COVID‐19.,The impact on early and long‐term outcomes of systemic inflammation and hypercoagulability in this specific population is warranted.
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Data whether the COVID-19 outbreak impacts the acute coronary syndromes (ACS) admissions and the time required to reverse the downward curve are scarce.,We included all consecutive patients referred for an ACS who underwent PCI from February 17, 2020 to April 26, 2020 in a high-volume PCI coronary care unit.,We compared the number of ACS patients in 2020 to the same period in 2018 and 2019.,Predictors of adverse outcome in ST-elevation myocardial infarction (STEMI) patients were recorded: symptom-onset-to-first medical contact (FMC), and FMC-to-sheath insertion times.,During the studied period (calendar weeks 8-17, 2018-2020), 144 ACS patients were included.,In 2020, we observed two distinct phases in the ACS admissions: a first significant fall, with a relative reduction of 73%, from the week of lockdown (week 12) to 3 weeks later and then an increase of ACS.,Median symptom-onset-to-FMC time was significantly higher in 2020 than in the two previous years (600 min [298-632] versus 121 min [55-291], p < 0.001).,Median FMC-to-sheath insertion did not differ significantly (93 min [81-131] in 2020 versus 90 min [67-137] in 2018-2019, p = 0.57).,The main findings are (1) a pattern of a U-curve in ACS admissions, with a first decrease in ACS admissions and a return to “normality” 4 weeks after; (2) a significant increase in the total ischemic time exclusively due to an increase in the symptom-onset-to-first-medical-contact time.
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COVID-19 has rapidly impacted on mortality worldwide.1 There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets.,Working on behalf of NHS England we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major primary care electronic health records vendor.,Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19 related deaths.,COVID-19 related death was associated with: being male (hazard ratio 1.59, 95%CI 1.53-1.65); older age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions.,Compared to people with white ethnicity, black and South Asian people were at higher risk even after adjustment for other factors (HR 1.48, 1.29-1.69 and 1.45, 1.32-1.58 respectively).,We have quantified a range of clinical risk factors for COVID-19 related death in the largest cohort study conducted by any country to date.,OpenSAFELY is rapidly adding further patients’ records; we will update and extend results regularly.
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A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries.,This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition.,Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients.,Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly.,This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2.,The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction.,And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition.,The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.
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Left ventricular free wall rupture (LVFWR) is a rare complication after myocardial infarction and usually occurs 1 to 4 days after the infarct.,Over the past decade, the overall incidence of LVFWR has decreased given the advancements in reperfusion therapies.,However, during the COVID-19 pandemic, there has been a significant delay in hospital presentation of patients suffering myocardial infarctions, leading to a higher incidence of mechanical complications from myocardial infarctions such as LVFWR.,We present a case in which a patient suffered a LVFWR as a mechanical complication from myocardial infarction due to delay in seeking care over fear of contracting COVID-19 from the medical setting.,The patient had been having chest pain for a few days but refused to seek medical care due to fear of contracting COVID-19 from within the medical setting.,He eventually suffered a cardiac arrest at home from a massive inferior myocardial infarction and found to be in cardiac tamponade from a left ventricular perforation.,He was emergently taken to the operating room to attempt to repair the rupture but he ultimately expired on the operating table.,The occurrence of LVFWR has been on a more significant rise over the course of the COVID-19 pandemic as patients delay seeking care over fear of contracting COVID-19 from within the medical setting.,Clinicians should consider mechanical complications of MI when patients present as an out-of-hospital cardiac arrest, particularly during the COVID-19 pandemic, as delay in seeking care is often the exacerbating factor.,The online version contains supplementary material available at 10.1186/s13019-021-01495-x.
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The COVID-19 virus is a devastating pandemic that has impacted the US healthcare system significantly.,More than one study reported a significant decrease in acute coronary syndrome admissions during that pandemic which is still due to unknown reasons.,This is a retrospective non-controlled multi-centered study of 180 patients (117 males and 63 females) with acute coronary syndrome (STEMI and NSTEMI) admitted during March/April of 2019 and March/April 2020 in Upstate New York.,A total of 113 patients (61.9% males, 38.1% females) with a mean age of 72.3 ± 14.2 presented during March/April 2019 with ACS (STEMI + NSTEMI) while only 67 (70.1% males, 29.9% females) COVID-19 negative patients with a mean age of 65.1 ± 14.5 presented during the same period (March/April) in 2020.,This is a drop by 40.7% (P < .05) of total ACS cases during the COVID-19 pandemic.,In NSTEMI patients, 36.4% presented late (>24 hours of symptoms) during the COVID-19 pandemic in comparison with 2019 (27.1%, P = .033).,The COVID-19 pandemic led to a substantial drop by 40.7% (P < .05) of total ACS admissions in our area.,This decrease in hospital admissions and late presentations can be a worrisome sign for an increase in future complications of myocardial infarctions.
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In order to cope with the exponentially increasing number of patients infected with SARS‐CoV‐2, European countries made enormous efforts to reorganize medical assistance and several diseases, including stroke, were particularly impacted.,We report the experience of stroke neurologists from three European countries (Italy, France and Germany) that faced the pandemic at diverse time points and with different approaches, depending on their resources and healthcare system organization.,Pre‐hospital and in‐hospital acute stroke pathways were reorganized to prioritize COVID‐19 management and, in severely affected regions of Italy and France, stroke care was centralized to a limited number of centers, whereas the remaining stroke units were dedicated to patients with COVID‐19.,Access to acute stroke diagnostics and time‐dependent therapies was limited or delayed because of reduced capacities of emergency services due to the burden of patients with COVID‐19.,A marked reduction in the number of patients presenting with transient ischaemic attack and stroke was noted in the emergency departments of all three countries.,Although we only have preliminary data, these conditions may have affected stroke outcome.,These indirect effects of the COVID‐19 pandemic could negate the efforts of stroke neurologists over the last few years to improve outcome and reduce mortality of stroke patients.,Although the SARS‐CoV‐2 infection rate is slowing down in Europe, the effects of ending lockdown in the next months are unpredictable.,It is important for the European and world stroke community to share what has been learned so far to be plan strategies to ensure stroke care in the future and upcoming challenging times.
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The COVID-19 pandemic has disrupted established care paths worldwide.,Patient awareness of the pandemic and executive limitations imposed on public life have changed the perception of when to seek care for acute conditions in some cases.,We sought to study whether there is a delay in presentation for acute ischemic stroke patients in the first month of the pandemic in the US.,The interval between last-known-well (LKW) time and presentation of 710 consecutive patients presenting with acute ischemic strokes to 12 stroke centers across the US were extracted from a prospectively maintained quality database.,We analyzed the timing and severity of the presentation in the baseline period from February to March 2019 and compared results with the timeframe of February and March 2020.,There were 320 patients in the 2-month baseline period in 2019, there was a marked decrease in patients from February to March of 2020 (227 patients in February, and 163 patients in March).,There was no difference in the severity of the presentation between groups and no difference in age between the baseline and the COVID period.,The mean interval from LKW to the presentation was significantly longer in the COVID period (603±1035 min) compared with the baseline period (442±435 min, P<0.02).,We present data supporting an association between public awareness and limitations imposed on public life during the COVID-19 pandemic in the US and a delay in presentation for acute ischemic stroke patients to a stroke center.
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SARS-CoV-2, the virus responsible for novel Coronavirus (COVID-19) infection, has recently been associated with a myriad of hematologic derangements; in particular, an unusually high incidence of venous thromboembolism has been reported in patients with COVID-19 infection.,It is postulated that either the cytokine storm induced by the viral infection or endothelial damage caused by viral binding to the ACE-2 receptor may activate a cascade leading to a hypercoaguable state.,Although pulmonary embolism and deep venous thrombosis have been well described in patients with COVID-19 infection, there is a paucity of literature on cerebral venous sinus thrombosis (cVST) associated with COVID-19 infection. cVST is an uncommon etiology of stroke and has a higher occurrence in women and young people.,We report a series of three patients at our institution with confirmed COVID-19 infection and venous sinus thrombosis, two of whom were male and one female.,These cases fall outside the typical demographic of patients with cVST, potentially attributable to COVID-19 induced hypercoaguability.,This illustrates the importance of maintaining a high index of suspicion for cVST in patients with COVID-19 infection, particularly those with unexplained cerebral hemorrhage, or infarcts with an atypical pattern for arterial occlusive disease.
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There has been increasing reports associating the coronavirus disease 2019 (COVID-19) with thromboembolic phenomenon including ischemic strokes and venous thromboembolism.,Cerebral venous thrombosis (CVT) is a rare neurovascular emergency that has been observed in some COVID-19 patients, yet much remains to be learnt of its underlying pathophysiology.,We present a case series of local patients with concomitant COVID-19 infection and CVT; and aim to perform a systematic review of known cases in the current literature.,We describe two patients with concomitant COVID-19 infection and CVT from a nationwide registry in Singapore.,We then conducted a literature search in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 11th June 2020.,All studies reporting CVT in COVID-19 patients were included.,Nine studies and 14 COVID-19 patients with CVT were studied.,The median age was 43 years (IQR=36-58) and majority had no significant past medical conditions (60.0%).,The time taken from onset of COVID-19 symptoms to CVT diagnosis was a median of 7 days (IQR=6-14).,CVT was commonly seen in the transverse (75.0%) and sigmoid sinus (50.0%); 33.3% had involvement of the deep venous sinus system.,A significant proportion of patients had raised D-dimer (75.0%) and CRP levels (50.0%).,Two patients reported presence of antiphospholipid antibodies.,Most patients received anticoagulation (91.7%) while overall mortality rate was 45.5%.,The high mortality rate of CVT in COVID-19 infection warrants a high index of suspicion from physicians, and early treatment with anticoagulation should be initiated.
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The coronavirus disease 2019 (COVID-19) pandemic would have particularly affected acute stroke care.,However, its impact is clearly inherent to the local stroke network conditions.,We aimed to assess the impact of COVID-19 pandemic on acute stroke care in the Lyon comprehensive stroke center during this period.,We conducted a prospective data collection of patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) during the COVID-19 period (from 29/02/2020 to 10/05/2020) and a control period (from 29/02/2019 to 10/05/2019).,The volume of reperfusion therapies and pre and intra-hospital delays were compared during both periods.,A total of 208 patients were included.,The volume of IVT significantly decreased during the COVID-period [55 (54.5%) vs 74 (69.2%); p = 0.03].,The volume of MT remains stable over the two periods [72 (71.3%) vs 65 (60.8%); p = 0.14], but the door-to-groin puncture time increased in patients transferred for MT (237 [187-339] vs 210 [163-260]; p < 0.01).,The daily number of Emergency Medical Dispatch calls considerably increased (1502 [1133-2238] vs 1023 [960-1410]; p < 0.01).,Our study showed a decrease in the volume of IVT, whereas the volume of MT remained stable although intra-hospital delays increased for transferred patients during the COVID-19 pandemic.,These results contrast in part with the national surveys and suggest that the impact of the pandemic may depend on local stroke care networks.
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Little is known about the effect of the Coronavirus disease 2019 pandemic on stroke care and the impact of the epidemic on acute stroke hospitalizations has not been described.,We analyze the stroke admission rate in three hospitals in New York City from January 1, 2020 through April 17, 2020, identifying all cases of acute ischemic stroke, intraparenchymal hemorrhage and subarachnoid hemorrhage.,We confirmed 518 cases of out-of-hospital stroke.,During the baseline period up to February 25, 2020, the daily stroke admission rate was stable, with the slope of the regression describing the number of admissions over time equal to -0.33 (se = 1.21), not significantly different from 0 (p = 0.79), with daily admissions averaging 41.,During the pandemic period, the slope was -4.4 (se = 1.00); i.e., the number of stroke admissions decreased an average of 4.4 per week, (p = 0.005), with weekly admissions averaging 23, a reduction of 44% versus baseline.,This general result was not different by patient age, sex, or race/ethnicity.,The weekly stroke admission rate started declining two weeks prior to the local surge of coronavirus admissions.,The consequences of lack of diagnosis and treatment of a large proportion of acute stroke patients are likely severe and lasting.
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Coronavirus disease 2019 (COVID-19) is a viral infection that can, in severe cases, result in cytokine storm, systemic inflammatory response and coagulopathy that is prognostic of poor outcomes.,While some, but not all, laboratory findings appear similar to sepsis-associated disseminated intravascular coagulopathy (DIC), COVID-19- induced coagulopathy (CIC) appears to be more prothrombotic than hemorrhagic.,It has been postulated that CIC may be an uncontrolled immunothrombotic response to COVID-19, and there is growing evidence of venous and arterial thromboembolic events in these critically ill patients.,Clinicians around the globe are challenged with rapidly identifying reasonable diagnostic, monitoring and anticoagulant strategies to safely and effectively manage these patients.,Thoughtful use of proven, evidence-based approaches must be carefully balanced with integration of rapidly emerging evidence and growing experience.,The goal of this document is to provide guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of anticoagulant therapies in patients with COVID-19.,We discuss in-hospital and post-discharge venous thromboembolism (VTE) prevention, treatment of suspected but unconfirmed VTE, laboratory monitoring of COVID-19, associated anticoagulant therapies, and essential elements for optimized transitions of care specific to patients with COVID-19.
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Few data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19.,We studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02.2020-10.04.2020).,The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI).,Secondary outcome was overt disseminated intravascular coagulation (DIC).,We included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]).,Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward.,Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%-11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward).,Half of the thromboembolic events were diagnosed within 24 h of hospital admission.,Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%).,Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA).,The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively.,Overt DIC was present in 8 (2.2%) patients.,The high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 h of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.,•COVID-19 is characterized by coagulation activation and endothelial dysfunction.,Few data are available on thromboembolic complications.,•We studied symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02-10.04.2020).,•Venous and arterial thromboembolic events occurred in 8% of hospitalized patients (cumulative rate 21.0%) and 50% of events were diagnosed within 24 h of hospital admission.,•Forty-four (11% of total) patients underwent VTE imaging tests; 16 were positive (36% of tests), suggesting underestimation of thromboembolic complications.,•There is an urgent need to investigate VTE diagnostic strategies and the impact of thromboprophylaxis in ambulatory COVID-19 patients.,COVID-19 is characterized by coagulation activation and endothelial dysfunction.,Few data are available on thromboembolic complications.,We studied symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02-10.04.2020).,Venous and arterial thromboembolic events occurred in 8% of hospitalized patients (cumulative rate 21.0%) and 50% of events were diagnosed within 24 h of hospital admission.,Forty-four (11% of total) patients underwent VTE imaging tests; 16 were positive (36% of tests), suggesting underestimation of thromboembolic complications.,There is an urgent need to investigate VTE diagnostic strategies and the impact of thromboprophylaxis in ambulatory COVID-19 patients.
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To investigate whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-induced myocarditis constitutes an important mechanism of cardiac injury, a review was conducted of the published data and the authors’ experience was added from autopsy examination of 16 patients dying of SARS-CoV-2 infection.,Myocarditis is an uncommon pathologic diagnosis occurring in 4.5% of highly selected cases undergoing autopsy or endomyocardial biopsy.,Although polymerase chain reaction-detectable virus could be found in the lungs of most coronavirus disease-2019 (COVID-19)-infected subjects in our own autopsy registry, in only 2 cases was the virus detected in the heart.,It should be appreciated that myocardial inflammation alone by macrophages and T cells can be seen in noninfectious deaths and COVID-19 cases, but the extent of each is different, and in neither case do such findings represent clinically relevant myocarditis.,Given its extremely low frequency and unclear therapeutic implications, the authors do not advocate use of endomyocardial biopsy to diagnose myocarditis in the setting of COVID-19.
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Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis.,However, the mechanisms of myocardial injury remain unclear and prior studies have not reported cardiovascular imaging data.,This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19.,We conducted an international, multicenter cohort study including 7 hospitals in New York City and Milan of hospitalized patients with laboratory-confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and electrocardiographic evaluation during their index hospitalization.,Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization.,A total of 305 patients were included.,Mean age was 63 years and 205 patients (67.2%) were male.,Overall, myocardial injury was observed in 190 patients (62.3%).,Compared with patients without myocardial injury, those with myocardial injury had more electrocardiographic abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities that included left ventricular wall motion abnormalities, global left ventricular dysfunction, left ventricular diastolic dysfunction grade II or III, right ventricular dysfunction and pericardial effusions.,Rates of in-hospital mortality were 5.2%, 18.6%, and 31.7% in patients without myocardial injury, with myocardial injury without TTE abnormalities, and with myocardial injury and TTE abnormalities.,Following multivariable adjustment, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities.,Among patients with COVID-19 who underwent TTE, cardiac structural abnormalities were present in nearly two-thirds of patients with myocardial injury.,Myocardial injury was associated with increased in-hospital mortality particularly if echocardiographic abnormalities were present.
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Coronavirus disease 2019 (COVID-19) is associated with a prothrombotic state with a high incidence of thrombotic events during hospitalization; however, data examining rates of thrombosis after discharge are limited.,We conducted a retrospective observational cohort study of discharged patients with confirmed COVID-19 not receiving anticoagulation.,The cohort included 163 patients with median time from discharge to last recorded follow-up of 30 days (interquartile range [IQR], 17-46 days).,The median duration of index hospitalization was 6 days (IQR, 3-12 days) and 26% required intensive care.,The cumulative incidence of thrombosis (including arterial and venous events) at day 30 following discharge was 2.5% (95% confidence interval [CI], 0.8-7.6); the cumulative incidence of venous thromboembolism alone at day 30 postdischarge was 0.6% (95% CI, 0.1-4.6).,The 30-day cumulative incidence of major hemorrhage was 0.7% (95% CI, 0.1-5.1) and of clinically relevant nonmajor bleeds was 2.9% (95% CI, 1.0-9.1).,We conclude that the rates of thrombosis and hemorrhage appear to be similar following hospital discharge for COVID-19, emphasizing the need for randomized data to inform recommendations for universal postdischarge thromboprophylaxis.,•Cumulative incidence of overall thrombosis was 2.5% and of bleeding was 3.7% at day 30 after discharge for hospitalization for COVID-19.,•These data highlight the importance of a data-driven risk-benefit ratio assessment for postdischarge extended thromboprophylaxis.,Cumulative incidence of overall thrombosis was 2.5% and of bleeding was 3.7% at day 30 after discharge for hospitalization for COVID-19.,These data highlight the importance of a data-driven risk-benefit ratio assessment for postdischarge extended thromboprophylaxis.
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Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE.,This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE.,A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19.,MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion.,Validated evaluation tools were used to grade the level of evidence to support each recommendation.,When evidence did not exist, guidance was developed based on consensus using the modified Delphi process.,The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements.,Very little evidence exists in the COVID-19 population.,The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements.,The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving.
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Stroke is a major disease that leads to high mortality and morbidity.,Given the ageing population and the potential risk factors, the prevalence of stroke and socioeconomic burden associated with stroke are expected to increase.,During the past decade, both prophylactic and therapeutic strategies for stroke have made significant progress.,However, current therapies still cannot adequately improve the outcomes of stroke and may not apply to all patients.,One of the significant advances in modern medicine is cell-derived neurovascular regeneration and neuronal repair.,Progress in stem cell biology has greatly contributed to ameliorating stroke-related brain injuries in preclinical studies and demonstrated clinical potential in stroke treatment.,Mesenchymal stem cells (MSCs) have the differentiating potential of chondrocytes, adipocytes, and osteoblasts, and they have the ability to transdifferentiate into endothelial cells, glial cells, and neurons.,Due to their great plasticity, MSCs have drawn much attention from the scientific community.,This review will focus on MSCs, stem cells widely utilized in current medical research, and evaluate their effect and potential of improving outcomes in ischemic stroke.
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Mesenchymal stem cells have previously been shown to mediate brain repair after stroke; they secrete 50-100 nm complexes called extracellular vesicles (EVs), which could be responsible for provoking neurovascular repair and functional recovery.,EVs have been observed by electron microscopy and NanoSight, and they contain associated proteins such as CD81 and Alix.,This purified, homogeneous population of EVs was administered intravenously after subcortical stroke in rats.,To evaluate the EVs effects, we studied the biodistribution, proteomics analysis, functional evaluation, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers.,We found that a single administration of EVs improved functional recovery, fiber tract integrity, axonal sprouting and white matter repair markers in an experimental animal model of subcortical stroke.,EVs were found in the animals’ brain and peripheral organs after euthanasia.,White matter integrity was in part restored by EVs administration mediated by molecular repair factors implicated in axonal sprouting, tract connectivity, remyelination and oligodendrogenesis.,These findings are associated with improved functional recovery.,This novel role for EVs presents a new perspective in the development of biologics for brain repair.
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Can Kawasaki disease be accurately diagnosed on the basis of the pattern of host gene expression in whole blood?,In this case-control study of 606 children (404 in the discovery cohort; 202 in the validation cohort), a 13-transcript signature was identified that accurately discriminated Kawasaki disease from comparator febrile diseases in discovery and validation cohorts.,A diagnostic blood test based on measurement of small numbers of host gene transcripts might enable early discrimination of Kawasaki disease from other infectious and inflammatory conditions.,This case-control study identifies a whole-blood gene expression signature that distinguishes children with Kawasaki disease in the first week of illness from other febrile conditions.,To date, there is no diagnostic test for Kawasaki disease (KD).,Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms.,To identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.,The case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness.,The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States.,The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls.,The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls.,The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017.,Whole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search).,The ability of transcript signatures (implemented as disease risk scores) to discriminate KD cases from controls was assessed by area under the curve (AUC), sensitivity, and specificity at the optimal cut point according to the Youden index.,Among 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male).,Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male).,A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set, with AUC of 96.2% (95% CI, 92.5%-99.9%), sensitivity of 81.7% (95% CI, 60.0%-94.8%), and specificity of 92.1% (95% CI, 84.0%-97.0%).,In the validation set, the signature distinguished KD from febrile controls, with AUC of 94.6% (95% CI, 91.3%-98.0%), sensitivity of 85.9% (95% CI, 76.8%-92.6%), and specificity of 89.1% (95% CI, 83.0%-93.7%).,The signature was applied to clinically defined categories of definite, highly probable, and possible KD, resulting in AUCs of 98.1% (95% CI, 94.5%-100%), 96.3% (95% CI, 93.3%-99.4%), and 70.0% (95% CI, 53.4%-86.6%), respectively, mirroring certainty of clinical diagnosis.,In this study, a 13-transcript blood gene expression signature distinguished KD from other febrile conditions.,Diagnostic accuracy increased with certainty of clinical diagnosis.,A test incorporating the 13-transcript disease risk score may enable earlier diagnosis and treatment of KD and reduce inappropriate treatment in those with other diagnoses.
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Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology.,Intravenous immunoglobulin (IVIG) is an effective treatment and decreases the risk of cardiac complications to less than 5%.,In spite of its effectiveness, some children do not respond to this therapy and still develop coronary aneurysms (CAA).,The optimal treatment for IVIG non-responsive patients remains controversial although corticoids have been suggested to be an effective treatment in some patients.,For those patients still resistant to IVIG and corticoids, interleukin-1 receptor antagonists (IL-1RA) such anakinra could be an alternative.,We present a 3 year-old Caucasian patient with KD without cardiac complications but with important resistance to treatment.,After becoming resistant to IVIG and corticoids, anakinra proved to be an effective treatment.,To our knowledge, this is the first report of the utility of IL-1RA in refractory KD without coronary impairment.,The patient fulfilled the classical criteria for KD and, after becoming resistant to first and second line treatments, anakinra proved to be an effective treatment.,Further studies are required to determine if this is an effective treatment option for other cases of resistant Kawasaki disease.
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Supplemental Digital Content is available in the text.,The full spectrum of coronavirus disease 2019 (COVID-19) infection ranges from asymptomatic to acute respiratory distress syndrome, characterized by hyperinflammation and thrombotic microangiopathy.,The pathogenic mechanisms are poorly understood, but emerging evidence suggest that excessive neutrophil extracellular trap (NET) formation plays a key role in COVID-19 disease progression.,Here, we evaluate if circulating markers of NETs are associated with COVID-19 disease severity and clinical outcome, as well as to markers of inflammation and in vivo coagulation and fibrinolysis.,One hundred six patients with COVID-19 with moderate to severe disease were enrolled shortly after hospital admission and followed for 4 months.,Acute and convalescent plasma samples as well as plasma samples from 30 healthy individuals were assessed for markers of NET formation: citrullinated histone H3, cell-free DNA, NE (neutrophil elastase).,We found that all plasma levels of NET markers were elevated in patients with COVID-19 relative to healthy controls, that they were associated with respiratory support requirement and short-term mortality, and declined to those found in healthy individuals 4 months post-infection.,The levels of the NET markers also correlated with white blood cells, neutrophils, inflammatory cytokines, and C-reactive protein, as well as to markers of in vivo coagulation, fibrinolysis, and endothelial damage.,Our findings suggest a role of NETs in COVID-19 disease progression, implicating their contribution to an immunothrombotic state.,Further, we observed an association between circulating markers of NET formation and clinical outcome, demonstrating a potential role of NET markers in clinical decision-making, as well as for NETs as targets for novel therapeutic interventions in COVID-19.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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The American Heart Association recognizes high triglycerides as a cardiovascular risk factor.,This retrospective observational administrative claims analysis (Optum Research Database) included statin‐treated patients ≥45 years old with diabetes mellitus and/or atherosclerotic cardiovascular disease, triglycerides 2.26 to 5.64 mmol/L, and a propensity‐matched comparator cohort with triglycerides <1.69 mmol/L and high‐density lipoprotein cholesterol >1.04 mmol/L.,In the high‐triglycerides cohort versus comparators (both n=10 990, 49% women), mean age was 61.7 versus 62.2 years and follow‐up was 41.3 versus 42.1 months, respectively.,Multivariate analysis of composite major cardiovascular events demonstrated significantly increased risk in the high‐triglycerides (n=13 411 patients) versus comparator (n=32 506 patients) cohorts (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.225-1.485; P<0.001), with significantly higher risk for nonfatal myocardial infarction (HR, 1.35; 95% CI, 1.19-1.52; P<0.001), nonfatal stroke (HR, 1.27; 95% CI, 1.14-1.42; P<0.001), and need for coronary revascularization (HR, 1.51; 95% CI, 1.34-1.69; P<0.001), but not unstable angina or cardiovascular death.,Increased cardiovascular risk in the high‐triglycerides versus comparator cohort was maintained, even with addition of non-high‐density lipoprotein cholesterol to the multivariate model and when analyzing high and low high‐density lipoprotein cholesterol subgroups.,Average total healthcare cost per patient per month (cost ratio, 1.15; 95% CI, 1.084-1.210; P<0.001) and rate of occurrence of inpatient hospital stay (HR, 1.17; 95% CI, 1.113-1.223; P<0.001) were also significantly greater in the high‐triglycerides cohort.,In this real‐world analysis, patients with high cardiovascular risk and high triglycerides had worse composite cardiovascular and health economic outcomes than patients with well‐managed triglycerides and high‐density lipoprotein cholesterol >1.04 mmol/L.
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Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clinicians in the twenty first century.,Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus.,Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fibrates), but these have low potency and limited selectivity for PPARα.,Modulating the unique receptor-cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, offers a new therapeutic approach and provides the rationale for development of pemafibrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα).,In clinical trials, pemafibrate either as monotherapy or as add-on to statin therapy was effective in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII.,Pemafibrate also increased serum fibroblast growth factor 21, implicated in metabolic homeostasis.,There were no clinically meaningful adverse effects on hepatic or renal function, including no relevant serum creatinine elevation.,A major outcomes study, PROMINENT, will provide definitive evaluation of the role of pemafibrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy.
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SARS‐CoV‐2, the cause of the COVID‐19 pandemic has significantly impacted cardiovascular healthcare.,Patients with pre‐existing cardiovascular disease are at higher risk of morbidity and mortality.,The virus may affect the heart directly and indirectly with clinical syndromes of acute myocardial injury, myocarditis, acute coronary syndromes, heart failure, arrhythmias, and venous thromboembolism.,Some therapeutics under investigation for COVID‐19 may also have adverse cardiac effects.,The involvement of the RAAS system in viral entry makes it pertinent to consider the effects of medications that modulate the system.,Comprehensive knowledge of peculiar cardiovascular manifestations of COVID‐19 and the role of RAAS in the prognosis of COVID‐19 disease is needed for optimal patient management.
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There is concern about the potential of an increased risk related to medications that act on the renin-angiotensin-aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2).,We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive.,Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class.,A difference of at least 10 percentage points was prespecified as a substantial difference.,Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness.,A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness.,There was no association between any single medication class and an increased likelihood of a positive test.,None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.,We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.
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Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk.,Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear.,Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients.,We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl3-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo.,We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count.,Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients.,Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming.,SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo.,Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation.,SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte-platelet aggregates.,Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation.,Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2.,SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients.
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COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation.,Reports on the incidence of thrombotic complications are however not available.,We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.,We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020.,All patients received at least standard doses thromboprophylaxis.,The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%).,PE was the most frequent thrombotic complication (n = 25, 81%).,Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.,The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high.,Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.
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The purpose of our study was to compare diagnostic performance of old and new Lake Louise Criteria (oLLC and nLLC) among different clinical presentations: infarct-like (IL), cardiomyopathic (CM) and arrhythmic (AR). 102 patients with clinical suspicion of acute myocarditis underwent cardiac magnetic resonance (CMR) on a 1.5 T scanner.,Protocol included cine-SSFP, T2-weighted STIR, T2 mapping, early and late gadolinium enhancement and T1 mapping acquired before and after gadolinium administration.,The degree of agreement has been calculated with Cohen’s K test. 42 patients also underwent endomyocardial biopsy (EMB).,IL onset was present in 54/102 patients, CM in 28/102 and AR in 20/102. nLLC were positive in 58.3% of the patients, while oLLC in 37.9%, k = 0.57 (IC: 0.428-0.713).,The degree of agreement between nLLC and oLLC was 0.49 (IC: 0.111-0.876) for AR onset (nLLC positive in 35% vs oLLC in 15%), 0.25 (IC: 0.035-0.459) for CM pattern (nLLC positive in 60.7% vs oLLC 17.9%) and 0.73 (IC: 0.543-0.912) for IL presentation (nLLC positive in 66.7% vs oLLC in 57.4%).,Diagnostic accuracy was 75% for both nLLC and oLLC among IL onset, and 41.6% for oLLC vs 66.7% for nLLC, as regards CM clinical presentation. nLLC have improved diagnostic performance of CMR for the diagnosis of acute myocarditis, in particular for atypical clinical presentation.
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What are the cardiovascular effects in unselected patients with recent coronavirus disease 2019 (COVID-19)?,In this cohort study including 100 patients recently recovered from COVID-19 identified from a COVID-19 test center, cardiac magnetic resonance imaging revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), which was independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis.,These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.,This cohort study evaluates the presence of myocardial injury in unselected patients recently recovered from coronavirus disease 2019 (COVID-19).,Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide.,Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown.,To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness.,In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020.,Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription-polymerase chain reaction on swab test of the upper respiratory tract.,Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained.,Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor-matched patients (n = 57).,Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years.,The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days.,Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization.,At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%).,Compared with healthy controls and risk factor-matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2.,A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22).,There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms; P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL; P = .002) but not for native T2 mapping.,None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = −0.07; P = .50).,High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33; P < .001) and native T2 mapping (r = 0.18; P = .01).,Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation.,Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19-related myocardial pathology.,In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis.,These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.
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Is psychological, social, and economic stress associated with coronavirus disease 2019 (COVID-19) associated with the incidence of stress cardiomyopathy?,This cohort study included 1914 patients with acute coronary syndrome to compare patients presenting during the COVID-19 pandemic with patients presenting across 4 timelines prior to the pandemic and found a significantly increased incidence of 7.8% of stress cardiomyopathy during the COVID-19 pandemic, compared with prepandemic incidences that ranged from 1.5% to 1.8%.,These findings suggest that psychological, social, and economic stress related to the COVID-19 pandemic was associated with an increased incidence of stress cardiomyopathy.,This cohort study compares the incidence of stress cardiomyopathy among patients presenting with acute coronary syndrome at 2 Ohio hospitals during the coronavirus disease 2019 pandemic vs prepandemic time points.,The coronavirus disease 2019 (COVID-19) pandemic has resulted in severe psychological, social, and economic stress in people’s lives.,It is not known whether the stress of the pandemic is associated with an increase in the incidence of stress cardiomyopathy.,To determine the incidence and outcomes of stress cardiomyopathy during the COVID-19 pandemic compared with before the pandemic.,This retrospective cohort study at cardiac catheterization laboratories with primary percutaneous coronary intervention capability at 2 hospitals in the Cleveland Clinic health system in Northeast Ohio examined the incidence of stress cardiomyopathy (also known as Takotsubo syndrome) in patients presenting with acute coronary syndrome who underwent coronary arteriography.,Patients presenting during the COVID-19 pandemic, between March 1 and April 30, 2020, were compared with 4 control groups of patients with acute coronary syndrome presenting prior to the pandemic across 4 distinct timelines: March to April 2018, January to February 2019, March to April 2019, and January to February 2020.,Data were analyzed in May 2020.,Patients were divided into 5 groups based on the date of their clinical presentation in relation to the COVID-19 pandemic.,Incidence of stress cardiomyopathy.,Among 1914 patient presenting with acute coronary syndrome, 1656 patients (median [interquartile range] age, 67 [59-74]; 1094 [66.1%] men) presented during the pre-COVID-19 period (390 patients in March-April 2018, 309 patients in January-February 2019, 679 patients in March-April 2019, and 278 patients in January-February 2020), and 258 patients (median [interquartile range] age, 67 [57-75]; 175 [67.8%] men) presented during the COVID-19 pandemic period (ie, March-April 2020).,There was a significant increase in the incidence of stress cardiomyopathy during the COVID-19 period, with a total of 20 patients with stress cardiomyopathy (incidence proportion, 7.8%), compared with prepandemic timelines, which ranged from 5 to 12 patients with stress cardiomyopathy (incidence proportion range, 1.5%-1.8%).,The rate ratio comparing the COVID-19 pandemic period to the combined prepandemic period was 4.58 (95% CI, 4.11-5.11; P < .001).,All patients during the COVID-19 pandemic had negative reverse transcription-polymerase chain reaction test results for COVID-19.,Patients with stress cardiomyopathy during the COVID-19 pandemic had a longer median (interquartile range) hospital length of stay compared with those hospitalized in the prepandemic period (COVID-19 period: 8 [6-9] days; March-April 2018: 4 [3-4] days; January-February 2019: 5 [3-6] days; March-April 2019: 4 [4-8] days; January-February: 5 [4-5] days; P = .006).,There were no significant differences between the COVID-19 period and the overall pre-COVID-19 period in mortality (1 patient [5.0%] vs 1 patient [3.6%], respectively; P = .81) or 30-day rehospitalization (4 patients [22.2%] vs 6 patients [21.4%], respectively; P = .90).,This study found that there was a significant increase in the incidence of stress cardiomyopathy during the COVID-19 pandemic when compared with prepandemic periods.
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The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients.,First, those with COVID-19 and pre-existing cardiovascular disease have an increased risk of severe disease and death.,Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism.,Third, therapies under investigation for COVID-19 may have cardiovascular side effects.,Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions.,Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become hosts or vectors of virus transmission.,We hereby review the peer-reviewed and pre-print reports pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.,•Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,•CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,•Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,•Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.,Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.
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The value of atherogenic index of plasma (AIP) as a predictive biomarker for coronary artery disease (CAD) remains controversial.,In addition, whether AIP is associated with the risk of acute coronary syndrome (ACS) in very young adults has not been well established.,We consecutively collected very young adults (≤35 years of age) undergoing coronary angiography (CAG) at Anzhen Hospital, between January 2008 and December 2017.,Total of 1, 478 very young participants, including 1, 059 ACS patients and 419 non-CAD subjects, were enrolled in the present study.,Very young patients with ACS had higher AIP level compared with non-CAD participants (0.35 ± 0.30 vs 0.21 ± 0.33, P < 0.001).,According to Gensini Score (GS) and number of lesion vessel, patients were divided into four groups, respectively.,With the elevated GS score and number of lesion vessels, the AIP level increased gradually (Pfor trend all< 0.05).,Multivariate logistic regression analyses suggested that AIP remained to be independently associated with the presence of ACS and was superior to traditional lipid profiles (for AIP, OR = 2.930, 95% CI = 1.855-4.627, P < 0.001; for total cholesterol, OR = 1.152, 95% CI = 1.048-1.266, P = 0.003; for triglyceride, OR = 1.078, 95% CI = 0.991-1.172, P = 0.079; for low-density lipoprotein cholesterol, OR = 1.046, 95% CI = 1.015-1.078, P < 0.001), after adjustment for other traditional confounders.,Moreover, the prevalence of ACS, acute myocardial infarction, unstable angina pectoris and the value of GS were also elevated as AIP quartiles increased (Pfor trend < 0.001).,Subgroup analysis based on gender revealed that AIP was only independently associated with the ACS risk in male.,AIP was independently associated with the presence and severity of ACS in very young patients in a gender-dependent manner, which might be superior to traditional lipid profiles.,The online version of this article (10.1186/s12944-019-1043-2) contains supplementary material, which is available to authorized users.
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The correlation between the weekly duration of aerobic exercise and atherogenic index of plasma (AIP) is still unknown.,A cross-sectional study was conducted involving 27,827 middle-aged Chinese men who had health examinations in our hospital.,The correlation between the duration of moderate-intensity aerobic exercise and AIP was determined.,The mean AIP levels were 0.1166 ± 0.34475, 0.1167 ± 0.32637, and 0.0765 ± 0.32872 in the non-exercise (PA1), occasional exercise (PA2), and frequent exercise groups (PA3), respectively.,Significantly higher AIP levels were observed in the PA1 and PA2 groups than the PA3 group, while no significant difference existed between the PA1 and PA2 groups.,Physical activity significantly reduced the AIP after adjustment for age, body mass index, diastolic blood pressure, and fasting blood glucose and uric acid levels.,In addition, the percentage of the population at high risk for atherosclerosis (AIP ≥ 0.21) was significantly lower in the PA3 group than the PA1 and PA2 groups.,Moderate-intensity aerobic exercise at a weekly duration of 90 min or longer is associated with the reduction of AIP among middle-aged men in southeastern China.
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Supplemental Digital Content is available in the text.,Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF).,However, their effects on cardiac structure and function in HFrEF are uncertain.,We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial [Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure]) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes.,Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes).,The coprimary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area and LV global longitudinal strain both measured using cardiovascular magnetic resonance.,Secondary efficacy outcomes included other cardiovascular magnetic resonance measures (LV end-diastolic volume index, LV ejection fraction), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, B-lines on lung ultrasound, and biomarkers (including N-terminal pro-B-type natriuretic peptide).,From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III.,Patients received standard treatment for HFrEF.,In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, -10.8 to -1.2) mL/m2 (P=0.015).,There was no difference in LV global longitudinal strain.,Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, -13.7 to -2.6) mL/m2 (P=0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%-47%), P=0.038.,There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines.,The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes.,Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF.,URL: https://www.clinicaltrials.gov.,Unique identifier: NCT03485092.
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Physiologic determinants, such as pulse pressure [difference between systolic blood pressure (SBP) and diastolic BP (DBP)], mean arterial pressure (2/3 DBP + 1/3 SBP), and double product [beats per minute (bpm) × SBP], are linked to cardiovascular outcomes.,The effects of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on pulse pressure, mean arterial pressure, and double product were assessed in patients with type 2 diabetes mellitus (T2DM).,This post hoc analysis was based on pooled data from four 26-week, randomized, double-blind, placebo-controlled studies evaluating canagliflozin in patients with T2DM (N = 2313) and a 6-week, randomized, double-blind, placebo-controlled, ambulatory BP monitoring (ABPM) study evaluating canagliflozin in patients with T2DM and hypertension (N = 169).,Changes from baseline in SBP, DBP, pulse pressure, mean arterial pressure, and double product were assessed using seated BP measurements (pooled studies) or averaged 24-h BP assessments (ABPM study).,Safety was assessed based on adverse event reports.,In the pooled studies, canagliflozin 100 and 300 mg reduced SBP (−4.3 and −5.0 vs −0.3 mmHg) and DBP (−2.5 and −2.4 vs −0.6 mmHg) versus placebo at week 26.,Reductions in pulse pressure (−1.8 and −2.6 vs 0.2 mmHg), mean arterial pressure (−3.1 and −3.3 vs −0.5 mmHg), and double product (−381 and −416 vs −30 bpm × mmHg) were also seen with canagliflozin 100 and 300 mg versus placebo.,In the ABPM study, canagliflozin 100 and 300 mg reduced mean 24-h SBP (−4.5 and −6.2 vs −1.2 mmHg) and DBP (−2.2 and −3.2 vs −0.3 mmHg) versus placebo at week 6.,Canagliflozin 300 mg provided reductions in pulse pressure (−3.3 vs −0.8 mmHg) and mean arterial pressure (−4.2 vs −0.6 mmHg) compared with placebo, while canagliflozin 100 mg had more modest effects on these parameters.,Canagliflozin was generally well tolerated in both study populations.,Canagliflozin improved all three cardiovascular physiologic markers, consistent with the hypothesis that canagliflozin may have beneficial effects on some cardiovascular outcomes in patients with T2DM.,Trial registration ClinicalTrials.gov Identifier: NCT01081834 (registered March 2010); NCT01106677 (registered April 2010); NCT01106625 (registered April 2010); NCT01106690 (registered April 2010); NCT01939496 (registered September 2013)
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An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19-associated coagulopathy, characterised by increased thrombotic and microvascular complications.,Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy.,To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19.,In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital.,Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range.,We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes.,We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable.,We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality.,Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival.,68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls.,Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0·0001) and soluble P-selectin (15·9 ng/mL [4·8] vs 11·2 ng/mL [3·1]; p=0·0014).,VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients.,We found mortality to be significantly correlated with VWF antigen (r = 0·38; p=0·0022) and soluble thrombomodulin (r = 0·38; p=0·0078) among all patients.,In all patients, soluble thrombomodulin concentrations greater than 3·26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0·0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5·9, 95% CI 1·9-18·4; p=0·0087).,Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death.,Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.,This work was supported by a gift donation from Jack Levin to the Benign Hematology programme at Yale, and the National Institutes of Health.
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The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among U.S. hospitalized patients with coronavirus disease-2019 (COVID-19) are unknown.,The purpose of this study was to describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19.,Patients with COVID-19 admitted to 1 of 5 Mount Sinai Health System hospitals in New York City between February 27, 2020, and April 12, 2020, with troponin-I (normal value <0.03 ng/ml) measured within 24 h of admission were included (n = 2,736).,Demographics, medical histories, admission laboratory results, and outcomes were captured from the hospitals’ electronic health records.,The median age was 66.4 years, with 59.6% men.,Cardiovascular disease (CVD), including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes.,A total of 506 (18.5%) patients died during hospitalization.,In all, 985 (36%) patients had elevated troponin concentrations.,After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g., troponin I >0.03 to 0.09 ng/ml; n = 455; 16.6%) were significantly associated with death (adjusted hazard ratio: 1.75; 95% CI: 1.37 to 2.24; p < 0.001) while greater amounts (e.g., troponin I >0.09 ng/dl; n = 530; 19.4%) were significantly associated with higher risk (adjusted HR: 3.03; 95% CI: 2.42 to 3.80; p < 0.001).,Myocardial injury is prevalent among patients hospitalized with COVID-19; however, troponin concentrations were generally present at low levels.,Patients with CVD are more likely to have myocardial injury than patients without CVD.,Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality.
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Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin are known to reduce the risk of hospitalizations related to heart failure irrespective of diabetic state.,Meanwhile, adverse cardiac remodeling remains the leading cause of heart failure and death in the USA.,Thus, understanding the mechanisms that are responsible for the beneficial effects of SGLT2 inhibitors is of the utmost relevance and importance.,Our previous work illustrated a connection between adverse cardiac remodeling and the regulation of mitochondrial turnover and cellular energetics using a short-acting glucagon-like peptide-1 receptor agonist (GLP1Ra).,Here, we sought to determine if the mechanism of the SGLT2 inhibitor empagliflozin (EMPA) in ameliorating adverse remodeling was similar and/or to identify what differences exist, if any.,To this end, we administered permanent coronary artery ligation to induce adverse remodeling in wild-type and Parkin knockout mice and examined the progression of adverse cardiac remodeling with or without EMPA treatment over time.,Like GLP1Ra, we found that EMPA affords a robust attenuation of PCAL-induced adverse remodeling.,Interestingly, unlike the GLP1Ra, EMPA does not require Parkin to improve/maintain mitochondria-related cellular energetics and afford its benefits against developing adverse remodeling.,These findings suggests that further investigation of EMPA is warranted as a potential path for developing therapy against adverse cardiac remodeling for patients that may have Parkin and/or mitophagy-related deficiencies.
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To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted region of the diabetic heart after myocardial infarction (MI).,OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling.,Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI).,The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO.,Fis1 expression level was higher in OLETF than in LETO, while phospho‐Ser637‐Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable.,MI further reduced the size of mitochondria with increased Drp1‐Ser616 phosphorylation in OLETF.,The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF.,Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF.,Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF.,Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF.,Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes‐induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.
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Observational series suggest a mortality benefit from metformin in the heart failure (HF) population.,However, the benefit of metformin in HF with preserved ejection fraction (HFpEF) has yet to be explored.,We performed a systematic review and meta-analysis to identify whether variation in EF impacts mortality outcomes in HF patients treated with metformin.,MEDLINE and EMBASE were searched up to October 2019.,Observational studies and randomised trials reporting mortality in HF patients and the proportion of patients with an EF > 50% at baseline were included.,Other baseline variables were used to assess for heterogeneity in treatment outcomes between groups.,Regression models were used to determine the interaction between metformin and subgroups on mortality.,Four studies reported the proportion of patients with a preserved EF and were analysed.,Metformin reduced mortality in both preserved or reduced EF after adjustment with HF therapies such as angiotensin converting enzyme inhibitors (ACEi) and beta-blockers (β = − 0.2 [95% CI − 0.3 to − 0.1], p = 0.02).,Significantly greater protective effects were seen with EF > 50% (p = 0.003).,Metformin treatment with insulin, ACEi and beta-blocker therapy were also shown to have a reduction in mortality (insulin p = 0.002; ACEi p < 0.001; beta-blocker p = 0.017), whereas female gender was associated with worse outcomes (p < 0.001).,Metformin treatment is associated with a reduction in mortality in patients with HFpEF.
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Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality.,The mechanisms remain unclear.,We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure.,The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13).,Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks.,After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses.,Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected.,Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation.,Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR.,In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues.,The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin.,Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes.,Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.
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Intracerebral hemorrhage (ICH) can be a devastating complication of coronavirus disease (COVID-19).,We aimed to assess risk factors associated with ICH in this population.,We performed a retrospective cohort study of adult patients admitted to NYU Langone Health system between March 1 and April 27 2020 with a positive nasopharyngeal swab polymerase chain reaction test result and presence of primary nontraumatic intracranial hemorrhage or hemorrhagic conversion of ischemic stroke on neuroimaging.,Patients with intracranial procedures, malignancy, or vascular malformation were excluded.,We used regression models to estimate odds ratios and 95% confidence intervals (OR, 95% CI) of the association between ICH and covariates.,We also used regression models to determine association between ICH and mortality.,Among 3824 patients admitted with COVID-19, 755 patients had neuroimaging and 416 patients were identified after exclusion criteria were applied.,The mean (standard deviation) age was 69.3 (16.2), 35.8% were women, and 34.9% were on therapeutic anticoagulation.,ICH occurred in 33 (7.9%) patients.,Older age, non-Caucasian race, respiratory failure requiring mechanical ventilation, and therapeutic anticoagulation were associated with ICH on univariate analysis (p < 0.01 for each variable).,In adjusted regression models, anticoagulation use was associated with a five-fold increased risk of ICH (OR 5.26, 95% CI 2.33-12.24, p < 0.001).,ICH was associated with increased mortality (adjusted OR 2.6, 95 % CI 1.2-5.9).,Anticoagulation use is associated with increased risk of ICH in patients with COVID-19.,Further investigation is required to elucidate underlying mechanisms and prevention strategies in this population.,The online version of this article (10.1007/s11239-020-02288-0) contains supplementary material, which is available to authorized users.
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•Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,•Some COVID-19 patients have exhibited widespread neurological manifestations including stroke.,•Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19.,•COVID-19-associated coagulopathy is likely caused by inflammation.,•Resultant ACE2 down-regulation causes RAS imbalance, which may lead to stroke.,Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,Some COVID-19 patients have exhibited widespread neurological manifestations including stroke.,Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19.,COVID-19-associated coagulopathy is likely caused by inflammation.,Resultant ACE2 down-regulation causes RAS imbalance, which may lead to stroke.,Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health threat.,Some COVID-19 patients have exhibited widespread neurological manifestations including stroke.,Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been reported in patients with COVID-19.,COVID-19-associated coagulopathy is increasingly recognized as a result of acute infection and is likely caused by inflammation, including inflammatory cytokine storm.,Recent studies suggest that axonal transport of SARS-CoV-2 to the brain can occur via the cribriform plate adjacent to the olfactory bulb that may lead to symptomatic anosmia.,The internalization of SARS-CoV-2 is mediated by the binding of the spike glycoprotein of the virus to the angiotensin-converting enzyme 2 (ACE2) on cellular membranes.,ACE2 is expressed in several tissues including lung alveolar cells, gastrointestinal tissue, and brain.,The aim of this review is to provide insights into the clinical manifestations and pathophysiological mechanisms of stroke in COVID-19 patients.,SARS-CoV-2 can down-regulate ACE2 and, in turn, overactivate the classical renin-angiotensin system (RAS) axis and decrease the activation of the alternative RAS pathway in the brain.,The consequent imbalance in vasodilation, neuroinflammation, oxidative stress, and thrombotic response may contribute to the pathophysiology of stroke during SARS-CoV-2 infection.
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Thromboembolic disease is common in coronavirus disease-2019 (COVID-19).,There is limited evidence on the association of in-hospital anticoagulation (AC) with outcomes and postmortem findings.,The purpose of this study was to examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies.,This retrospective analysis examined the association of AC with mortality, intubation, and major bleeding.,Subanalyses were also conducted on the association of therapeutic versus prophylactic AC initiated ≤48 h from admission.,Thromboembolic disease was contextualized by premortem AC among consecutive autopsies.,Among 4,389 patients, median age was 65 years with 44% women.,Compared with no AC (n = 1,530; 34.9%), therapeutic AC (n = 900; 20.5%) and prophylactic AC (n = 1,959; 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]: 0.53; 95% confidence interval [CI]: 0.45 to 0.62 and aHR: 0.50; 95% CI: 0.45 to 0.57, respectively), and intubation (aHR: 0.69; 95% CI: 0.51 to 0.94 and aHR: 0.72; 95% CI: 0.58 to 0.89, respectively).,When initiated ≤48 h from admission, there was no statistically significant difference between therapeutic (n = 766) versus prophylactic AC (n = 1,860) (aHR: 0.86; 95% CI: 0.73 to 1.02; p = 0.08).,Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3.0%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic, and 29 of 1,530 (1.9%) on no AC.,Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3 of 11 (27%) were on therapeutic AC.,AC was associated with lower mortality and intubation among hospitalized COVID-19 patients.,Compared with prophylactic AC, therapeutic AC was associated with lower mortality, although not statistically significant.,Autopsies revealed frequent thromboembolic disease.,These data may inform trials to determine optimal AC regimens.
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Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly heterogeneous.,The objective was to determine incidence and risk factors of venous thromboembolism (VTE) in COVID-19 inpatients receiving thromboprophylaxis.,In this retrospective French cohort study, patients hospitalized in medical wards non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included.,A systematic low limb venous duplex ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected.,Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected.,Of 71 patients, 16 developed VTE (22.5%) and 7 PE (10%) despite adequate thromboprophylaxis.,D-dimers at baseline were significantly higher in patients with DVT (p < 0.001).,Demographics, comorbidities, disease manifestations, severity score, and other biological parameters, including inflammatory markers, were similar in patients with and without VTE.,The negative predictive value of a baseline D-dimer level < 1.0 µg/ml was 90% for VTE and 98% for PE.,The positive predictive value for VTE was 44% and 67% for D-dimer level ≥ 1.0 µg/ml and ≥ 3 µg/ml, respectively.,The association between D-dimer level and VTE risk increased by taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitoring of D-dimer.,Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients.,Increased D-dimer concentrations of more than 1.0 μg/ml predict the risk of venous thromboembolism.,D-dimer level-guided aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.
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This study investigated continued and discontinued use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) during hospitalization of 614 hypertensive laboratory-confirmed COVID-19 patients.,Demographics, comorbidities, vital signs, laboratory data, and ACEi/ARB usage were analyzed.,To account for confounders, patients were substratified by whether they developed hypotension and acute kidney injury (AKI) during the index hospitalization.,Mortality (22% vs 17%, P > .05) and intensive care unit (ICU) admission (26% vs 12%, P > .05) rates were not significantly different between non-ACEi/ARB and ACEi/ARB groups.,However, patients who continued ACEi/ARBs in the hospital had a markedly lower ICU admission rate (12% vs 26%; P = .001; odds ratio [OR] = 0.347; 95% confidence interval [CI], .187-.643) and mortality rate (6% vs 28%; P = .001; OR = 0.215; 95% CI, .101-.455) compared to patients who discontinued ACEi/ARB.,The odds ratio for mortality remained significantly lower after accounting for development of hypotension or AKI.,These findings suggest that continued ACEi/ARB use in hypertensive COVID-19 patients yields better clinical outcomes.,In hypertensive patients with COVID-19, in-hospital continuation of ACE inhibitors or ARBs is associated with lower rates of mortality and intensive care admission in the absence of hypotension or acute kidney injury.
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Whether pulmonary artery (PA) dimension and coronary artery calcium (CAC) score, as assessed by chest computed tomography (CT), are associated with myocardial injury in patients with coronavirus disease 2019 (COVID-19) is not known.,The aim of this study was to explore the risk factors for myocardial injury and death and to investigate whether myocardial injury has an independent association with all-cause mortality in patients with COVID-19.,This is a single-centre cohort study including consecutive patients with laboratory-confirmed COVID-19 undergoing chest CT on admission.,Myocardial injury was defined as high-sensitivity troponin I >20 ng/L on admission.,A total of 332 patients with a median follow-up of 12 days were included.,There were 68 (20.5%) deaths; 123 (37%) patients had myocardial injury.,PA diameter was higher in patients with myocardial injury compared with patients without myocardial injury [29.0 (25th-75th percentile, 27-32) mm vs.,27.7 (25-30) mm, P < 0.001).,PA diameter was independently associated with an increased risk of myocardial injury [adjusted odds ratio 1.10, 95% confidence interval (CI) 1.02-1.19, P = 0.01] and death [adjusted hazard ratio (HR) 1.09, 95% CI 1.02-1.17, P = 0.01].,Compared with patients without myocardial injury, patients with myocardial injury had a lower prevalence of a CAC score of zero (25% vs.,55%, P < 0.001); however, the CAC score did not emerge as a predictor of myocardial injury by multivariable logistic regression.,Myocardial injury was independently associated with an increased risk of death by multivariable Cox regression (adjusted HR 2.25, 95% CI 1.27-3.96, P = 0.005).,Older age, lower estimated glomerular filtration rate, and lower PaO2/FiO2 ratio on admission were other independent predictors for both myocardial injury and death.,An increased PA diameter, as assessed by chest CT, is an independent risk factor for myocardial injury and mortality in patients with COVID-19.,Myocardial injury is independently associated with an approximately two-fold increased risk of death.
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Messenger RNA (mRNA) coronavirus disease of 2019 (COVID-19) vaccine are known to cause minor side effects at the injection site and mild global systemic symptoms in first 24-48 h.,Recently published case series have reported a possible association between acute myocarditis and COVID-19 vaccination, predominantly in young males.,We report a case series of 5 young male patients with cardiovascular magnetic resonance (CMR)-confirmed acute myocarditis within 72 h after receiving a dose of an mRNA-based COVID-19 vaccine.,Our case series suggests that myocarditis in this setting is characterized by myocardial edema and late gadolinium enhancement in the lateral wall of the left ventricular (LV) myocardium, reduced global LV longitudinal strain, and preserved LV ejection fraction.,All patients in our series remained clinically stable during a relatively short inpatient hospital stay.,In conjunction with other recently published case series and national vaccine safety surveillance data, this case series suggests a possible association between acute myocarditis and COVID-19 vaccination in young males and highlights a potential pattern in accompanying CMR abnormalities.
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We report two cases of myocarditis, in two young and previously healthy individuals, temporally related to the second dose of the mRNA-COVID-19 vaccine.,Both patients developed acute chest pain, changes on electrocardiogram (ECG), and elevated serum troponin within two days of receiving their second dose.,Cardiac magnetic resonance (CMR) findings were consistent with acute myocarditis.
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The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide.,We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior).,Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers.,The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers.,The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, −19.7 to −18.7), 11.5% (95%CI, −12.6 to −10.6), and 12.7% (95%CI, −13.6 to −11.8), respectively.,The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers.,High-volume COVID-19 centers (−20.5%) had greater declines in mechanical thrombectomy volumes than mid- (−10.1%) and low-volume (−8.7%) centers (p < 0.0001).,There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations.,SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions.,The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes.,Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.
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Background/Purpose: Coronavirus disease 2019 (COVID-19) is associated with increased risk of acute ischemic stroke (AIS), however, there is a paucity of data regarding outcomes after administration of intravenous tissue plasminogen activator (IV tPA) for stroke in patients with COVID-19.,Methods: We present a multicenter case series from 9 centers in the United States of patients with acute neurological deficits consistent with AIS and COVID-19 who were treated with IV tPA.,Results: We identified 13 patients (mean age 62 (±9.8) years, 9 (69.2%) male).,All received IV tPA and 3 cases also underwent mechanical thrombectomy.,All patients had systemic symptoms consistent with COVID-19 at the time of admission: fever (5 patients), cough (7 patients), and dyspnea (8 patients).,The median admission NIH stroke scale (NIHSS) score was 14.5 (range 3-26) and most patients (61.5%) improved at follow up (median NIHSS score 7.5, range 0-25).,No systemic or symptomatic intracranial hemorrhages were seen.,Stroke mechanisms included cardioembolic (3 patients), large artery atherosclerosis (2 patients), small vessel disease (1 patient), embolic stroke of undetermined source (3 patients), and cryptogenic with incomplete investigation (1 patient).,Three patients were determined to have transient ischemic attacks or aborted strokes.,Two out of 12 (16.6%) patients had elevated fibrinogen levels on admission (mean 262.2 ± 87.5 mg/dl), and 7 out of 11 (63.6%) patients had an elevated D-dimer level (mean 4284.6 ±3368.9 ng/ml).,Conclusions: IV tPA may be safe and efficacious in COVID-19, but larger studies are needed to validate these results.
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Consecutively hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) in Wuhan, China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin-angiotensin system inhibitor (RAS-I) and the outcome of this disease.,Associations between the use of RAS-I (angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)), ACEI, and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status.,A total of 2771 patients with COVID-19 were included, with moderate and severe cases accounting for 45.0% and 36.5%, respectively.,A total of 195 (7.0%) patients died.,RAS-I (hazard ratio (HR)= 0.499, 95% confidence interval (CI) 0.325-0.767) and ARB (HR = 0.410, 95% CI 0.240-0.700) use was associated with a reduced risk of all-cause mortality among patients with COVID-19.,For patients with hypertension, RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352 (95% CI 0.162-0.764) and 0.279 (95% CI 0.115-0.677), respectively.,RAS-I exhibited protective effects on the survival outcome of COVID-19.,ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.
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Supplemental Digital Content is available in the text.,Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension.,To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.,This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020.,In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03).,In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03).,Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension.,Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers.,While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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Three months ago, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) broke out in Wuhan, China, and spread rapidly around the world.,Severe novel coronavirus pneumonia (NCP) patients have abnormal blood coagulation function, but their venous thromboembolism (VTE) prevalence is still rarely mentioned.,To determine the incidence of VTE in patients with severe NCP.,In this study, 81 severe NCP patients in the intensive care unit (ICU) of Union Hospital (Wuhan, China) were enrolled.,The results of conventional coagulation parameters and lower limb vein ultrasonography of these patients were retrospectively collected and analyzed.,The incidence of VTE in these patients was 25% (20/81), of which 8 patients with VTE events died.,The VTE group was different from the non‐VTE group in age, lymphocyte counts, activated partial thromboplastin time (APTT), D‐dimer, etc.,If 1.5 µg/mL was used as the D‐dimer cut‐off value to predicting VTE, the sensitivity was 85.0%, the specificity was 88.5%, and the negative predictive value (NPV) was 94.7%.,The incidence of VTE in patients with severe NCP is 25% (20/81), which may be related to poor prognosis.,The significant increase of D‐dimer in severe NCP patients is a good index for identifying high‐risk groups of VTE.
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The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide.,However, little is known about the causes of death and the virus's pathologic features.,To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests.,Prospective cohort study.,Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction-confirmed diagnosis of COVID-19.,The first 12 consecutive COVID-19-positive deaths.,Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed.,Clinical data and medical course were evaluated.,Results: Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2).,Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively).,Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients.,Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients.,In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart.,Limited sample size.,The high incidence of thromboembolic events suggests an important role of COVID-19-induced coagulopathy.,Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19-related death, as well as possible therapeutic interventions to reduce it.,University Medical Center Hamburg-Eppendorf.,Little is known of the pathologic changes that lead to death in patients with COVID-19.,This study reports the autopsy findings of consecutive patients who died with a diagnosis of COVID-19.
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Preapproval trials showed that messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a good safety profile, yet these trials were subject to size and patient-mix limitations.,An evaluation of the safety of the BNT162b2 mRNA vaccine with respect to a broad range of potential adverse events is needed.,We used data from the largest health care organization in Israel to evaluate the safety of the BNT162b2 mRNA vaccine.,For each potential adverse event, in a population of persons with no previous diagnosis of that event, we individually matched vaccinated persons to unvaccinated persons according to sociodemographic and clinical variables.,Risk ratios and risk differences at 42 days after vaccination were derived with the use of the Kaplan-Meier estimator.,To place these results in context, we performed a similar analysis involving SARS-CoV-2-infected persons matched to uninfected persons.,The same adverse events were studied in the vaccination and SARS-CoV-2 infection analyses.,In the vaccination analysis, the vaccinated and control groups each included a mean of 884,828 persons.,Vaccination was most strongly associated with an elevated risk of myocarditis (risk ratio, 3.24; 95% confidence interval [CI], 1.55 to 12.44; risk difference, 2.7 events per 100,000 persons; 95% CI, 1.0 to 4.6), lymphadenopathy (risk ratio, 2.43; 95% CI, 2.05 to 2.78; risk difference, 78.4 events per 100,000 persons; 95% CI, 64.1 to 89.3), appendicitis (risk ratio, 1.40; 95% CI, 1.02 to 2.01; risk difference, 5.0 events per 100,000 persons; 95% CI, 0.3 to 9.9), and herpes zoster infection (risk ratio, 1.43; 95% CI, 1.20 to 1.73; risk difference, 15.8 events per 100,000 persons; 95% CI, 8.2 to 24.2).,SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis (risk ratio, 18.28; 95% CI, 3.95 to 25.12; risk difference, 11.0 events per 100,000 persons; 95% CI, 5.6 to 15.8) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia.,In this study in a nationwide mass vaccination setting, the BNT162b2 vaccine was not associated with an elevated risk of most of the adverse events examined.,The vaccine was associated with an excess risk of myocarditis (1 to 5 events per 100,000 persons).,The risk of this potentially serious adverse event and of many other serious adverse events was substantially increased after SARS-CoV-2 infection.,(Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.)
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The involvement of viruses and SARS-CoV-2 in autoimmune diseases is well known.,The recent demonstration that ChAdOx1 nCoV-19 Covid-19 (AstraZeneca) vaccine (ChA) favors the production of anti-platelet factor 4 (anti-PF4) antibodies, blood clots, and thrombocytopenia raises the question of whether other anti-CoViD-19 vaccines favor the same patterns of events.,We assessed the frequency of severe adverse events (SAEs) documented in the EudraVigilance European database up to April 16, 2021 related to thrombocytopenia, bleeding, and blood clots in recipients of ChA compared to that of recipients of the BNT162b2 Covid-19 (Pfizer/BioNTech) vaccine (BNT).,ChA administration was associated with a much higher frequency of SAEs in each AE Reaction Group as compared with that elicited by BNT.,When considering AEs caused by thrombocytopenia, bleeding and blood clots, we observed 33 and 151 SAEs/1 million doses in BNT and ChA recipients, respectively.,When considering patients with AEs related to cerebral/splanchnic venous thrombosis, and/or thrombocytopenia, we documented 4 and 30 SAEs and 0.4 and 4.8 deaths/1 million doses for BNT and ChA recipients, respectively.,The highest risk following ChA vaccination is in young people and, likely, women of reproductive age, as suggested by hypothesized scenarios.,In conclusion, the immune reaction promoted by ChA vaccine may lead to not only thrombocytopenia and cerebral/splanchnic venous thrombosis but also other thrombotic and thromboembolic SAEs.,These events are not favored by BNT vaccine.,Our study may help in the evaluation of the benefit/risk profile of the ChA vaccine considering the epidemic curve present in a country.
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The coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 that has significant implications for the cardiovascular care of patients.,First, those with COVID-19 and pre-existing cardiovascular disease have an increased risk of severe disease and death.,Second, infection has been associated with multiple direct and indirect cardiovascular complications including acute myocardial injury, myocarditis, arrhythmias, and venous thromboembolism.,Third, therapies under investigation for COVID-19 may have cardiovascular side effects.,Fourth, the response to COVID-19 can compromise the rapid triage of non-COVID-19 patients with cardiovascular conditions.,Finally, the provision of cardiovascular care may place health care workers in a position of vulnerability as they become hosts or vectors of virus transmission.,We hereby review the peer-reviewed and pre-print reports pertaining to cardiovascular considerations related to COVID-19 and highlight gaps in knowledge that require further study pertinent to patients, health care workers, and health systems.,•Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,•CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,•Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,•Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.,Patients with pre-existing CVD appear to have worse outcomes with COVID-19.,CV complications include biomarker elevations, myocarditis, heart failure, and venous thromboembolism, which may be exacerbated by delays in care.,Therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications.,Health care workers and health systems should take measures to ensure safety while providing high-quality care for COVID-19 patients.
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Little evidence of increased thrombotic risk is available in COVID-19 patients.,Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.,All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included.,Medical history, symptoms, biological data and imaging were prospectively collected.,Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.,150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points).,Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting.,Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO.,Most patients (> 95%) had elevated D-dimer and fibrinogen.,No patient developed disseminated intravascular coagulation.,Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant.,Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs.,2.1%, p < 0.008).,Coagulation parameters significantly differed between the two groups.,Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications.,Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.,The online version of this article (10.1007/s00134-020-06062-x) contains supplementary material, which is available to authorized users.
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