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Emerging data indicate an increased risk of cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and highlight the potential impact of coronavirus disease (COVID‐19) on the management and outcomes of acute stroke.,We conducted a systematic review and meta‐analysis to evaluate the aforementioned considerations.,We performed a meta‐analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS‐CoV‐2 infection status.,We used a random‐effects model.,Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).,We identified 18 cohort studies including 67,845 patients.,Among patients with SARS‐CoV‐2, 1.3% (95% CI = 0.9-1.6%, I 2 = 87%) were hospitalized for cerebrovascular events, 1.1% (95% CI = 0.8-1.3%, I 2 = 85%) for ischemic stroke, and 0.2% (95% CI = 0.1-0.3%, I 2 = 64%) for hemorrhagic stroke.,Compared to noninfected contemporary or historical controls, patients with SARS‐CoV‐2 infection had increased odds of ischemic stroke (OR = 3.58, 95% CI = 1.43-8.92, I 2 = 43%) and cryptogenic stroke (OR = 3.98, 95% CI = 1.62-9.77, I 2 = 0%).,Diabetes mellitus was found to be more prevalent among SARS‐CoV‐2 stroke patients compared to noninfected historical controls (OR = 1.39, 95% CI = 1.00-1.94, I 2 = 0%).,SARS‐CoV‐2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR = 1.42, 95% CI = 0.65-3.10, I 2 = 0%) or endovascular thrombectomy (OR = 0.78, 95% CI = 0.35-1.74, I 2 = 0%) among hospitalized ischemic stroke patients during the COVID‐19 pandemic.,Odds of in‐hospital mortality were higher among SARS‐CoV‐2 stroke patients compared to noninfected contemporary or historical stroke patients (OR = 5.60, 95% CI = 3.19-9.80, I 2 = 45%).,SARS‐CoV‐2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular.,It may also be related to an increased mortality risk.,ANN NEUROL 2021;89:380-388 | COVID-19 is an infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).,Apart from respiratory complications, acute cerebrovascular disease (CVD) has been observed in some patients with COVID-19.,Therefore, we described the clinical characteristics, laboratory features, treatment and outcomes of CVD complicating SARS-CoV-2 infection.,Demographic and clinical characteristics, laboratory findings, treatments and clinical outcomes were collected and analysed.,Clinical characteristics and laboratory findings of patients with COVID-19 with or without new-onset CVD were compared.,Of 219 patients with COVID-19, 10 (4.6%) developed acute ischaemic stroke and 1 (0.5%) had intracerebral haemorrhage.,COVID-19 with new onset of CVD were significantly older (75.7±10.8 years vs 52.1±15.3 years, p<0.001), more likely to present with severe COVID-19 (81.8% vs 39.9%, p<0.01) and were more likely to have cardiovascular risk factors, including hypertension, diabetes and medical history of CVD (all p<0.05).,In addition, they were more likely to have increased inflammatory response and hypercoagulable state as reflected in C reactive protein (51.1 (1.3-127.9) vs 12.1 (0.1-212.0) mg/L, p<0.05) and D-dimer (6.9 (0.3-20.0) vs 0.5 (0.1-20.0) mg/L, p<0.001).,Of 10 patients with ischemic stroke; 6 received antiplatelet treatment with aspirin or clopidogrel; and 3 of them died.,The other four patients received anticoagulant treatment with enoxaparin and 2 of them died.,As of 24 March 2020, six patients with CVD died (54.5%).,Acute CVD is not uncommon in COVID-19.,Our findings suggest that older patients with risk factors are more likely to develop CVD.,The development of CVD is an important negative prognostic factor which requires further study to identify optimal management strategy to combat the COVID-19 outbreak. | 1 |
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. | Hypertension is proved to be associated with severity and mortality in coronavirus disease 2019 (COVID‐19).,However, little is known about the effects of pre‐admission and/or in‐hospital antihypertension treatments on clinical outcomes.,Thus, this study aimed to investigate the association between in‐hospital blood pressure (BP) control and COVID‐19-related outcomes and to compare the effects of different antihypertension treatments.,This study included 2864 COVID‐19 patients and 1628 were hypertensive.,Patients were grouped according to their BP during hospitalization and records of medication application.,Patients with higher BP showed worse cardiac and renal functions and clinical outcomes.,After adjustment, subjects with pre‐admission usage of renin‐angiotensin‐aldosterone system (RAAS) inhibitors (HR = 0.35, 95%CI 0.14‐0.86, P = .022) had a lower risk of adverse clinical outcomes, including death, acute respiratory distress syndrome, respiratory failure, septic shock, mechanical ventilation, and intensive care unit admission.,Particularly, hypertension patients receiving RAAS inhibitor treatment either before (HR = 0.35, 95%CI 0.13‐0.97, P = .043) or after (HR = 0.18, 95%CI 0.04‐0.86, P = .031) admission showed a significantly lower risk of adverse clinical outcomes than those receiving application of other antihypertensive medicines.,Furthermore, consecutive application of RAAS inhibitors in COVID‐19 patients with hypertension showed better clinical outcomes (HR = 0.10, 95%CI 0.01‐0.83, P = .033) than non‐RAAS inhibitors users.,We revealed that COVID‐19 patients with poor BP control during hospitalization had worse clinical outcomes.,Compared with other antihypertension medicines, RAAS inhibitors were beneficial for improving clinical outcomes in COVID‐19 patients with hypertension.,Our findings provide direct evidence to support the administration of RAAS inhibitors to COVID‐19 patients with hypertension before and after admission. | 1 |
Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19).,We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.,In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care.,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.,The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation.,Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis).,The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%).,The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11).,Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.,In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.,(REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.) | 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. | 1 |
Neonatal encephalopathy due to hypoxia-ischemia (HI) is a leading cause of death and disability in term newborns.,Therapeutic hypothermia (HT) is the only recommended therapy.,However, 30% still suffer from neurological deficits.,Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation.,In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice.,Nine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia.,Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature.,Analyses were performed at 1, 3 and 7 days post HI.,Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry.,A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages.,Purity and composition of isolated cells was determined by flow cytometry.,Immediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI.,Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT.,However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3.,HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT.,Our data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.,The online version contains supplementary material available at 10.1186/s12974-021-02314-9. | Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE).,Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states.,However, the effects of microglial depletion on neonatal HIE remain unclear.,Tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ (microglia-depleted model) and Cx3cr1CreER/+Rosa26DTA/− (control) mice at P8 and P9 to assess the effect of microglial depletion.,The density of microglia was quantified using Iba-1 staining.,Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis.,At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10.,The infarct size and apoptotic cells were analyzed at P13.,Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.,At P10, tamoxifen administration induced > 99% microglial depletion in DTA+ mice.,Following HI insult, there was persisted microglial depletion over 97% at P13.,Compared to male DTA− mice, male DTA+ mice exhibited significantly larger infarct volumes; however, there were no significant differences among females.,Moreover, compared to male DTA− mice, male DTA+ mice had a significantly higher density of TUNEL+ cells in the caudoputamen, cerebral cortex, and thalamus.,Moreover, compared to female DTA− mice, female DTA+ mice showed a significantly greater number of TUNEL+ cells in the hippocampus and thalamus.,Compared to DTA− mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA+ mice under both normal conditions and after HI (more pronounced).,We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males. | 1 |
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. | 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. | 1 |
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. | Admission rates for acute decompensated heart failure (HF) declined during the COVID‐19 pandemic.,However, the impact of this reduction on hospital mortality is unknown.,We describe temporal trends in the presentation of patients with acute HF and their in‐hospital outcomes at two referral centres in London during the COVID‐19 pandemic.,A total of 1372 patients hospitalized for HF in two referral centres in South London between 7 January and 14 June 2020 were included in the study and their outcomes compared with those of equivalent patients of the same time period in 2019.,The primary outcome was all‐cause in‐hospital mortality.,The number of HF hospitalizations was significantly reduced during the COVID‐19 pandemic, compared with 2019 (P < 0.001).,Specifically, we observed a temporary reduction in hospitalizations during the COVID‐19 peak, followed by a return to 2019 levels.,Patients admitted during the COVID‐19 pandemic had demographic characteristics similar to those admitted during the equivalent period in 2019.,However, in‐hospital mortality was significantly higher in 2020 than in 2019 (P = 0.015).,Hospitalization in 2020 was independently associated with worse in‐hospital mortality (hazard ratio 2.23, 95% confidence interval 1.34-3.72; P = 0.002).,During the COVID‐19 pandemic there was a reduction in HF hospitalization and a higher rate of in‐hospital mortality.,Hospitalization for HF in 2020 is independently associated with more adverse outcomes.,Further studies are required to investigate the predictors of these adverse outcomes to help inform potential changes to the management of HF patients while some constraints to usual care remain.,Temporal trends in heart failure admission and adjusted Kaplan-Meier curves for in‐hospital mortality during the COVID‐19 pandemic. | 1 |
The association of severe coronavirus disease 2019 (COVID-19) with an increased risk of venous thromboembolism (VTE) has resulted in specific guidelines for its prevention and management.,The VTE risk appears highest in those with critical care admission.,The need for postdischarge thromboprophylaxis remains controversial, which is reflected in conflicting expert guideline recommendations.,Our local protocol provides thromboprophylaxis to COVID-19 patients during admission only.,We report postdischarge VTE data from an ongoing quality improvement program incorporating root-cause analysis of hospital-associated VTE (HA-VTE).,Following 1877 hospital discharges associated with COVID-19, 9 episodes of HA-VTE were diagnosed within 42 days, giving a postdischarge rate of 4.8 per 1000 discharges.,Over 2019, following 18 159 discharges associated with a medical admission; there were 56 episodes of HA-VTE within 42 days (3.1 per 1000 discharges).,The odds ratio for postdischarge HA-VTE associated with COVID-19 compared with 2019 was 1.6 (95% confidence interval, 0.77-3.1).,COVID-19 hospitalization does not appear to increase the risk of postdischarge HA-VTE compared with hospitalization with other acute medical illness.,Given that the risk-benefit ratio of postdischarge thromboprophylaxis remains uncertain, randomized controlled trials to evaluate the role of continuing thromboprophylaxis in COVID-19 patients following hospital discharge are required.,•The rate of symptomatic postdischarge VTE following hospitalization with COVID-19 is low.,The rate of symptomatic postdischarge VTE following hospitalization with COVID-19 is low. | 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. | 1 |
Multiple myeloma (MM) cell lines are routinely used to model the disease.,However, a long-standing question is how well these cell lines truly represent tumor cells in patients.,Here, we employ a recently described method of transcriptional correlation profiling to compare similarity of 66 MM cell lines to 779 newly diagnosed MM patient tumors.,We found that individual MM lines differ significantly with respect to patient tumor representation, with median R ranging from 0.35 to 0.54.,ANBL-6 was the “best” line, markedly exceeding all others (p < 2.2e−16).,Notably, some widely used cell lines (RPMI-8226, U-266) scored poorly in our patient similarity ranking (48 and 52 of 66, respectively).,Lines cultured with interleukin-6 showed significantly improved correlations with patient tumor (p = 9.5e−4).,When common MM genomic features were matched between cell lines and patients, only t(4;14) and t(14;16) led to increased transcriptional correlation.,To demonstrate the utility of our top-ranked line for preclinical studies, we showed that intravenously implanted ANBL-6 proliferates in hematopoietic organs in immunocompromised mice.,Overall, our large-scale quantitative correlation analysis, utilizing emerging datasets, provides a resource informing the MM community of cell lines that may be most reliable for modeling patient disease while also elucidating biological differences between cell lines and tumors. | Multiple myeloma (MM) is a plasma cell malignancy and most patients eventually succumb to the disease.,Chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) on MM cells have shown high-response rates, but limited durability.,CD229/LY9 is a cell surface receptor present on B and T lymphocytes that is universally and strongly expressed on MM plasma cells.,Here, we develop CD229 CAR T cells that are highly active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells.,We do not observe fratricide during CD229 CAR T cell production, as CD229 is downregulated in T cells during activation.,In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells.,These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM.,CD229 is expressed on the surface of multiple myeloma cells, as well as B and T lymphocytes.,Here, the authors engineer CD229-specific CAR T cells and, using patient samples and mouse models, show that treatment with these cells reduces tumour burden and results in limited targeting of T cells. | 1 |
Supplemental Digital Content is available in the text.,Patients with coronavirus disease 2019 (COVID-19) who develop cardiac injury are reported to experience higher rates of malignant cardiac arrhythmias.,However, little is known about these arrhythmias-their frequency, the underlying mechanisms, and their impact on mortality.,We extracted data from a registry (NCT04358029) regarding consecutive inpatients with confirmed COVID-19 who were receiving continuous telemetric ECG monitoring and had a definitive disposition of hospital discharge or death.,Between patients who died versus discharged, we compared a primary composite end point of cardiac arrest from ventricular tachycardia/fibrillation or bradyarrhythmias such as atrioventricular block.,Among 800 patients with COVID-19 at Mount Sinai Hospital with definitive dispositions, 140 patients had telemetric monitoring, and either died (52) or were discharged (88).,The median (interquartile range) age was 61 years (48-74); 73% men; and ethnicity was White in 34%.,Comorbidities included hypertension in 61%, coronary artery disease in 25%, ventricular arrhythmia history in 1.4%, and no significant comorbidities in 16%.,Compared with discharged patients, those who died had elevated peak troponin I levels (0.27 versus 0.02 ng/mL) and more primary end point events (17% versus 4%, P=0.01)-a difference driven by tachyarrhythmias.,Fatal tachyarrhythmias invariably occurred in the presence of severe metabolic imbalance, while atrioventricular block was largely an independent primary event.,Hospitalized patients with COVID-19 who die experience malignant cardiac arrhythmias more often than those surviving to discharge.,However, these events represent a minority of cardiovascular deaths, and ventricular tachyarrhythmias are mainly associated with severe metabolic derangement.,URL: https://www.clinicaltrials.gov; Unique identifier: NCT04358029. | 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. | 1 |
This study interrogated the transcriptional features and immune cellular landscape of the retinae of rats subjected to oxygen-induced retinopathy (OIR).,Bulk RNA sequencing was performed with retinal RNA isolated from control and OIR rats.,Gene set enrichment analysis (GSEA) was undertaken to identify gene sets associated with immune responses in retinal neovascularization.,Bulk gene expression deconvolution analysis by CIBERSORTx was performed to identify immune cell types involved in retinal neovascularization, followed by functional enrichment analysis of differentially expressed genes (DEGs).,Protein-protein interaction analysis was performed to predict the hub genes relevant to identified immune cell types.,CIBERSORTx was applied to profile immune cell types in the macula of patients with both proliferative diabetic retinopathy (PDR) and diabetic macular edema using a public RNA-seq dataset.,Transcriptome analysis by GSEA revealed that the retina of OIR rats and patients with PDR is characterized by increased immunoregulatory interactions and complement cascade.,Deconvolution analysis demonstrated that M2 macrophages infiltrate the retinae of OIR rats and patients with PDR.,Functional enrichment analysis of DEGs in OIR rats showed that the dysregulated genes are related to leukocyte-mediated immunity and myeloid leukocyte activation.,Downstream protein-protein interaction analysis revealed that several potential hub genes, including Ccl2, Itgam, and Tlr2, contribute to M2 macrophage infiltration in the ischemic retina.,This study highlights application of the gene expression deconvolution tool to identify immune cell types in inflammatory ocular diseases with transcriptomes, providing a new approach to assess changes in immune cell types in diseased ocular tissues. | To quantitatively characterize macrophage-like cells (MLCs) at the vitreoretinal interface in different severity stages of diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA).,The study included 72 eyes of 72 subjects: 18 healthy controls, 22 diabetes mellitus (DM) without DR, 17 nonproliferative DR (NPDR), and 15 proliferative DR (PDR).,We obtained repeated (average, 6.5; range, 3-10) macular OCTA scans for each eye.,We registered and averaged the 3-µm OCT slab above the vitreoretinal interface to visualize MLCs.,Using a semiautomated method, we binarized and quantified MLCs and compared MLC densities among groups.,We also evaluated MLC distribution relative to underlying superficial capillary plexus vasculature and quantified MLCs overlying blood vessels within the perivascular 30-µm watershed region and within ischemic zones (defined as >30 µm from the nearest vessel).,MLC density was 2.8- to 3.8-fold higher in PDR compared with all other groups (P < 0.05 for all).,MLC density in PDR was most increased in perivascular areas (3.3- to 4.2-fold; P < 0.05 vs. all) and on blood vessels (3.0- to 4.0-fold; P < 0.05 vs. all), and elevated to a lesser extent in ischemic areas (2.3- to 3.4-fold; P < 0.05 vs. all).,MLCs were more likely to localize on blood vessels in DM without DR, NPDR, and PDR (P < 0.05 for all), but not healthy eyes.,MLC density was significantly increased in PDR.,MLCs clustered on blood vessels in diabetic but not in healthy eyes.,Further studies are needed to confirm the origin, identity, and function of MLCs during DR. | 1 |
We report 3 patients with coronavirus disease who had a decline in respiratory status during their hospital course that responded well to intravenous steroids and interleukin-6 receptor antagonist therapy.,These patients later showed development of persistent hypoxia with increased levels of d-dimer levels and were given a diagnosis of pulmonary embolisms. | 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. | 1 |
Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury.,However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury.,This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury.,Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites.,We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury.,Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro.,However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis.,We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1).,This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury. | Intestinal ischemia/reperfusion (I/R) injury remains a major clinical event and contributes to high morbidity and mortality rates, but the underlying mechanisms remain elusive.,Recent studies have demonstrated that microRNAs (miRNAs) have important roles in organ I/R injury, but the changes and potential roles of miRNAs in intestinal I/R-induced intestinal injury are unclear.,This study was designed to analyze the miRNA expression profiles in intestinal mucosa after I/R injury and to explore the role of target miRNA during this process.,Using miRNA microarray analysis, we found changes of 19 miRNAs from the expression profile of miRNAs in a mouse model of intestinal I/R and further verified them by RT-qPCR.,Here, we report that miR-378 is one of the markedly decreased miRNAs and found the putative target mRNA that is linked to cell death after applying the TargetScan, miRanda, CLIP-Seq and miRDB prediction algorithms.,Our results show that the overexpression of miR-378 significantly ameliorated intestinal tissue damage in wild-type and transgenic mice and oxygen glucose deprivation/reperfusion-challenged IEC-6 cell injury.,Moreover, miR-378 overexpression reduced intestinal epithelial cell apoptosis in both in vivo and in vitro ischemic models and attenuated cleaved caspase-3 expression.,Collectively, our results revealed that the suppression of caspase-3 activation by miRNA-378 overexpression may be involved in the protective effects of intestinal ischemic damage.,MiRNA-378 may serve as a key regulator and therapeutic target in intestinal I/R injury. | 1 |
The coexistence of coronavirus disease 2019 (COVID-19) and pulmonary embolism (PE), two life-threatening illnesses, in the same patient presents a unique challenge.,Guidelines have delineated how best to diagnose and manage patients with PE.,However, the unique aspects of COVID-19 confound both the diagnosis and treatment of PE, and therefore require modification of established algorithms.,Important considerations include adjustment of diagnostic modalities, incorporation of the prothrombotic contribution of COVID-19, management of two critical cardiorespiratory illnesses in the same patient, and protecting patients and health-care workers while providing optimal care.,The benefits of a team-based approach for decision-making and coordination of care, such as that offered by pulmonary embolism response teams (PERTs), have become more evident in this crisis.,The importance of careful follow-up care also is underscored for patients with these two diseases with long-term effects.,This position paper from the PERT Consortium specifically addresses issues related to the diagnosis and management of PE in patients with COVID-19. | 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. | 1 |
Using combined positron emission tomography and CT (PET-CT), we measured aortic inflammation and calcification in patients with abdominal aortic aneurysms (AAA), and compared them with matched controls with atherosclerosis.,We prospectively recruited 63 patients (mean age 76.1±6.8 years) with asymptomatic aneurysm disease (mean size 4.33±0.73 cm) and 19 age-and-sex-matched patients with confirmed atherosclerosis but no aneurysm.,Inflammation and calcification were assessed using combined 18F-FDG PET-CT and quantified using tissue-to-background ratios (TBRs) and Agatston scores.,In patients with AAA, 18F-FDG uptake was higher within the aneurysm than in other regions of the aorta (mean TBRmax2.23±0.46 vs 2.12±0.46, p=0.02).,Compared with atherosclerotic control subjects, both aneurysmal and non-aneurysmal aortae showed higher 18F-FDG accumulation (total aorta mean TBRmax2.16±0.51 vs 1.70±0.22, p=0.001; AAA mean TBRmax2.23±0.45 vs 1.68±0.21, p<0.0001).,Aneurysms containing intraluminal thrombus demonstrated lower 18F-FDG uptake within their walls than those without (mean TBRmax2.14±0.43 vs 2.43±0.45, p=0.018), with thrombus itself showing low tracer uptake (mean TBRmax thrombus 1.30±0.48 vs aneurysm wall 2.23±0.46, p<0.0001).,Calcification in the aneurysmal segment was higher than both non-aneurysmal segments in patients with aneurysm (Agatston 4918 (2901-8008) vs 1017 (139-2226), p<0.0001) and equivalent regions in control patients (442 (304-920) vs 166 (80-374) Agatston units per cm, p=0.0042).,The entire aorta is more inflamed in patients with aneurysm than in those with atherosclerosis, perhaps suggesting a generalised inflammatory aortopathy in patients with aneurysm.,Calcification was prominent within the aneurysmal sac, with the remainder of the aorta being relatively spared.,The presence of intraluminal thrombus, itself metabolically relatively inert, was associated with lower levels of inflammation in the adjacent aneurysmal wall. | Aortic aneurysm is a life-threatening disease due to the risk of aortic rupture.,The only curative treatment available relies on surgical approaches; drug-based therapies are lacking, highlighting an unmet need for clinical practice.,Abdominal aortic aneurysm (AAA) is frequently associated with atherosclerosis and cardiovascular risk factors including male sex, age, smoking, hypertension, and dyslipidaemia.,Thoracic aortic aneurysm (TAA) is more often linked to genetic disorders of the extracellular matrix and the contractile apparatus but also share similar cardiovascular risk factors.,Intriguingly, a large body of evidence points to an inverse association between diabetes and both AAA and TAA.,A better understanding of the mechanisms underlying the negative association between diabetes and aortic aneurysm could help the development of innovative diagnostic and therapeutic approaches to tackle the disease.,Here, we summarize current knowledge on the relationship between glycaemic parameters, diabetes, and the development of aortic aneurysm.,Cellular and molecular pathways that underlie the protective effect of diabetes itself and its treatment are reviewed and discussed, along with their potential implications for clinical translation. | 1 |
COVID-19 infections are associated with a high prevalence of venous thromboembolism, particularly pulmonary embolism (PE).,It is suggested that COVID-19 associated PE represents in situ immunothrombosis rather than venous thromboembolism, although the origin of thrombotic lesions in COVID-19 patients remains largely unknown.,In this study, we assessed the clinical and computed tomography (CT) characteristics of PE in 23 consecutive patients with COVID-19 pneumonia and compared these to those of 100 consecutive control patients diagnosed with acute PE before the COVID-19 outbreak.,Specifically, RV/LV diameter ratio, pulmonary artery trunk diameter and total thrombus load (according to Qanadli score) were measured and compared.,We observed that all thrombotic lesions in COVID-19 patients were found to be in lung parenchyma affected by COVID-19.,Also, the thrombus load was lower in COVID-19 patients (Qanadli score −8%, 95% confidence interval [95%CI] −16 to −0.36%) as was the prevalence of the most proximal PE in the main/lobar pulmonary artery (17% versus 47%; −30%, 95%CI −44% to −8.2).,Moreover, the mean RV/LV ratio (mean difference −0.23, 95%CI −0.39 to −0.07) and the prevalence of RV/LV ratio >1.0 (prevalence difference −23%, 95%CI −41 to −0.86%) were lower in the COVID-19 patients.,Our findings therefore suggest that the phenotype of COVID-19 associated PE indeed differs from PE in patients without COVID-19, fuelling the discussion on its pathophysiology.,•COVID-19 pneumonia is associated with high incidence of pulmonary embolism (PE).,•The origin of COVID-19 associated PE is debated.,•We compared radiological PE parameters in COVID-19 patients with control patients.,•In COVID-19 patients, thrombus load and prevalence of RV dysfunction was lower.,•Our findings support the concept of in situ immunothrombosis in COVID-19 patients,COVID-19 pneumonia is associated with high incidence of pulmonary embolism (PE).,The origin of COVID-19 associated PE is debated.,We compared radiological PE parameters in COVID-19 patients with control patients.,In COVID-19 patients, thrombus load and prevalence of RV dysfunction was lower.,Our findings support the concept of in situ immunothrombosis in COVID-19 patients | There is no known effective therapy for patients with coronavirus disease 2019 (COVID-19).,Initial reports suggesting the potential benefit of hydroxychloroquine/azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide.,However, while the true efficacy of this regimen is unknown, initial reports have raised concerns about the potential risk of QT interval prolongation and induction of torsade de pointes (TdP).,The purpose of this study was to assess the change in corrected QT (QTc) interval and arrhythmic events in patients with COVID-19 treated with HY/AZ.,This is a retrospective study of 251 patients from 2 centers who were diagnosed with COVID-19 and treated with HY/AZ.,We reviewed electrocardiographic tracings from baseline and until 3 days after the completion of therapy to determine the progression of QTc interval and the incidence of arrhythmia and mortality.,The QTc interval prolonged in parallel with increasing drug exposure and incompletely shortened after its completion.,Extreme new QTc interval prolongation to >500 ms, a known marker of high risk of TdP, had developed in 23% of patients.,One patient developed polymorphic ventricular tachycardia suspected as TdP, requiring emergent cardioversion.,Seven patients required premature termination of therapy.,The baseline QTc interval of patients exhibiting extreme QTc interval prolongation was normal.,The combination of HY/AZ significantly prolongs the QTc interval in patients with COVID-19.,This prolongation may be responsible for life-threatening arrhythmia in the form of TdP.,This risk mandates careful consideration of HY/AZ therapy in light of its unproven efficacy.,Strict QTc interval monitoring should be performed if the regimen is given. | 1 |
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. | Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition.,Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated.,Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS.,The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology.,This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy. | 1 |
Subpleural consolidations have been found in lung ultrasound in patients with COVID-19, possibly deriving from pulmonary embolism (PE).,The diagnostic utility of impact of lung ultrasound in critical-ill patients with COVID-19 for PE diagnostics however is unclear.,We retrospectively evaluated all SARS-CoV2-associated ARDS patients admitted to our ICU between March 8th and May 31th 2020.,They were enrolled in this study, when a lung ultrasound and a computed tomography pulmonary angiography (CTPA) were documented.,In addition, wells score was calculated to estimate the probability of PE.,The CTPA was used as the gold standard for the detection of PE.,Twenty out of 25 patients met the inclusion criteria.,In 12/20 patients (60%) (sub-) segmental PE were detected by CT-angiography.,Lung ultrasound found subpleural consolidations in 90% of patients.,PE-typical large supleural consolidations with a size ≥ 1 cm were detectable in 65% of patients and were significant more frequent in patients with PE compared to those without (p = 0.035).,Large consolidations predicted PE with a sensitivity of 77% and a specificity of 71%.,The Wells score was significantly higher in patients with PE compared to those without (2.7 ± 0.8 and 1.7 ± 0.5, respectively, p = 0.042) and predicted PE with an AUC of 0.81.,When combining the two modalities, comparing patients with considered/probable PE using LUS plus a Wells score ≥ 2 to patients with possible/unlikely PE in LUS plus a Wells score < 2, PE could be predicted with a sensitivity of 100% and a specificity of 80%.,Large consolidations detected in lung ultrasound were found frequently in COVID-19 ARDS patients with pulmonary embolism.,In combination with a Wells score > 2, this might indicate a high-risk for PE in COVID-19.,The online version of this article (10.1007/s11239-020-02323-0) contains supplementary material, which is available to authorized users. | 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. | 1 |
Authors have noticed an increase in lung apex abnormalities on CT angiography (CTA) of the head and neck performed for stroke workup during the coronavirus disease 2019 (COVID-19) pandemic.,To evaluate the incidence of these CTA findings and their relation to COVID-19 infection.,In this retrospective multicenter institutional review board-approved study, assessment was made of CTA findings of code patients who had a stroke between March 16 and April 5, 2020 at six hospitals across New York City.,Demographic data, comorbidities, COVID-19 status, and neurological findings were collected.,Assessment of COVID-19 related lung findings on CTA was made blinded to COVID-19 status.,Incidence rates of COVID-19 related apical findings were assessed in all code patients who had a stroke and in patients with a stroke confirmed by imaging.,The cohort consisted of a total of 118 patients with mean±SD age of 64.9±15.7 years and 57.6% (68/118) were male.,Among all code patients who had a stroke, 28% (33/118) had COVID-19 related lung findings.,RT-PCR was positive for COVID-19 in 93.9% (31/33) of these patients with apical CTA findings.,Among patients who had a stroke confirmed by imaging, 37.5% (18/48) had COVID-19 related apical findings.,RT-PCR was positive for COVID-19 in all (18/18) of these patients with apical findings.,The incidence of COVID-19 related lung findings in stroke CTA scans was 28% in all code patients who had a stroke and 37.5% in patients with a stroke confirmed by imaging.,Stroke teams should closely assess the lung apices during this COVID-19 pandemic as CTA findings may be the first indicator of COVID-19 infection. | 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. | 1 |
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. | A novel coronavirus disease (COVID-19) in Wuhan has caused an outbreak and become a major public health issue in China and great concern from international community.,Myocarditis and myocardial injury were suspected and may even be considered as one of the leading causes for death of COVID-19 patients.,Therefore, we focused on the condition of the heart, and sought to provide firsthand evidence for whether myocarditis and myocardial injury were caused by COVID-19.,We enrolled patients with confirmed diagnosis of COVID-19 retrospectively and collected heart-related clinical data, mainly including cardiac imaging findings, laboratory results and clinical outcomes.,Serial tests of cardiac markers were traced for the analysis of potential myocardial injury/myocarditis.,112 COVID-19 patients were enrolled in our study.,There was evidence of myocardial injury in COVID-19 patients and 14 (12.5%) patients had presented abnormalities similar to myocarditis.,Most of patients had normal levels of troponin at admission, that in 42 (37.5%) patients increased during hospitalization, especially in those that died.,Troponin levels were significantly increased in the week preceding the death.,15 (13.4%) patients have presented signs of pulmonary hypertension.,Typical signs of myocarditis were absent on echocardiography and electrocardiogram.,The clinical evidence in our study suggested that myocardial injury is more likely related to systemic consequences rather than direct damage by the 2019 novel coronavirus.,The elevation in cardiac markers was probably due to secondary and systemic consequences and can be considered as the warning sign for recent adverse clinical outcomes of the patients.,•The evidence from clinical standpoint and front-line data in Wuhan for COVID-19.,•The novel coronavirus in COVID-19 less likely caused myocardial injury directly.,•Elevation in cardiac markers is the warning sign of adverse outcomes for COVID-19.,The evidence from clinical standpoint and front-line data in Wuhan for COVID-19.,The novel coronavirus in COVID-19 less likely caused myocardial injury directly.,Elevation in cardiac markers is the warning sign of adverse outcomes for COVID-19. | 1 |
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. | 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. | 1 |
The association between coronavirus disease 2019 (COVID-19) and hypercoagulability has been extensively described, and pulmonary embolism is a recognized complication of COVID-19.,Currently, the need for computed tomography pulmonary angiogram (CTPA) relies on the Wells score and serum D-dimer levels.,However, because COVID-19 patients have a different thrombotic and inflammatory milieu, the usefulness of the Wells score deserves further exploration for this patient population.,We aimed to explore the ability of the Wells score to predict pulmonary embolism in patients with COVID-19.,In this retrospective study, patients found to have a CTPA and a COVID-19 diagnosis during the same admission were selected for analysis.,Age and sex, CTPA results, and associated D-dimer levels were entered in a database.,The Wells score sensitivity and specificity were calculated at different values, and the area under the curve of the receiver operating characteristic curve measured.,Of 459 patients with COVID-19, 64 had a CTPA and 12 (19%) had evidence of pulmonary embolism.,Previous or current evidence of deep vein thrombosis, a Wells score above 4 points, and serum D-dimer levels 5 times above age-adjusted upper normal values were associated with pulmonary embolism.,However, only 33% of patients with pulmonary embolism had a Wells score of 4 points or higher.,The area under the curve of the receiver operating characteristic showed non-discriminating values (0.54),Although a Wells score of 4 or more points predicted pulmonary embolism in our cohort, the outcome can be present even with lower scores. | 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. | 1 |
Increasing studies demonstrated that the cardiac involvements are related to coronavirus disease 2019 (COVID‐19).,Thus, we investigated the clinical characteristics of patients with COVID‐19 and further determined the risk factors for cardiac involvement in them.,We analyzed data from 102 consecutive laboratory‐confirmed and hospitalized patients with COVID‐19 (52 women aged 19-87 years).,Epidemiologic and demographic characteristics, clinical features, routine laboratory tests (including cardiac injury biomarkers), echocardiography, electrocardiography, chest imaging findings, management methods, and clinical outcomes were collected.,Patients were divided into acute cardiac injury, with and without cardiac marker abnormities groups according to different level of cardiac markers.,In this research, cardiac involvement was found in 72 of the 102 (70.6%) patients: tachycardia (n=20), electrocardiography abnormalities (n=23), echocardiography abnormalities (n=59), elevated myocardial enzymes (n=55), and acute cardiac injury (n=9).,Eight patients with acute cardiac injury were aged >60 years; seven of them had ≥2 underlying comorbidities (hypertension, diabetes mellitus, cardiovascular diseases, chronic obstructive pulmonary disease, and chronic kidney disease).,Novel coronavirus pneumonia was much more severe in the patients with acute cardiac injury than in patients with nondefinite acute cardiac injury (P<0.001).,Multivariate analyses showed that CRP (C‐reactive protein) levels, old age, novel coronavirus pneumonia severity, and underlying comorbidities were the risk factors for cardiac abnormalities in patients with COVID‐19.,Cardiac involvements are common in patients with COVID‐19.,Elevated CRP levels, old age, underlying comorbidities, and novel coronavirus pneumonia severity are the main risk factors for cardiac involvement in patients with COVID‐19.,More attention should be given to cardiovascular protection during COVID‐19 treatment for mortality reduction.,URL: https://www.chictr.org; Unique identifier: ChiCTR2000029955. | Studies have reminded that cardiovascular metabolic comorbidities made patients more susceptible to suffer 2019 novel corona virus (2019-nCoV) disease (COVID-19), and exacerbated the infection.,The aim of this analysis is to determine the association of cardiovascular metabolic diseases with the development of COVID-19.,A meta-analysis of eligible studies that summarized the prevalence of cardiovascular metabolic diseases in COVID-19 and compared the incidences of the comorbidities in ICU/severe and non-ICU/severe patients was performed.,Embase and PubMed were searched for relevant studies.,A total of six studies with 1527 patients were included in this analysis.,The proportions of hypertension, cardia-cerebrovascular disease and diabetes in patients with COVID-19 were 17.1%, 16.4% and 9.7%, respectively.,The incidences of hypertension, cardia-cerebrovascular diseases and diabetes were about twofolds, threefolds and twofolds, respectively, higher in ICU/severe cases than in their non-ICU/severe counterparts.,At least 8.0% patients with COVID-19 suffered the acute cardiac injury.,The incidence of acute cardiac injury was about 13 folds higher in ICU/severe patients compared with the non-ICU/severe patients.,Patients with previous cardiovascular metabolic diseases may face a greater risk of developing into the severe condition and the comorbidities can also greatly affect the prognosis of the COVID-19.,On the other hand, COVID-19 can, in turn, aggravate the damage to the heart. | 1 |
COVID‐19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis.,Lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential.,Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases.,During the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including LDH, CRP and IL‐6 may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes.,Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors.,Furthermore, blood hypercoagulability is common among hospitalized COVID‐19 patients.,Elevated D‐Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening.,Other coagulation abnormalities such as PT and aPTT prolongation, fibrin degradation products increase, with severe thrombocytopenia lead to life‐threatening disseminated intravascular coagulation (DIC), which necessitates continuous vigilance and prompt intervention.,So, COVID‐19 infected patients, whether hospitalized or ambulatory, are at high risk for venous thromboembolism, and an early and prolonged pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended.,Last but not least, the need for assuring blood donations during the pandemic is also highlighted. | Acute stroke remains a medical emergency even during the COVID-19 pandemic.,Most patients with COVID-19 infection present with constitutional and respiratory symptoms; while others present with atypical gastrointestinal, cardiovascular, or neurological manifestations.,Here we present a series of four patients with COVID-19 that presented with acute stroke.,We searched the hospital databases for patients that presented with acute stroke and concomitant features of suspected COVID-19 infection.,All patients who had radiographic evidence of stroke and PCR-confirmed COVID-19 infection were included in the study.,Patients admitted to the hospital with PCR- confirmed COVID-19 disease whose hospital course was complicated with acute stroke while inpatient were excluded from the study.,Retrospective patient data were obtained from electronic medical records.,Informed consent was obtained.,We identified four patients who presented with radiographic confirmation of acute stroke and PCR-confirmed SARS-CoV-2 infection.,We elucidate the clinical characteristics, imaging findings, and the clinical course.,Timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke.,Stroke teams should be wary of the fact that COVID-19 patients can present with cerebrovascular accidents and should don appropriate personal protective equipment in every suspected patient.,Further studies are urgently needed to improve current understandings of neurological pathology in the setting of COVID-19 infection. | 1 |
Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with COVID-19.,Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis.,The electronic health record (EHR) of a New Orleans-based health system was searched for all patients with polymerase chain reaction-confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between 1 March 2020 and 1 May 2020.,From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR.: Between 1 March 2020 and 1 May 2020, 6153 patients with COVID-19 were identified; 2748 of these patients were admitted, while 3405 received care exclusively through the emergency department.,In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy.,Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%).,In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%).,After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2075 admitted who were discharged alive (0.14%).,Among 6153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk.,Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19.,•VTE incidence for a large cohort in New Orleans, LA, does not differ from previous hospitalized populations matched for acuity.,•Noted large subpopulation of dialysis thrombosis may account for high incidence of thrombosis not related to typical VTE.,VTE incidence for a large cohort in New Orleans, LA, does not differ from previous hospitalized populations matched for acuity.,Noted large subpopulation of dialysis thrombosis may account for high incidence of thrombosis not related to typical VTE. | 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. | 1 |
Cardiac energetic impairment is a major finding in takotsubo patients.,We investigate specific metabolic adaptations to direct future therapies.,An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7.,Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB).,Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length.,Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates).,Cardiac 18F-FDG metabolic rate was increased in takotsubo (P = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P > 0.0001).,Both lactate and pyruvate were lower (P < 0.05) despite increases in LDH-RNA and PDH (P < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P = 0.01) with decreased fatty acids and acyl-carnitines levels (P = 0.0001-0.02).,Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P < 0.05) as was cellular ATP reporter dihydroorotate (P = 0.003).,Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P < 0.0001), inducing the oxidation of NAD(P)H and FAD (P = 0.03) but resolved by Day 7.,There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte.,Inflammation and remodelling were upregulated-increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P < 0.05).,Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium.,The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity.,Graphical Abstract | Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition.,Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated.,Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS.,The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology.,This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy. | 1 |
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. | 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. | 1 |
Questions persist about how learning healthcare systems should integrate audit and feedback (A&F) into quality improvement (QI) projects to support clinical teams’ use of performance data to improve care quality.,To identify how a virtual “Hub” dashboard that provided performance data for patients with transient ischemic attack (TIA), a resource library, and a forum for sharing QI plans and tools supported QI activities among newly formed multidisciplinary clinical teams at six Department of Veterans Affairs (VA) medical centers.,An observational, qualitative evaluation of how team members used a web-based Hub.,External facilitators and multidisciplinary team members at VA facilities engaged in QI to improve the quality of TIA care.,Qualitative implementation process and summative evaluation of observational Hub data (interviews with Hub users, structured field notes) to identify emergent, contextual themes and patterns of Hub usage.,The Hub supported newly formed multidisciplinary teams in implementing QI plans in three main ways: as an information interface for integrated monitoring of TIA performance; as a repository used by local teams and facility champions; and as a tool for team activation.,The Hub enabled access to data that were previously inaccessible and unavailable and integrated that data with benchmark and scientific evidence to serve as a common data infrastructure.,Led by champions, each implementation team used the Hub differently: local adoption of the staff and patient education materials; benchmarking facility performance against national rates and peer facilities; and positive reinforcement for QI plan development and monitoring.,External facilitators used the Hub to help teams leverage data to target areas of improvement and disseminate local adaptations to promote resource sharing across teams.,As a dynamic platform for A&F operating within learning health systems, hubs represent a promising strategy to support local implementation of QI programs by newly formed, multidisciplinary teams.,The online version of this article (10.1007/s11606-020-06160-y) contains supplementary material, which is available to authorized users. | Transient ischemic attack (TIA) patients are at high risk of recurrent vascular events; timely management can reduce that risk by 70%.,The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurological Symptoms (PREVENT) developed, implemented, and evaluated a TIA quality improvement (QI) intervention aligned with Learning Healthcare System principles.,This stepped-wedge trial developed, implemented and evaluated a provider-facing, multi-component intervention to improve TIA care at six facilities.,The unit of analysis was the medical center.,The intervention was developed based on benchmarking data, staff interviews, literature, and electronic quality measures and included: performance data, clinical protocols, professional education, electronic health record tools, and QI support.,The effectiveness outcome was the without-fail rate: the proportion of patients who receive all processes of care for which they are eligible among seven processes.,The implementation outcomes were the number of implementation activities completed and final team organization level.,The intervention effects on the without-fail rate were analyzed using generalized mixed-effects models with multilevel hierarchical random effects.,Mixed methods were used to assess implementation, user satisfaction, and sustainability.,PREVENT advanced three aspects of a Learning Healthcare System.,Learning from Data: teams examined and interacted with their performance data to explore hypotheses, plan QI activities, and evaluate change over time.,Learning from Each Other: Teams participated in monthly virtual collaborative calls.,Sharing Best Practices: Teams shared tools and best practices.,The approach used to design and implement PREVENT may be generalizable to other clinical conditions where time-sensitive care spans clinical settings and medical disciplines.,clinicaltrials.gov: NCT02769338 [May 11, 2016]. | 1 |
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. | Since its recognition in December 2019, covid-19 has rapidly spread globally causing a pandemic.,Pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease are associated with a greater severity and higher fatality rate of covid-19.,Furthermore, COVID-19 contributes to cardiovascular complications, including acute myocardial injury as a result of acute coronary syndrome, myocarditis, stress-cardiomyopathy, arrhythmias, cardiogenic shock, and cardiac arrest.,The cardiovascular interactions of COVID-19 have similarities to that of severe acute respiratory syndrome, Middle East respiratory syndrome and influenza.,Specific cardiovascular considerations are also necessary in supportive treatment with anticoagulation, the continued use of renin-angiotensin-aldosterone system inhibitors, arrhythmia monitoring, immunosuppression or modulation, and mechanical circulatory support. | 1 |
Although patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk patient segment.,This study sought to examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care health system.,Acute cardiovascular hospitalizations were tracked between January 1, 2019, and March 31, 2020.,Daily hospitalization rates were estimated using negative binomial models.,Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference.,From January 1, 2019, to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons.,There were 43.4% (95% confidence interval [CI]: 27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 compared with March 2019 (p < 0.001).,The daily rate of hospitalizations did not change throughout 2019 (-0.01% per day [95% CI: -0.04% to +0.02%]; p = 0.50), January 2020 (-0.5% per day [95% CI: -1.6% to +0.5%]; p = 0.31), or February 2020 (+0.7% per day [95% CI: -0.6% to +2.0%]; p = 0.27).,There was significant daily decline in hospitalizations in March 2020 (-5.9% per day [95% CI: -7.6% to -4.3%]; p < 0.001).,Length of stay was shorter (4.8 days [25th to 75th percentiles: 2.4 to 8.3 days] vs.,6.0 days [25th to 75th percentiles: 3.1 to 9.6 days]; p = 0.003) and in-hospital mortality was not significantly different (6.2% vs.,4.4%; p = 0.30) in March 2020 compared with March 2019.,During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations, and patients who were admitted had shorter lengths of stay.,These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic. | 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. | 1 |
Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection.,Increasing reports suggest an association between COVID-19 and AIS, although the underlying mechanism remains uncertain.,We performed a systematic review to characterize the clinical characteristics, neuroimaging findings, and outcomes of AIS in COVID-19 patients.,A literature search was performed in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 29th May 2020.,All studies reporting AIS occurrence in COVID-19 patients were included.,A total of 39 studies comprising 135 patients were studied.,The pooled incidence of AIS in COVID-19 patients from observational studies was 1.2% (54/4466) with a mean age of 63.4 ± 13.1 years.,The mean duration of AIS from COVID-19 symptoms onset was 10 ± 8 days, and the mean NIHSS score was 19 ± 8.,Laboratory investigations revealed an elevated mean d-dimer (9.2 ± 14.8 mg/L) and fibrinogen (5.8 ± 2.0 g/L).,Antiphospholipid antibodies were detected in a significant number of cases.,The majority of AIS neuroimaging patterns observed was large vessel thrombosis, embolism or stenosis (62.1%, 64/103), followed by multiple vascular territory (26.2%, 27/103).,A high mortality rate was reported (38.0%, 49/129).,We report the pooled incidence of AIS in COVID-19 patients to be 1.2%, with a high mortality rate.,Elevated d-dimer, fibrinogen and the presence of antiphospholipid antibodies appear to be prominent in COVID-19 patients with concomitant AIS, but further mechanistic studies are required to elucidate their role in pathogenesis.,The online version of this article (10.1007/s11239-020-02228-y) contains supplementary material, which is available to authorized users. | 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. | 1 |
Galectin-3 is a β-galactoside-binding lectin which is important in cell proliferation and apoptotic regulation.,Recently, serum galectin-3 has been shown to have prognostic value as a biomarker in heart failure.,Encephalomyocarditis virus (EMCV) can cause severe myocarditis, congestive heart failure and dilated cardiomyopathy as well as encephalitis in various animals including mice.,The pathophysiological role of galectin-3 in acute myocarditis following viral infection is not fully understood.,The goal of this study is to determine the cardiac localization and the time-course of galectin-3 expression in heart failure after viral inoculation with EMCV.,At 12, 24, 48, 96 hours, 7 and 10 days after intraperitoneal EMCV inoculation, animals were examined histologically and analyzed for the expression of galectin-3 and Iba1.,Galectin-3 was up-regulated in degenerated fibrotic lesions of cardiac tissues 96 hours after viral inoculation and were followed by myocardial fibrosis.,At the same time, Iba1 positive macrophages were observed within the inflammatory sites.,A time-course correlation between the number of galectin-3 positive cells and the cardiac area of degenerated fibrotic lesions was detected-serum galectin-3 increased at 96 hours and correlated well with the number of cardiac galectin-3 positive cells.,Our results indicate that galectin-3 expression may be a useful biomarker of cardiac fibrotic degeneration in acute myocarditis following viral infection.,In addition, measuring serum galectin-3 levels might be an early diagnostic method for detecting cardiac degeneration in acute myocarditis. | Mechanisms of maintenance of both atrial fibrillation and structural left ventricular disease are known to include fibrosis.,Galectin-3, a biomarker of fibrosis, is elevated both in patients with heart failure and persistent atrial fibrillation.,We sought to find whether galectin-3 has a prognostic value in patients with heart failure and a reduced left ventricular ejection fraction undergoing ablation of persistent atrial fibrillation.,Serum concentrations of galectin-3 were determined in a consecutive series of patients with an ejection fraction ≤40%, addressed for ablation of persistent atrial fibrillation.,Responders to ablation were patients in sinus rhythm and with an ejection fraction ≥50% at 6 months.,A combined endpoint of heart failure hospitalization, transplantation and/or death was used at 12 months.,Seventy-five patients were included (81% male, age 63±10 years, ejection fraction 34±7%, galectin-3 21±12 ng/mL).,During follow-up, eight patients were hospitalized for decompensated heart failure, 1 underwent heart transplantation, and 4 died; 50 patients were considered as responders to ablation.,After adjustment, galectin-3 level independently predicted both 6-month absence of response to ablation (OR = 0.89 per unit increase, p = 0.002).,Patients with galectin-3 levels <26 had a 95% 1-year event-free survival versus 46% in patients with galectin-3 ≥26 ng/mL (p<0.0001).,Galectin-3 levels independently predict outcomes in patients with reduced left ventricular systolic function addressed for ablation of persistent AF, and may be of interest in defining the therapeutic strategy in this population. | 1 |
Coronavirus disease 2019 (COVID-19) may predispose to venous thromboembolism.,We determined factors independently associated with computed tomography pulmonary angiography (CTPA)-confirmed pulmonary embolism (PE) in hospitalised severe COVID-19 patients.,Among all (n=349) patients hospitalised for COVID-19 in a university hospital in a French region with a high rate of COVID-19, we analysed patients who underwent CTPA for clinical signs of severe disease (oxygen saturation measured by pulse oximetry ≤93% or breathing rate ≥30 breaths·min−1) or rapid clinical worsening.,Multivariable analysis was performed using Firth penalised maximum likelihood estimates.,162 (46.4%) patients underwent CTPA (mean±sd age 65.6±13.0 years; 67.3% male (95% CI 59.5-75.5%).,PE was diagnosed in 44 (27.2%) patients.,Most PEs were segmental and the rate of PE-related right ventricular dysfunction was 15.9%.,By multivariable analysis, the only two significant predictors of CTPA-confirmed PE were D-dimer level and the lack of any anticoagulant therapy (OR 4.0 (95% CI 2.4-6.7) per additional quartile and OR 4.5 (95% CI 1.1-7.4), respectively).,Receiver operating characteristic curve analysis identified a D-dimer cut-off value of 2590 ng·mL−1 to best predict occurrence of PE (area under the curve 0.88, p<0.001, sensitivity 83.3%, specificity 83.8%).,D-dimer level >2590 ng·mL−1 was associated with a 17-fold increase in the adjusted risk of PE.,Elevated D-dimers (>2590 ng·mL−1) and absence of anticoagulant therapy predict PE in hospitalised COVID-19 patients with clinical signs of severity.,These data strengthen the evidence base in favour of systematic anticoagulation, and suggest wider use of D-dimer guided CTPA to screen for PE in acutely ill hospitalised patients with COVID-19.,We studied predictors of pulmonary embolism in severe COVID-19 and found that D-dimer level and lack of any anticoagulant therapy were associated with a 17-fold and four-fold increase in PE, respectively, in COVID-19 patients with clinical signs of severityhttps://bit.ly/2ETfAfo | Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become pandemic, with substantial mortality.,To evaluate the pathologic changes of organ systems and the clinicopathologic basis for severe and fatal outcomes.,Prospective autopsy study.,Single pathology department.,11 deceased patients with COVID-19 (10 of whom were selected at random for autopsy).,Systematic macroscopic, histopathologic, and viral analysis (SARS-CoV-2 on real-time polymerase chain reaction assay), with correlation of pathologic and clinical features, including comorbidities, comedication, and laboratory values.,Patients' age ranged from 66 to 91 years (mean, 80.5 years; 8 men, 3 women).,Ten of the 11 patients received prophylactic anticoagulant therapy; venous thromboembolism was not clinically suspected antemortem in any of the patients.,Both lungs showed various stages of diffuse alveolar damage (DAD), including edema, hyaline membranes, and proliferation of pneumocytes and fibroblasts.,Thrombosis of small and mid-sized pulmonary arteries was found in various degrees in all 11 patients and was associated with infarction in 8 patients and bronchopneumonia in 6 patients.,Kupffer cell proliferation was seen in all patients, and chronic hepatic congestion in 8 patients.,Other changes in the liver included hepatic steatosis, portal fibrosis, lymphocytic infiltrates and ductular proliferation, lobular cholestasis, and acute liver cell necrosis, together with central vein thrombosis.,Additional frequent findings included renal proximal tubular injury, focal pancreatitis, adrenocortical hyperplasia, and lymphocyte depletion of spleen and lymph nodes.,Viral RNA was detectable in pharyngeal, bronchial, and colonic mucosa but not bile.,The sample was small.,COVID-19 predominantly involves the lungs, causing DAD and leading to acute respiratory insufficiency.,Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation.,Studies are needed to further understand the thrombotic complications of COVID-19, together with the roles for strict thrombosis prophylaxis, laboratory, and imaging studies and early anticoagulant therapy for suspected pulmonary arterial thrombosis or thromboembolism.,None.,The clinicopathological basis for morbidity and mortality with SARS-CoV-2 infection is not well understood.,This study reports the clinical and autopsy findings of patients who died of COVID-19. | 1 |
ST-segment elevation myocardial infarction (STEMI) is a fatal cardiovascular emergency requiring rapid reperfusion treatment.,During the coronavirus disease-2019 (COVID-19) pandemic, medical professionals need to strike a balance between providing timely treatment for STEMI patients and implementing infection control procedures to prevent nosocomial spread of COVID-19 among health care workers and other vulnerable cardiovascular patients.,This study evaluates the impact of the COVID-19 outbreak and China Chest Pain Center’s modified STEMI protocol on the treatment and prognosis of STEMI patients in China.,Based on the data of 28,189 STEMI patients admitted to 1,372 Chest Pain Centers in China between December 27, 2019 and February 20, 2020, the study analyzed how the COVID-19 outbreak and China Chest Pain Center’s modified STEMI protocol influenced the number of admitted STEMI cases, reperfusion strategy, key treatment time points, and in-hospital mortality and heart failure for STEMI patients.,The COVID-19 outbreak reduced the number of STEMI cases reported to China Chest Pain Centers.,Consistent with China Chest Pain Center’s modified STEMI protocol, the percentage of patients undergoing primary percutaneous coronary intervention declined while the percentage of patients undergoing thrombolysis increased.,With an average delay of approximately 20 min for reperfusion therapy, the rate of in-hospital mortality and in-hospital heart failure increased during the outbreak, but the rate of in-hospital hemorrhage remained stable.,There were reductions in STEMI patients’ access to care, delays in treatment timelines, changes in reperfusion strategies, and an increase of in-hospital mortality and heart failure during the COVID-19 pandemic in China. | The current study aimed to examine the impact of COVID-19 pandemic on patient-related delay with ST-segment elevation myocardial infarction (STEMI) at a tertiary center in the United Kingdom.,The study demonstrated a significant delay in symptom-to-first medical contact and a higher cardiac troponin-I level on admission in patients with STEMI during the COVID-19 pandemic versus the pre-COVID era. | 1 |
Infection with the novel severe acute respiratory syndrome coronavirus 2 has been associated with a hypercoagulable state.,Emerging data from China and Europe have consistently shown an increased incidence of venous thromboembolism (VTE).,We aimed to identify the VTE incidence and early predictors of VTE at our high-volume tertiary care center.,We performed a retrospective cohort study of 147 patients who had been admitted to Temple University Hospital with coronavirus disease 2019 (COVID-19) from April 1, 2020 to April 27, 2020.,We first identified the VTE (pulmonary embolism [PE] and deep vein thrombosis [DVT]) incidence in our cohort.,The VTE and no-VTE groups were compared by univariable analysis for demographics, comorbidities, laboratory data, and treatment outcomes.,Subsequently, multivariable logistic regression analysis was performed to identify the early predictors of VTE.,The 147 patients (20.9% of all admissions) admitted to a designated COVID-19 unit at Temple University Hospital with a high clinical suspicion of acute VTE had undergone testing for VTE using computed tomography pulmonary angiography and/or extremity venous duplex ultrasonography.,The overall incidence of VTE was 17% (25 of 147).,Of the 25 patients, 16 had had acute PE, 14 had had acute DVT, and 5 had had both PE and DVT.,The need for invasive mechanical ventilation (adjusted odds ratio, 3.19; 95% confidence interval, 1.07-9.55) and the admission D-dimer level ≥1500 ng/mL (adjusted odds ratio, 3.55; 95% confidence interval, 1.29-9.78) were independent markers associated with VTE.,The all-cause mortality in the VTE group was greater than that in the non-VTE group (48% vs 22%; P = .007).,Our study represents one of the earliest reported from the United States on the incidence rate of VTE in patients with COVID-19.,Patients with a high clinical suspicion and the identified risk factors (invasive mechanical ventilation, admission D-dimer level ≥1500 ng/mL) should be considered for early VTE testing.,We did not screen all patients admitted for VTE; therefore, the true incidence of VTE could have been underestimated.,Our findings require confirmation in future prospective studies. | Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become pandemic, with substantial mortality.,To evaluate the pathologic changes of organ systems and the clinicopathologic basis for severe and fatal outcomes.,Prospective autopsy study.,Single pathology department.,11 deceased patients with COVID-19 (10 of whom were selected at random for autopsy).,Systematic macroscopic, histopathologic, and viral analysis (SARS-CoV-2 on real-time polymerase chain reaction assay), with correlation of pathologic and clinical features, including comorbidities, comedication, and laboratory values.,Patients' age ranged from 66 to 91 years (mean, 80.5 years; 8 men, 3 women).,Ten of the 11 patients received prophylactic anticoagulant therapy; venous thromboembolism was not clinically suspected antemortem in any of the patients.,Both lungs showed various stages of diffuse alveolar damage (DAD), including edema, hyaline membranes, and proliferation of pneumocytes and fibroblasts.,Thrombosis of small and mid-sized pulmonary arteries was found in various degrees in all 11 patients and was associated with infarction in 8 patients and bronchopneumonia in 6 patients.,Kupffer cell proliferation was seen in all patients, and chronic hepatic congestion in 8 patients.,Other changes in the liver included hepatic steatosis, portal fibrosis, lymphocytic infiltrates and ductular proliferation, lobular cholestasis, and acute liver cell necrosis, together with central vein thrombosis.,Additional frequent findings included renal proximal tubular injury, focal pancreatitis, adrenocortical hyperplasia, and lymphocyte depletion of spleen and lymph nodes.,Viral RNA was detectable in pharyngeal, bronchial, and colonic mucosa but not bile.,The sample was small.,COVID-19 predominantly involves the lungs, causing DAD and leading to acute respiratory insufficiency.,Death may be caused by the thrombosis observed in segmental and subsegmental pulmonary arterial vessels despite the use of prophylactic anticoagulation.,Studies are needed to further understand the thrombotic complications of COVID-19, together with the roles for strict thrombosis prophylaxis, laboratory, and imaging studies and early anticoagulant therapy for suspected pulmonary arterial thrombosis or thromboembolism.,None.,The clinicopathological basis for morbidity and mortality with SARS-CoV-2 infection is not well understood.,This study reports the clinical and autopsy findings of patients who died of COVID-19. | 1 |
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. | 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. | 1 |
There is an increased attention to stroke following SARS-CoV-2.,The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients.,This multicentre, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand).,The outcome was the risk of subsequent stroke.,Centres were included by non-probability sampling.,The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined protocol.,Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test.,The risk of subsequent stroke was estimated through meta-analyses with random effect models.,Bivariate logistic regression was used to determine the parameters with predictive outcome value.,The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines.,We received data from 26,175 hospitalized SARS-CoV-2 patients from 99 tertiary centres in 65 regions of 11 countries until May 1st, 2020.,A total of 17,799 patients were included in meta-analyses.,Among them, 156(0.9%) patients had a stroke-123(79%) ischaemic stroke, 27(17%) intracerebral/subarachnoid hemorrhage, and 6(4%) cerebral sinus thrombosis.,Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5% among all centres in all countries, and 0.7% among countries with higher health expenditures.,The need for mechanical ventilation (OR: 1.9, 95% CI:1.1-3.5, p = 0.03) and the presence of ischaemic heart disease (OR: 2.5, 95% CI:1.4-4.7, p = 0.006) were predictive of stroke.,The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5%(pooled risk: 0.9%).,The need for mechanical ventilation and the history of ischaemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients.,None. | 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. | 1 |
Coronavirus disease-2019 (COVID-19) is thought to predispose patients to thrombotic disease.,To date there are few reports of ST-segment elevation myocardial infarction (STEMI) caused by type 1 myocardial infarction in patients with COVID-19.,The aim of this study was to describe the demographic, angiographic, and procedural characteristics alongside clinical outcomes of consecutive cases of COVID-19-positive patients with STEMI compared with COVID-19-negative patients.,This was a single-center, observational study of 115 consecutive patients admitted with confirmed STEMI treated with primary percutaneous coronary intervention at Barts Heart Centre between March 1, 2020, and May 20, 2020.,Patients with STEMI presenting with concurrent COVID-19 infection had higher levels of troponin T and lower lymphocyte count, but elevated D-dimer and C-reactive protein.,There were significantly higher rates of multivessel thrombosis, stent thrombosis, higher modified thrombus grade post first device with consequently higher use of glycoprotein IIb/IIIa inhibitors and thrombus aspiration.,Myocardial blush grade and left ventricular function were significantly lower in patients with COVID-19 with STEMI.,Higher doses of heparin to achieve therapeutic activated clotting times were also noted.,Importantly, patients with STEMI presenting with COVID-19 infection had a longer in-patient admission and higher rates of intensive care admission.,In patients presenting with STEMI and concurrent COVID-19 infection, there is a strong signal toward higher thrombus burden and poorer outcomes.,This supports the need for establishing COVID-19 status in all STEMI cases.,Further work is required to understand the mechanism of increased thrombosis and the benefit of aggressive antithrombotic therapy in selected cases. | Severe acute respiratory syndrome coronavirus 2 causes acute myocardial damage and arrhythmia in coronavirus disease 2019 (COVID‐19) patients.,Studying the changes of electrocardiogram is of great significance for the diagnosis of patients with COVID‐19.,A retrospective analysis method was adopted to compare the electrocardiogram changes between COVID‐19 critically severe and severe patients.,Univariate and multivariate logistic regression were used to analyze the correlation of the levels of serum indexes and past medical history with ST‐T changes and atrial fibrillation.,And the correlation of ECG parameters with in‐hospital death and ventilator use were investigated by using the same methods.,The incidence of male, stroke, elevated cardiac troponin I (cTnI), N‐terminal of the prohormone brain natriuretic peptide (NT‐proBNP), d‐dimer, high‐sensitivity C‐reactive protein (hs‐CRP), hyperkalemia, and hypocalcemia in the critically ill patients was higher than that in severe patients.,There were differences in ST‐T changes, sinus tachycardia, atrial fibrillation, and atrial tachycardia between the two groups.,Multivariate logistic regression analysis showed that elevated cTnI and NT‐proBNP were the independent risk factors of ST‐T changes.,Elevated NT‐proBNP and age were the independent risk factors of atrial fibrillation.,Sinus tachycardia and atrial fibrillation were the independent risk factors of in‐hospital death and ventilator use.,ST‐T changes, sinus tachycardia, and atrial fibrillation are with great significance in the diagnosis of the severity, myocardia injury, and cardiac insufficiency of COVID‐19 patients.,Sinus tachycardia and atrial fibrillation could be used as independent variables predicting in‐hospital death and ventilator use. | 1 |
A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19.,Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail.,We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes.,For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results.,We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria.,We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L.,We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study).,The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis.,Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK.,Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging.,Of the remaining 95 patients, 70 had VITT and 25 did not.,The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045).,Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003).,The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061).,This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022).,Cerebral venous thrombosis is more severe in the context of VITT.,Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis.,Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.,None. | 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.) | 1 |
•Stroke is an infrequent, but potentially life-threatening, complication of COVID-19.,•Typical features include large vessel occlusion and multi-territory stroke.,•Atypical presentations include PRES, vasculitis, and arterial dissection.,•Sedation interruption may be required for neurologic evaluation of ICU patients.,•Older age, elevated D-dimer, LDH, and creatinine are associated with poor outcome.,Stroke is an infrequent, but potentially life-threatening, complication of COVID-19.,Typical features include large vessel occlusion and multi-territory stroke.,Atypical presentations include PRES, vasculitis, and arterial dissection.,Sedation interruption may be required for neurologic evaluation of ICU patients.,Older age, elevated D-dimer, LDH, and creatinine are associated with poor outcome.,Acute cerebrovascular disease, particularly ischemic stroke, has emerged as a serious complication of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the Coronavirus disease‐2019 (COVID-19).,Accumulating data on patients with COVID-19-associated stroke have shed light on specificities concerning clinical presentation, neuroimaging findings, and outcome.,Such specificities include a propensity towards large vessel occlusion, multi-territory stroke, and involvement of otherwise uncommonly affected vessels.,Conversely, small-vessel brain disease, cerebral venous thrombosis, and intracerebral hemorrhage appear to be less frequent.,Atypical neurovascular presentations were also described, ranging from bilateral carotid artery dissection to posterior reversible encephalopathy syndrome (PRES), and vasculitis.,Cases presenting with encephalopathy or encephalitis with seizures heralding stroke were particularly challenging.,The pathogenesis and optimal management of ischemic stroke associated with COVID-19 still remain uncertain, but emerging evidence suggest that cytokine storm-triggered coagulopathy and endotheliopathy represent possible targetable mechanisms.,Some specific management issues in this population include the difficulty in identifying clinical signs of stroke in critically ill patients in the intensive care unit, as well as the need for a protected pathway for brain imaging, intravenous thrombolysis, and mechanical thrombectomy, keeping in mind that “time is brain” also for COVID-19 patients.,In this review, we discuss the novel developments and challenges for the diagnosis and treatment of stroke in patients with COVID-19, and delineate the principles for a rational approach toward precision medicine in this emerging field. | Supplemental Digital Content is available in the text.,Coronavirus disease 2019 (COVID-19) evolved quickly into a global pandemic with myriad systemic complications, including stroke.,We report the largest case series to date of cerebrovascular complications of COVID-19 and compare with stroke patients without infection.,Retrospective case series of COVID-19 patients with imaging-confirmed stroke, treated at 11 hospitals in New York, between March 14 and April 26, 2020.,Demographic, clinical, laboratory, imaging, and outcome data were collected, and cases were compared with date-matched controls without COVID-19 from 1 year prior.,Eighty-six COVID-19-positive stroke cases were identified (mean age, 67.4 years; 44.2% women).,Ischemic stroke (83.7%) and nonfocal neurological presentations (67.4%) predominated, commonly involving multivascular distributions (45.8%) with associated hemorrhage (20.8%).,Compared with controls (n=499), COVID-19 was associated with in-hospital stroke onset (47.7% versus 5.0%; P<0.001), mortality (29.1% versus 9.0%; P<0.001), and Black/multiracial race (58.1% versus 36.9%; P=0.001).,COVID-19 was the strongest independent risk factor for in-hospital stroke (odds ratio, 20.9 [95% CI, 10.4-42.2]; P<0.001), whereas COVID-19, older age, and intracranial hemorrhage independently predicted mortality.,COVID-19 is an independent risk factor for stroke in hospitalized patients and mortality, and stroke presentations are frequently atypical. | 1 |
COVID‐19 is associated with increased risk of venous thromboembolic events (VTE).,However, there is significant heterogeneity in the thromboembolic phenotypes of COVID‐19 patients (deep vein thrombosis, pulmonary embolism/thrombosis).,The latter might be partly attributed to the variation in VTE risk factors in COVID‐19 patients including: (i) patients’ characteristics; (ii) hospitalization conditions and interventions; and (iii) SARS‐CoV‐2‐specific factors (coagulopathy, endothelial injury/microthrombosis).,Furthermore, there is methodological heterogeneity in relation to the assessment of VTE (indications for screening, diagnostic methodology, etc).,Physicians should be aware of the increased VTE risk, strongly consider VTE screening, and use thromboprophylaxis in all hospitalized patients. | 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. | 1 |
Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM).,The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk.,The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort.,A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1-16 years independent of the HCM Risk-Kids development and internal validation cohort was studied.,Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation.,The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed.,Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48-2.78].,Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52-0.97) and Uno’s C-index 0.714 (95% 0.58-0.85) with a calibration slope of 1.15 (95% 0.51-1.80).,A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60-0.81).,This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population.,A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM. | Supplemental Digital Content is available in the text.,Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults.,Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies.,In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible.,The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators.,Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD.,The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations.,The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models.,The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285).,Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up.,The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD).,Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant.,Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD.,Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD.,Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively).,Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy.,An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion.,URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679. | 1 |
Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy.,Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner.,The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice.,Thirty diabetic KK-Ay mice were administered empagliflozin (10 mg/kg/day) by oral gavage daily for 8 weeks.,After 8 weeks, heart structure and function were evaluated by echocardiography.,Oxidants and antioxidants were measured and cardiac fibrosis was analysed using immunohistochemistry, Masson’s trichrome stain and Western blot.,Results showed that empagliflozin improved diabetic myocardial structure and function, decreased myocardial oxidative stress and ameliorated myocardial fibrosis.,Further study indicated that empagliflozin suppressed oxidative stress and fibrosis through inhibition of the transforming growth factor β/Smad pathway and activation of Nrf2/ARE signaling.,Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice.,Taken together, these results indicate that the empagliflozin is a promising agent for the prevention and treatment of diabetic cardiomyopathy. | Type 2 diabetes mellitus (T2DM) greatly increases the risks of cardiovascular disease and heart failure.,In particular, left ventricular diastolic dysfunction that develops from the early stages of T2DM is an important factor in the onset and exacerbation of heart failure.,The effect of sodium-glucose cotransporter 2 inhibitors on left ventricular diastolic function has not been elucidated.,We have performed the first prospective study on the effects of canagliflozin on left ventricular diastolic function in T2DM.,This study was performed to evaluate the effects of additional treatment with canagliflozin for 3 months on left ventricular diastolic function in patients with T2DM.,A total of 38 patients with T2DM were consecutively recruited for this study.,Left ventricular diastolic function was assessed by echocardiography.,The primary study outcome was a change in the septal E/e′ as a parameter of left ventricular diastolic function.,A total of 37 patients (25 males and 12 females) were included in the analysis.,Mean age of participants was 64.2 ± 8.1 years (mean ± SD), mean duration of diabetes was 13.5 ± 8.1 years, and mean HbA1c was 7.9 ± 0.7%.,Of the participants, 86.5% had hypertension, 100% had dyslipidemia, and 32.4% had cardiovascular disease.,Canagliflozin significantly improved left ventricular diastolic function (septal E/e′ ratio 13.7 ± 3.5-12.1 ± 2.8, p = 0.001).,Furthermore, among the various parameters that changed through the administration of canagliflozin, only changes in hemoglobin significantly correlated with changes in the septal E/e′ ratio (p = 0.002).,In multiple regression analysis, changes in hemoglobin were also revealed to be an independent predictive factor for changes in the septal E/e′ ratio.,This study showed for the first time that canagliflozin could improve left ventricular diastolic function within 3 months in patients with T2DM.,The benefit was especially apparent in patients with substantially improved hemoglobin values.,Trial registration UMIN Clinical Trials Registry UMIN000028141,The online version of this article (10.1186/s12933-018-0717-9) contains supplementary material, which is available to authorized users. | 1 |
To quantitatively summarize the available epidemiological evidence on the survival rate of out-of-hospital cardiac arrest (OHCA) patients who received cardiopulmonary resuscitation (CPR).,We systematically searched the PubMed, Embase, and Web of Science databases, and the references of retrieved articles were manually reviewed to identify studies reporting the outcome of OHCA patients who received CPR.,The overall incidence and outcome of OHCA were assessed using a random-effects meta-analysis.,A total of 141 eligible studies were included in this meta-analysis.,The pooled incidence of return of spontaneous circulation (ROSC) was 29.7% (95% CI 27.6-31.7%), the rate of survival to hospital admission was 22.0% (95% CI 20.7-23.4%), the rate of survival to hospital discharge was 8.8% (95% CI 8.2-9.4%), the pooled 1-month survival rate was 10.7% (95% CI 9.1-13.3%), and the 1-year survival rate was 7.7% (95% CI 5.8-9.5%).,Subgroup analysis showed that survival to hospital discharge was more likely among OHCA patients whose cardiac arrest was witnessed by a bystander or emergency medical services (EMS) (10.5%; 95% CI 9.2-11.7%), who received bystander CPR (11.3%, 95% CI 9.3-13.2%), and who were living in Europe and North America (Europe 11.7%; 95% CI 10.5-13.0%; North America: 7.7%; 95% CI 6.9-8.6%).,The survival to discharge (8.6% in 1976-1999 vs.,9.9% in 2010-2019), 1-month survival (8.0% in 2000-2009 vs.,13.3% in 2010-2019), and 1-year survival (8.0% in 2000-2009 vs.,13.3% in 2010-2019) rates of OHCA patients who underwent CPR significantly increased throughout the study period.,The Egger’s test did not indicate evidence of publication bias for the outcomes of OHCA patients who underwent CPR.,The global survival rate of OHCA patients who received CPR has increased in the past 40 years.,A higher survival rate post-OHCA is more likely among patients who receive bystander CPR and who live in Western countries.,The online version of this article (10.1186/s13054-020-2773-2) contains supplementary material, which is available to authorized users. | For many years, bystander cardiopulmonary resuscitation (BCPR) has been considered as a favorable factor to improve survival of out-of-hospital cardiac arrests (OHCAs).,To examine the effect of BCPR on the survival of OHCAs and whether BCPR might also improve survival when the initial rhythm of OHCAs is limited, we performed a meta-analysis on published observational studies.,We did a systematic review to identify all studies published up to March, 2018, in any language, that reported the relation between BCPR and the survival of OHCAs.,Using standard forms, two authors independently identified studies for inclusion and extracted information.,The outcome was survival.,Meta-regression was done to ascertain weighted factors for the outcomes.,Data were extracted from 19 studies involving 232,703 patients.,Firstly, pooled odds ratio (OR) from 16 cohort studies showed that BCPR was associated with improved chance of survival of OHCAs compared with NO-BCPR (OR 1.95, 95% confidence interval [CI]: 1.66-2.30).,Secondly, from 8 cohort studies of OHCAs whose initial rhythm is limited, the pooled OR was 2.10 (95% CI, 1.68-2.63) of 6 articles for shockable rhythm and 1.07 (95% CI, 0.37-3.13) of 2 articles for non-shockable rhythm.,Meta-regression showed a relation between the survival of OHCAs and BCPR was influenced by area (p < 0.05).,Based on currently available evidence, the findings of this meta-analysis suggest that BCPR increases the survival of OHCAs, and it also help OHCAs whose initial rhythm is shockable.,That is to say BCPR is also helpful when emergency department response time is short.,Therefore global priority should be given to increasing the incidence of BCPR by evidence-based best practice. | 1 |
Emerging evidence shows that severe coronavirus disease 2019 (COVID‐19) can be complicated with coagulopathy, namely disseminated intravascular coagulation, which has a rather prothrombotic character with high risk of venous thromboembolism.,The incidence of venous thromboembolism among COVID‐19 patients in intensive care units appears to be somewhat higher compared to that reported in other studies including such patients with other disease conditions.,D‐dimer might help in early recognition of these high‐risk patients and also predict outcome.,Preliminary data show that in patients with severe COVID‐19, anticoagulant therapy appears to be associated with lower mortality in the subpopulation meeting sepsis‐induced coagulopathy criteria or with markedly elevated d‐dimer.,Recent recommendations suggest that all hospitalized COVID‐19 patients should receive thromboprophylaxis, or full therapeutic‐intensity anticoagulation if such an indication is present. | 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. | 1 |
Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization.,Electrophysiologists have been impacted personally and professionally by this global catastrophe.,In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators.,We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities.,We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations.,In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients. | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system.,Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19. | 1 |
Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19).,What is the incidence of VTE and bleeding among hospitalized patients with COVID-19?,In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language.,Incidence estimates were pooled by using random effects meta-analyses.,Heterogeneity was evaluated by using the I2 statistic, and publication bias was assessed by using the Begg and Egger tests.,The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding.,In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs.,The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%).,Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies.,Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection.,Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes.,PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/. | 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. | 1 |
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. | Coronavirus disease 2019 (COVID-19) is a pandemic that has affected more than 1.8 million people worldwide, overwhelmed health care systems owing to the high proportion of critical presentations, and resulted in more than 100,000 deaths.,Since the first data analyses in China, elevated cardiac troponin has been noted in a substantial proportion of patients, implicating myocardial injury as a possible pathogenic mechanism contributing to severe illness and mortality.,Accordingly, high troponin levels are associated with increased mortality in patients with COVID-19.,This brief review explores the available evidence regarding the association between COVID-19 and myocardial injury. | 1 |
Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease.,Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome.,Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases.,The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging.,Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected.,As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM.,Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias.,In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis.,An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.,Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and impaired contractility without an underlying ischaemic origin.,DCM has heterogeneous aetiologies (including gene mutations, infections and inflammation) and clinical presentations and can eventually result in heart failure. | Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption.,It is largely unknown which factors determine cardiac toxicity on exposure to alcohol.,This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity.,The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers.,The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM.,They evaluated the effect of genotype and alcohol consumption on phenotype in DCM.,Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13.5% vs.,2.9%; p = 1.2 ×10−5), but similar between patients with ACM and DCM (19.4%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9%).,Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria.,On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% confidence interval: −2.3% to −15.1%; p < 0.007) compared with those without TTNtv and excess alcohol consumption.,The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients.,TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels.,Familial evaluation and genetic testing should be considered in patients presenting with ACM. | 1 |
To assess the association of COVID-19 vaccines and non-COVID-19 vaccines with cerebral venous sinus thrombosis (CVST).,We retrospectively analyzed a cohort of 771,805 vaccination events across 266,094 patients in the Mayo Clinic Health System between 01/01/2017 and 03/15/2021.,The primary outcome was a positive diagnosis of CVST, identified either by the presence of a corresponding ICD code or by an NLP algorithm which detected positive diagnosis of CVST within free-text clinical notes.,For each vaccine we calculated the relative risk by dividing the incidence of CVST in the 30 days following vaccination to that in the 30 days preceding vaccination.,We identified vaccination events for all FDA-approved COVID-19 vaccines including Pfizer-BioNTech (n = 94,818 doses), Moderna (n = 36,350 doses) and Johnson & Johnson - J&J (n = 1,745 doses).,We also identified vaccinations events for 10 common FDA-approved non-COVID-19 vaccines (n = 771,805 doses).,There was no statistically significant difference in the incidence rate of CVST in 30-days before and after vaccination for any vaccine in this population.,We further found the baseline CVST incidence in the study population between 2017 and 2021 to be 45 to 98 per million patient years.,This real-world evidence-based study finds that CVST is rare and is not significantly associated with COVID-19 vaccination in our patient cohort.,Limitations include the rarity of CVST in our dataset, a relatively small number of J&J COVID-19 vaccination events, and the use of a population drawn from recipients of a SARS-CoV-2 PCR test in a single health system. | 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.) | 1 |
Long-term exposure of humans to air pollution enhances the risk of cardiovascular and respiratory diseases.,A novel Global Exposure Mortality Model (GEMM) has been derived from many cohort studies, providing much-improved coverage of the exposure to fine particulate matter (PM2.5).,We applied the GEMM to assess excess mortality attributable to ambient air pollution on a global scale and compare to other risk factors.,We used a data-informed atmospheric model to calculate worldwide exposure to PM2.5 and ozone pollution, which was combined with the GEMM to estimate disease-specific excess mortality and loss of life expectancy (LLE) in 2015.,Using this model, we investigated the effects of different pollution sources, distinguishing between natural (wildfires, aeolian dust) and anthropogenic emissions, including fossil fuel use.,Global excess mortality from all ambient air pollution is estimated at 8.8 (7.11-10.41) million/year, with an LLE of 2.9 (2.3-3.5) years, being a factor of two higher than earlier estimates, and exceeding that of tobacco smoking.,The global mean mortality rate of about 120 per 100 000 people/year is much exceeded in East Asia (196 per 100 000/year) and Europe (133 per 100 000/year).,Without fossil fuel emissions, the global mean life expectancy would increase by 1.1 (0.9-1.2) years and 1.7 (1.4-2.0) years by removing all potentially controllable anthropogenic emissions.,Because aeolian dust and wildfire emission control is impracticable, significant LLE is unavoidable.,Ambient air pollution is one of the main global health risks, causing significant excess mortality and LLE, especially through cardiovascular diseases.,It causes an LLE that rivals that of tobacco smoking.,The global mean LLE from air pollution strongly exceeds that by violence (all forms together), i.e. by an order of magnitude (LLE being 2.9 and 0.3 years, respectively).,Graphical Abstract | Exposure to ambient air pollution increases morbidity and mortality, and is a leading contributor to global disease burden.,We explored spatial and temporal trends in mortality and burden of disease attributable to ambient air pollution from 1990 to 2015 at global, regional, and country levels.,We estimated global population-weighted mean concentrations of particle mass with aerodynamic diameter less than 2·5 μm (PM2·5) and ozone at an approximate 11 km × 11 km resolution with satellite-based estimates, chemical transport models, and ground-level measurements.,Using integrated exposure-response functions for each cause of death, we estimated the relative risk of mortality from ischaemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infections from epidemiological studies using non-linear exposure-response functions spanning the global range of exposure.,Ambient PM2·5 was the fifth-ranking mortality risk factor in 2015.,Exposure to PM2·5 caused 4·2 million (95% uncertainty interval [UI] 3·7 million to 4·8 million) deaths and 103·1 million (90·8 million 115·1 million) disability-adjusted life-years (DALYs) in 2015, representing 7·6% of total global deaths and 4·2% of global DALYs, 59% of these in east and south Asia.,Deaths attributable to ambient PM2·5 increased from 3·5 million (95% UI 3·0 million to 4·0 million) in 1990 to 4·2 million (3·7 million to 4·8 million) in 2015.,Exposure to ozone caused an additional 254 000 (95% UI 97 000-422 000) deaths and a loss of 4·1 million (1·6 million to 6·8 million) DALYs from chronic obstructive pulmonary disease in 2015.,Ambient air pollution contributed substantially to the global burden of disease in 2015, which increased over the past 25 years, due to population ageing, changes in non-communicable disease rates, and increasing air pollution in low-income and middle-income countries.,Modest reductions in burden will occur in the most polluted countries unless PM2·5 values are decreased substantially, but there is potential for substantial health benefits from exposure reduction.,Bill & Melinda Gates Foundation and Health Effects Institute. | 1 |
Standard evaluation and management of the patient with suspected or proven cardiovascular complications of coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome related-coronavirus-2 (SARS-CoV-2), is challenging.,Routine history, physical examination, laboratory testing, electrocardiography, and plain x-ray imaging may often suffice for such patients, but given overlap between COVID-19 and typical cardiovascular diagnoses such as heart failure and acute myocardial infarction, need frequently arises for advanced imaging techniques to assist in differential diagnosis and management.,This document provides guidance in several common scenarios among patients with confirmed or suspected COVID-19 infection and possible cardiovascular involvement, including chest discomfort with electrocardiographic changes, acute hemodynamic instability, newly recognized left ventricular dysfunction, as well as imaging during the subacute/chronic phase of COVID-19.,For each, the authors consider the role of biomarker testing to guide imaging decision-making, provide differential diagnostic considerations, and offer general suggestions regarding application of various advanced imaging techniques. | Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy.,Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure.,Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing.,This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE).,The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients. | 1 |
Coronavirus disease 2019 (COVID-19) is a global pandemic impacting 213 countries/territories and more than 5,934,936 patients worldwide.,Cardiac injury has been reported to occur in severe and death cases.,This meta-analysis was done to summarize available findings on the association between cardiac injury and severity of COVID-19 infection.,Online databases including Scopus, PubMed, Web of Science, Cochrane Library and Google Scholar were searched to detect relevant publications up to 20 May 2020, using relevant keywords.,To pool data, a fixed- or random-effects model was used depending on the heterogeneity between studies.,In total, 22 studies with 3684 COVID-19 infected patients (severe cases=1095 and death cases=365) were included in this study.,Higher serum levels of lactate dehydrogenase (weighted mean difference (WMD) =108.86 U/L, 95% confidence interval (CI)=75.93-141.79, p<0.001) and creatine kinase-MB (WMD=2.60 U/L, 95% CI=1.32-3.88, p<0.001) were associated with a significant increase in the severity of COVID-19 infection.,Furthermore, higher serum levels of lactate dehydrogenase (WMD=213.44 U/L, 95% CI=129.97-296.92, p<0.001), cardiac troponin I (WMD=26.35 pg/mL, 95% CI=14.54-38.15, p<0.001), creatine kinase (WMD=48.10 U/L, 95% CI=0.27-95.94, p = 0.049) and myoglobin (WMD=159.77 ng/mL, 95% CI=99.54-220.01, p<0.001) were associated with a significant increase in the mortality of COVID-19 infection.,Cardiac injury, as assessed by serum analysis (lactate dehydrogenase, cardiac troponin I, creatine kinase (-MB) and myoglobin), was associated with severe outcome and death from COVID-19 infection. | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system.,Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19. | 1 |
Post-cardiac arrest syndrome, which has no specific curative treatment, contributes to the high mortality rate of victims who suffer traumatic cardiac arrest (TCA) and initially can be resuscitated.,In the present study, we investigated the potential of ulinastatin to mitigate multiple organ injury after resuscitation in a swine TCA model.,Twenty-one male pigs were subjected to hemodynamic shock (40% estimated blood loss in 20 min) followed by cardiac arrest (electrically induced ventricular fibrillation) and respiratory suspension for 5 min, and finally manual resuscitation.,At 5 min after resuscitation, pigs were randomized to receive 80,000 U/kg ulinastatin (n = 7) or the same volume of saline (n = 9) in the TCA group.,Pigs in the sham group (n = 5) were not exposed to bleeding or cardiac arrest.,At baseline and at 1, 3, and 6 h after the return of spontaneous circulation, blood samples were collected and assayed for tumor necrosis factor-alpha, interleukin 6, and other indicators of organ injury.,At 24 h after resuscitation, pigs were sacrificed and apoptosis levels were assessed in samples of heart, brain, kidney, and intestine.,One pig died in the ulinastatin group and one pig died in the TCA group; the remaining animals were included in the final analysis.,TCA and resuscitation caused significant increases in multiple organ function biomarkers in serum, increases in tumor necrosis factor-alpha, and interleukin 6 in serum and increases in the extent of apoptosis in key organs.,All these increases were lower in the ulinastatin group.,Ulinastatin may attenuate multiple organ injury after TCA, which should be explored in clinical studies.,The online version of this article (10.1186/s13017-018-0212-3) contains supplementary material, which is available to authorized users. | The aim of the present study was to assess the therapeutic effects of atorvastatin on cerebral vessel autoregulation and to explore the underlying mechanisms in a rabbit model of subarachnoid hemorrhage (SAH).,A total of 48 healthy male New Zealand rabbits (weight, 2-2.5 kg) were randomly allocated into SAH, Sham or SAH + atorvastatin groups (n=16/group).,The Sham group received 20 mg/kg/d saline solution, whereas 20 mg/kg/d atorvastatin was administered to rabbits in the SAH + atorvastatin group following SAH induction.,Changes in diameter, perimeter and basilar artery (BA) area were assessed and expression levels of the vasoactive molecules endothelin-1 (ET-1), von Willebrand factor (vWF) and thrombomodulin (TM) were measured.,Neuronal apoptosis was analyzed 72 h following SAH by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) staining.,The mortality rate in the SAH group was 18.75, 25% in the SAH + atorvastatin treated group and 0% in the Sham group (n=16/group).,The neurological score in the SAH + atorvastatin group was 1.75±0.68, which was significantly higher compared with the Sham group (0.38±0.49; P<0.05).,The BA area in the SAH + atorvastatin group (89.6±9.11) was significantly lower compared with the SAH group (115.4±11.0; P<0.01).,The present study demonstrated that SAH induction resulted in a significant increase in the diameter, perimeter and cross-sectional area of the BA in the SAH + atorvastatin group.,Administration of atorvastatin may significantly downregulate the expression levels of ET-1, vWF and TM (all P<0.01) vs. sham and SAH groups.,TUNEL staining demonstrated that neuronal apoptosis was remarkably reduced in the hippocampus of SAH rabbits following treatment with atorvastatin (P<0.05).,Atorvastatin treatment may alleviate cerebral vasospasm and mediate structural and functional remodeling of vascular endothelial cells, in addition to promoting anti-apoptotic signaling.,These results provided supporting evidence for the use of atorvastatin as an effective and well-tolerated treatment for SAH in various clinical settings and may protect the autoregulation of cerebral vessels. | 1 |
The coronavirus disease 2019 (COVID-19), elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a pandemic public health emergency of global concern.,Other than the profound severe pulmonary damage, SARS-CoV-2 infection also leads to a series of cardiovascular abnormalities, including myocardial injury, myocarditis and pericarditis, arrhythmia and cardiac arrest, cardiomyopathy, heart failure, cardiogenic shock, and coagulation abnormalities.,Meanwhile, COVID-19 patients with preexisting cardiovascular diseases are often at a much higher risk of increased morbidity and mortality.,Up-to-date, a number of mechanisms have been postulated for COVID-19-associated cardiovascular damage including SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) activation, cytokine storm, hypoxemia, stress and cardiotoxicity of antiviral drugs.,In this context, special attention should be given towards COVID-19 patients with concurrent cardiovascular diseases, and special cardiovascular attention is warranted for treatment of COVID-19. | 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. | 1 |
SARS-CoV-2 infection is associated with hypercoagulability which predisposes to venous thromboembolism (VTE).,We analyzed platelet and neutrophil activation in COVID-19 patients and their association with VTE.,Hospitalized COVID-19 patients and age- and sex-matched healthy controls were studied.,Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase-9 (MMP-9), a neutrophil-released enzyme, were measured.,Four patients were re-studied after recovery.,The activating effect of COVID-19 plasma on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied.,36 COVID-19 patients and 31 healthy controls were studied; 8/36 COVID-19 patients (22.2%) developed VTE.,Platelets and neutrophils were activated in COVID-19 patients.,NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis.,Plasmatic MMP-9 was significantly increased in COVID-19 patients.,Platelet and neutrophil activation markers, but less so NETs, normalized after recovery.,In vitro, plasma from COVID-19 patients triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic dose low-molecular weight heparin, but not by aspirin or dypiridamole.,Platelet and neutrophil activation are key features of COVID-19 patients.,NET biomarkers may help to predict clinical worsening and VTE, and may guide LMWH-treatment intensity. | Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs.,The processes that trigger organ damage in COVID-19 are incompletely understood.,Samples were donated from hospitalized patients.,Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry.,Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels.,Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage.,In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs.,In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity.,Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage.,These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage.,Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung | 1 |
N6-methyladenosine (m6A) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis.,However, the potential involvement of m6A in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear.,In this study, we aimed to investigate the essential role of m6A modification in heart regeneration during postnatal and adult injury.,Methods and results: In this study, we identified the downregulation of m6A demethylase ALKBH5, an m6A “eraser” that is responsible for increased m6A methylation, in the heart after birth.,Notably, ALKBH5 knockout mice exhibited decreased cardiac regenerative ability and heart function after neonatal apex resection.,Conversely, forced expression of ALKBH5 via adeno-associated virus-9 (AAV9) delivery markedly reduced the infarct size, restored cardiac function and promoted CM proliferation after myocardial infarction in juvenile (7 days old) and adult (8-weeks old) mice.,Mechanistically, ALKBH5-mediated m6A demethylation improved the mRNA stability of YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP).,The modulation of ALKBH5 and YTHDF1 expression in human induced pluripotent stem cell-derived cardiomyocytes consistently yielded similar results.,Conclusion: Taken together, our findings highlight the vital role of the ALKBH5-m6A-YTHDF1-YAP axis in the regulation of CMs to re-enter the cell cycle.,This finding suggests a novel potential therapeutic strategy for cardiac regeneration. | Aims: The N6-methyladenosine (m6A) modification plays an important role in various biological processes, but its role in atherosclerosis remains unknown.,The aim of this study was to investigate the role and mechanism of m6A modification in endothelial cell inflammation and its influence on atherosclerosis development.,Methods: We constructed a stable TNF-α-induced endothelial cell inflammation model and assessed the changes in the expression of m6A modification-related proteins to identify the major factors involved in this process.,The m6A-modified mRNAs were identified by methylated RNA immunoprecipitation (RIP) sequencing and forkhead box O1 (FOXO1) was selected as a potential target.,Through cytological experiments, we verified whether methyltransferase-like 14 (METTL14) regulates FOXO1 expression by regulating m6A-dependent mRNA and protein interaction.,The effect of METTL14 on atherosclerosis development in vivo was verified using METTL14 knockout mice.,Results: These findings confirmed that METTL14 plays major roles in TNF-α-induced endothelial cell inflammation.,During endothelial inflammation, m6A modification of FOXO1, an important transcription factor, was remarkably increased.,Moreover, METTL14 knockdown significantly decreased TNF-α-induced FOXO1 expression.,RIP assay confirmed that METTL14 directly binds to FOXO1 mRNA, increases its m6A modification, and enhances its translation through subsequent YTH N6-methyladenosine RNA binding protein 1 recognition.,Furthermore, METTL14 was shown to interact with FOXO1 and act directly on the promoter regions of VCAM-1 and ICAM-1 to promote their transcription, thus mediating endothelial cell inflammatory response.,In vivo experiments showed that METTL14 gene knockout significantly reduced the development of atherosclerotic plaques.,Conclusion: METTL14 promotes FOXO1 expression by enhancing its m6A modification and inducing endothelial cell inflammatory response as well as atherosclerotic plaque formation.,Decreased expression of METTL14 can inhibit endothelial inflammation and atherosclerosis development.,Therefore, METTL14 may serve as a potential target for the clinical treatment of atherosclerosis. | 1 |
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. | 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. | 1 |
Cardiovascular complications related to coronavirus disease 2019 (COVID‐19) have led to the need for echocardiographic services during the pandemic.,The present study aimed to identify the echocardiographic findings in hospitalized COVID‐19 patients and their utility in disease management.,We included patients who were diagnosed with COVID‐19 using polymerase chain reaction and those who underwent echocardiographic examination during their hospitalization.,Altogether, 45 patients were evaluated.,The mean age was 61.4 ± 12.2 years.,Hypertension (n = 29, 64%) and diabetes mellitus (n = 25, 55%) were the most common comorbidities followed by congestive heart failure (n = 11, 24%), coronary artery disease (n = 9, 20%), and valvular heart disease (n = 3, 7%).,Eight patients (18%) showed evidence of myocardial injury, as suggested by elevated troponin levels.,Brain natriuretic peptide was elevated in 14 patients (36%), and 14 patients had left ventricular dysfunction in the form of reduced ejection fraction (31%).,Right ventricular (RV) dilatation was observed in six patients, and five patients had reduced RV ejection fraction.,RV pressure and volume overload were observed in three patients.,RV thrombus was observed in one patient.,Pulmonary pressure was elevated in 10 patients (24%).,Two‐dimensional echocardiography can be an important bedside tool for the assessment of cardiovascular abnormalities and hemodynamic status of COVID‐19 patients. | Myocardial involvement induced by SARS-CoV-2 infection might be important for long-term prognosis.,The aim of this observational study was to characterize the myocardial effects during SARS-CoV-2 infections by echocardiography.,An extended echocardiographic image acquisition protocol was performed in 18 patients with SARS-CoV-2 infection assessing LV longitudinal, radial, and circumferential deformation including rotation, twist, and untwisting.,Furthermore, LV deformation was analyzed in an age-matched control group of healthy individuals (n = 20).,The most prevalent finding was a reduced longitudinal strain observed predominantly in more than one basal LV segment (n = 10/14 patients, 71%).,This pattern reminded of a “reverse tako-tsubo” morphology that is not typical for other viral myocarditis.,Additional findings included a biphasic pattern with maximum post-systolic or negative regional radial strain predominantly basal (n = 5/14 patients, 36%); the absence or dispersion of basal LV rotation (n = 6/14 patients, 43%); a reduced or positive regional circumferential strain in more than one segment (n = 7/14 patients, 50%); a net rotation showing late post-systolic twist or biphasic pattern (n = 8/14 patients, 57%); a net rotation showing polyphasic pattern and/or higher maximum net values during diastole (n = 8/14 patients, 57%).,Myocardial involvement due to SARS-CoV-2-infection was highly prevalent in the present cohort-even in patients with mild symptoms.,It appears to be characterized by specific speckle tracking deformation abnormalities in the basal LV segments.,These data set the stage to prospectively test whether these parameters are helpful for risk stratification and for the long-term follow-up of these patients. | 1 |
Cardiovascular complications represent the major cause of morbidity and mortality of type 2 diabetes mellitus (T2DM) patients.,In particular, peripheral artery disease (PAD) represents a frequent T2DM vascular complication and a risk factor for the development of major adverse cardiovascular events (MACE).,Among adipokines, omentin-1 serum levels are reduced in T2DM patients with PAD and are inversely related to disease severity.,To study the relationship between omentin-1 levels, at baseline, with outcomes after endovascular procedures in T2DM patients with PAD and chronic limb-threatening ischemia (CLTI).,We enrolled for our prospective non-randomized study, 207 T2DM patients with PAD and CLTI, requiring revascularization.,Omentin-1 serum levels were collected before revascularization and patients incidence outcomes were evaluated at 1, 3, 6 and 12 months.,Omentin-1 was reduced in patients with more severe disease (27.24 ± 4.83 vs 30.82 ± 5.48 ng/mL, p < 0.001).,Overall, 84 MACE and 96 major adverse limb events (MALE) occurred during the 12-month follow-up.,We observed that omentin-1 levels were lower in patients with MACE (26.02 ± 4.05 vs 31.33 ± 5.29 ng/mL, p < 0.001) and MALE (26.67 ± 4.21 vs 31.34 ± 5.54 ng/mL, p < 0.001).,The association between omentin-1, MACE and MALE remained significant after adjusting for major risk factors in a multivariate analysis.,Receiver operating characteristics (ROC) curve using omentin-1 levels predicted incidence events (area under the curve = 0.80).,We demonstrated that reduced omentin-1 levels, at baseline, are related with worse vascular outcomes in T2DM patients with PAD and CLTI undergoing an endovascular procedure. | Type-2 diabetes mellitus is one of the major risk factors of atherosclerosis, particularly in peripheral artery disease (PAD).,Several studies have documented a correlation between omentin-1 serum levels, atherosclerosis, and cardiovascular diseases.,However, a clear link between circulating omentin-1 and PAD in diabetic patients has yet to be established.,The aim of this study was to investigate the potential role of omentin-1 in PAD in type-2 diabetic patients.,In this cross-sectional study, we analyzed omentin-1 serum levels by ELISA in 600 type-2 diabetic patients with (n = 300) and without (n = 300) PAD at Fontaine’s stage II, III, or IV.,We found that omentin-1 serum levels were significantly lower in diabetic patients with PAD than in diabetic controls (29.46 vs 49.24 ng/mL, P < 0.001) and that the levels gradually decreased in proportion to disease severity (P < 0.05).,The association between omentin-1 levels and PAD remained significant after adjusting for major risk factors in a multivariate analysis.,Our results suggest that omentin-1 is reduced in type 2 diabetic patients with PAD and that omentin-1 levels are related to disease severity. | 1 |
Mass vaccination with the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine (BNT162b2) in Korea has resulted in many reported adverse effects.,These side effects are the object of much scrutiny in the medical community.,We report the case of a 29-year-old male who was diagnosed with myopericarditis after his second dose of Pfizer-BioNTech COVID-19 vaccine.,This patient is the second recognized case of Pfizer-BioNTech COVID-19 vaccine induced myopericarditis in Korea and the first to have recovered from it.,He originally presented with chest discomfort and exertional chest pain.,Lab tests revealed elevated cardiac marker levels and echocardiographic findings displayed minimal pericardial effusion, prompting diagnosis as myopericarditis.,We decided on two weeks of outpatient treatment with non-steroidal anti-inflammatory drugs (NSAIDs) due to the patient's mild symptoms and his occupation in the military.,When this proved insufficient, we shifted to combination therapy with low dose corticosteroids and NSAIDs.,After two weeks of treatment, the patient's symptoms and pericardial effusion had improved, and he was recovered completely 37 days after the onset. | We report the case of a previously healthy 16‐year‐old male who developed myopericarditis following the second dose of his Pfizer‐BioNTech COVID‐19 vaccine, with no other identified triggers.,Adolescents and young adults experiencing chest pain after COVD‐19 vaccination should seek emergent medical care, and emergency providers should have a low threshold to consider and evaluate for myopericarditis.,More data are needed to better understand the potential association between COVID‐19 vaccines and myopericarditis.,If a true causal link is identified, the risk must also be viewed in context with the millions of patients who have been safely vaccinated and the known morbidity and mortality from COVID‐19 infection.,As we see widespread vaccine rollout, it is important that all potential adverse reactions are reported as we continue to monitor for more rare but potentially serious side effects not identified in vaccination trials. | 1 |
The development of SARS-CoV-2 vaccines has raised several concerns regarding venous thromboembolism, namely cerebral venous thrombosis.,Although cerebral venous thrombosis has been reported after administration of a viral vector vaccine, due to a possible auto-immune mechanism inducing thrombocytopenia, the same has not happened in mRNA vaccines.,We report two cases of cerebral venous thrombosis, shortly after administration of mRNA vaccine.,In both patients, there was no evidence of thrombocytopenia or antiplatelet antibodies, and alternative causes for cerebral venous thrombosis were found.,As such, despite the temporal relation of both cases to vaccine administration, these types of cerebral venous thrombosis do not seem to be pathophysiological different from cerebral venous thrombosis not associated to SARS-CoV-2 vaccination.,Continuous pharmacovigilance is necessary to monitor possible new events and clarify this association. | Since the emergence of COVID-19 pandemic, several cases of cerebral venous sinus thrombosis (CVST) have been reported in SARS-CoV-2 infected individuals.,Consecutive patients with documented SARS-CoV-2 infection, as well as clinical and radiological characteristics of CVST, were reported from three teaching hospitals in the South West, North West, and the center of Iran between June and July 2020.,We also searched the abstract archives until the end of August 2020 and gathered 28 reported cases.,The diagnostic criteria for SARS-CoV-2 infection were determined according to SARS-CoV-2 detection in oropharyngeal or nasopharyngeal samples in clinically suspected patients.,Demographics, prominent COVID-19 symptoms, confirmatory tests for SARS-CoV-2 infection diagnosis, the interval between the diagnosis of SARS-CoV-2 infection and CVST, clinical and radiological features of CVST, therapeutic strategies, CVST outcomes, rate of hemorrhagic transformation, and mortality rate were investigated.,Six patients (31-62 years-old) with confirmed CVST and SARS-CoV-2 infection were admitted to our centers.,Four patients had no respiratory symptoms of SARS-CoV-2 infection.,Five patients developed the clinical manifestations of CVST and SARS-CoV-2 infection simultaneously.,Three patients had known predisposing factors for CVST.,Despite receiving CVST and SARS-CoV-2 infection treatments, four patients died.,SARS-COV-2 associated CVST patients were older (49.26 vs.,37.77 years-old), had lower female/male ratio (1.42 vs.,2.19), and higher mortality rate (35.29% vs.,6.07%) than CVST not associated with COVID-19.,The role of SARS-CoV-2 as a “cause” versus an “additive contributor” remains to be elucidated.,Practitioners should be aware of the possibility of CVST in SARS-CoV-2 infection.,The online version contains supplementary material available at 10.1007/s00415-021-10450-8. | 1 |
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. | 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. | 1 |
Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction.,The cardiac pathological changes in these patients with COVID-19 have yet to be well described.,In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists.,The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry.,Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement.,Lymphocytic myocarditis was present in 3 (14%) of the cases.,In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant.,Increased interstitial macrophage infiltration was present in 18 (86%) of the cases.,A mild pericarditis was present in four cases.,Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases.,There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis.,Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.,In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases.,Other forms of myocardial injury are also present in these patients.,The macrophage infiltration may reflect underlying diseases rather than COVID-19. | Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization.,Electrophysiologists have been impacted personally and professionally by this global catastrophe.,In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators.,We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities.,We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations.,In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients. | 1 |
the SARS-CoV-2 infection ranges from asymptomatic to critical forms and several prognostic factors have been described.,Atrial fibrillation (AF) is common in acute situations where it is linked with more complications and mortality.,We aimed to evaluate the prognostic information of AF in this population.,retrospective analysis of a cohort of 517 patients consecutively admitted in a tertiary hospital due to SARS-CoV-2 infection.,We divided the patients in two groups according the development of AF and compared the main features of both groups.,An univariable and multivariable analysis of mortality were also performed.,among 517 patients with SARS-CoV-2 infection admitted in a tertiary center, 54 (10.4%) developed AF.,These patients are older (81.6 vs 66.5 years old, p < 0.001) and present more hypertension (74% vs 47%, p < 0.001), cardiomyopathy (9% vs 1%, p = 0.002), previous heart failure admission (9% vs 0.4%, p < 0.001), previous episodes of AF (83% vs 1%, p < 0.001) and bigger left atrium (47.8 vs 39.9 mm, p < 0.001).,AF COVID-19 patients present more acute respiratory failure (72% vs 40%, p < 0.001) and higher in-hospital mortality (50% vs 22%, p < 0.001).,Predictors of AF development are age and previous AF.,AF is not an independent predictor of in-hospital mortality.,Predictors are age, creatinine > 1.5 mg/dL at admission, LDH > 250 UI/L at admission and acute respiratory failure.,Atrial fibrillation appears in 10% of hospitalized patients with SARS-CoV-2 infection.,These patients present more comorbidities and two-fold increase in hospital mortality.,Atrial fibrillation is not an independent prognostic factor. | 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. | 1 |
Reports have suggested an association between the development of myocarditis and the receipt of messenger RNA (mRNA) vaccines against coronavirus disease 2019 (Covid-19), but the frequency and severity of myocarditis after vaccination have not been extensively explored.,We searched the database of Clalit Health Services, the largest health care organization (HCO) in Israel, for diagnoses of myocarditis in patients who had received at least one dose of the BNT162b2 mRNA vaccine (Pfizer-BioNTech).,The diagnosis of myocarditis was adjudicated by cardiologists using the case definition used by the Centers for Disease Control and Prevention.,We abstracted the presentation, clinical course, and outcome from the patient’s electronic health record.,We performed a Kaplan-Meier analysis of the incidence of myocarditis up to 42 days after the first vaccine dose.,Among more than 2.5 million vaccinated HCO members who were 16 years of age or older, 54 cases met the criteria for myocarditis.,The estimated incidence per 100,000 persons who had received at least one dose of vaccine was 2.13 cases (95% confidence interval [CI], 1.56 to 2.70).,The highest incidence of myocarditis (10.69 cases per 100,000 persons; 95% CI, 6.93 to 14.46) was reported in male patients between the ages of 16 and 29 years.,A total of 76% of cases of myocarditis were described as mild and 22% as intermediate; 1 case was associated with cardiogenic shock.,After a median follow-up of 83 days after the onset of myocarditis, 1 patient had been readmitted to the hospital, and 1 had died of an unknown cause after discharge.,Of 14 patients who had left ventricular dysfunction on echocardiography during admission, 10 still had such dysfunction at the time of hospital discharge.,Of these patients, 5 underwent subsequent testing that revealed normal heart function.,Among patients in a large Israeli health care system who had received at least one dose of the BNT162b2 mRNA vaccine, the estimated incidence of myocarditis was 2.13 cases per 100,000 persons; the highest incidence was among male patients between the ages of 16 and 29 years.,Most cases of myocarditis were mild or moderate in severity.,(Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.) | The severe acute respiratory syndrome-coronavirus-2 outbreak has rapidly reached pandemic proportions and has become a major threat to global health.,Although the predominant clinical feature of coronavirus disease-2019 (COVID-19) is an acute respiratory syndrome of varying severity, ranging from mild symptomatic interstitial pneumonia to acute respiratory distress syndrome, the cardiovascular system can be involved in several ways.,As many as 40% of patients hospitalized with COVID-19 have histories of cardiovascular disease, and current estimates report a proportion of myocardial injury in patients with COVID-19 of up to 12%.,Multiple pathways have been suggested to explain this finding and the related clinical scenarios, encompassing local and systemic inflammatory responses and oxygen supply-demand imbalance.,From a clinical point of view, cardiac involvement during COVID-19 may present a wide spectrum of severity, ranging from subclinical myocardial injury to well-defined clinical entities (myocarditis, myocardial infarction, pulmonary embolism, and heart failure), whose incidence and prognostic implications are currently largely unknown because of a significant lack of imaging data.,Integrated heart and lung multimodality imaging plays a central role in different clinical settings and is essential in the diagnosis, risk stratification, and management of patients with COVID-19.,The aims of this review are to summarize imaging-oriented pathophysiological mechanisms of lung and cardiac involvement in COVID-19 and to provide a guide for integrated imaging assessment in these patients.,•Cardiac involvement is present in up to 12% of patients with COVID-19.,•Multimodality imaging is essential in different clinical settings in COVID-19.,•Multimodality imaging is useful in diagnosis, risk stratification, and management.,•Strategies for preventing viral transmission during examinations must be adopted.,Cardiac involvement is present in up to 12% of patients with COVID-19.,Multimodality imaging is essential in different clinical settings in COVID-19.,Multimodality imaging is useful in diagnosis, risk stratification, and management.,Strategies for preventing viral transmission during examinations must be adopted. | 1 |
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. | 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. | 1 |
To describe the place and causes of acute cardiovascular death during the COVID-19 pandemic.,Retrospective cohort of adult (age ≥18 years) acute cardiovascular deaths (n=5 87 225) in England and Wales, from 1 January 2014 to 30 June 2020.,The exposure was the COVID-19 pandemic (from onset of the first COVID-19 death in England, 2 March 2020).,The main outcome was acute cardiovascular events directly contributing to death.,After 2 March 2020, there were 28 969 acute cardiovascular deaths of which 5.1% related to COVID-19, and an excess acute cardiovascular mortality of 2085 (+8%).,Deaths in the community accounted for nearly half of all deaths during this period.,Death at home had the greatest excess acute cardiovascular deaths (2279, +35%), followed by deaths at care homes and hospices (1095, +32%) and in hospital (50, +0%).,The most frequent cause of acute cardiovascular death during this period was stroke (10 318, 35.6%), followed by acute coronary syndrome (ACS) (7 098, 24.5%), heart failure (6 770, 23.4%), pulmonary embolism (2 689, 9.3%) and cardiac arrest (1 328, 4.6%).,The greatest cause of excess cardiovascular death in care homes and hospices was stroke (715, +39%), compared with ACS (768, +41%) at home and cardiogenic shock (55, +15%) in hospital.,The COVID-19 pandemic has resulted in an inflation in acute cardiovascular deaths, nearly half of which occurred in the community and most did not relate to COVID-19 infection suggesting there were delays to seeking help or likely the result of undiagnosed COVID-19. | To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs).,We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019.,We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001).,The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001).,Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191).,A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%).,The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001].,A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009).,Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates.,This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies. | 1 |
Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19).,What is the incidence of VTE and bleeding among hospitalized patients with COVID-19?,In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language.,Incidence estimates were pooled by using random effects meta-analyses.,Heterogeneity was evaluated by using the I2 statistic, and publication bias was assessed by using the Begg and Egger tests.,The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding.,In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs.,The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%).,Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies.,Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection.,Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes.,PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/. | 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. | 1 |
The results show that a functional lymphatic drainage of the aorta is critical to inhibit atherosclerosis progression and mediate its regression.,A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance.,Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood.,We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe.,Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression.,Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis.,Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis. | Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation.,Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure.,Mice (C57BL/6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days.,Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days.,Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure.,Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ‐51 and blocking endogenous vascular endothelial growth factor C with a neutralizing antibody blunted the increase in lymphatic vessel density, blunted lymphatic transport, increased inflammation, increased edema, and increased cardiac dysfunction.,Subsequent studies revealed that augmentation of the endogenous lymphangiogenesis response with vascular endothelial growth factor C treatment reduced inflammation, reduced edema, and improved cardiac dysfunction.,These results suggest that the endogenous lymphangiogenesis response plays an adaptive role in the development of ischemic‐induced heart failure and supports the emerging concept that therapeutic lymphangiogenesis is a promising new approach for the treatment of cardiovascular disease. | 1 |
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. | COVID-19 predisposes patients to a prothrombotic state with demonstrated microvascular involvement.,The degree of hypercoagulability appears to correlate with outcomes; however, optimal criteria to assess for the highest-risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography measurements of coagulation would correlate with thromboembolic events.,Patients admitted to an ICU with COVID-19 diagnoses who had thromboelastography analyses performed were studied.,Conventional coagulation assays, d-dimer levels, and viscoelastic measurements were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new-onset renal failure.,Forty-four patients with COVID-19 were included in the analysis.,Derangements in coagulation laboratory values, including elevated d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time, were confirmed; viscoelastic measurements showed an elevated maximum amplitude and low lysis of clot at 30 minutes.,A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted venous thromboembolic events with an area under the receiver operating characteristic curve of 0.742 (p = 0.021).,A d-dimer cutoff of 2,600 ng/mL predicted need for dialysis with an area under the receiver operating characteristic curve of 0.779 (p = 0.005).,Overall, patients with no lysis of clot at 30 minutes and a d-dimer > 2,600 ng/mL had a venous thromboembolic event rate of 50% compared with 0% for patients with neither risk factor (p = 0.008), and had a hemodialysis rate of 80% compared with 14% (p = 0.004).,Fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at 30 minutes on thromboelastography predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19.,Additional clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown. | 1 |
Recent studies suggest that thrombotic complications are a common phenomenon in the novel SARS-CoV-2 infection.,The main objective of our study is to assess cumulative incidence of pulmonary embolism (PE) in non critically ill COVID-19 patients and to identify its predicting factors associated to the diagnosis of pulmonary embolism.,We retrospectevely reviewed 452 electronic medical records of patients admitted to Internal Medicine Department of a secondary hospital in Madrid during Covid 19 pandemic outbreak.,We included 91 patients who underwent a multidetector Computed Tomography pulmonary angiography(CTPA) during conventional hospitalization.,The cumulative incidence of PE was assessed ant the clinical, analytical and radiological characteristics were compared between patients with and without PE.,PE incidence was 6.4% (29/452 patients).,Most patients with a confirmed diagnosed with PE recieved low molecular weight heparin (LMWH): 79.3% (23/29).,D-dimer peak was significatly elevated in PE vs non PE patients (14,480 vs 7230 mcg/dL, p = 0.03).,In multivariate analysis of patients who underwent a CTPA we found that plasma D-dimer peak was an independen predictor of PE with a best cut off point of > 5000 µg/dl (OR 3.77; IC95% (1.18-12.16), p = 0.03).,We found ninefold increased risk of PE patients not suffering from dyslipidemia (OR 9.06; IC95% (1.88-43.60).,Predictive value of AUC for ROC is 75.5%.,We found a high incidence of PE in non critically ill hospitalized COVID 19 patients despite standard thromboprophylaxis.,An increase in D-dimer levels is an independent predictor for PE, with a best cut-off point of > 5000 µg/ dl. | COVID-19 predisposes patients to a prothrombotic state with demonstrated microvascular involvement.,The degree of hypercoagulability appears to correlate with outcomes; however, optimal criteria to assess for the highest-risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography measurements of coagulation would correlate with thromboembolic events.,Patients admitted to an ICU with COVID-19 diagnoses who had thromboelastography analyses performed were studied.,Conventional coagulation assays, d-dimer levels, and viscoelastic measurements were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new-onset renal failure.,Forty-four patients with COVID-19 were included in the analysis.,Derangements in coagulation laboratory values, including elevated d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time, were confirmed; viscoelastic measurements showed an elevated maximum amplitude and low lysis of clot at 30 minutes.,A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted venous thromboembolic events with an area under the receiver operating characteristic curve of 0.742 (p = 0.021).,A d-dimer cutoff of 2,600 ng/mL predicted need for dialysis with an area under the receiver operating characteristic curve of 0.779 (p = 0.005).,Overall, patients with no lysis of clot at 30 minutes and a d-dimer > 2,600 ng/mL had a venous thromboembolic event rate of 50% compared with 0% for patients with neither risk factor (p = 0.008), and had a hemodialysis rate of 80% compared with 14% (p = 0.004).,Fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at 30 minutes on thromboelastography predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19.,Additional clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown. | 1 |
This study determined the influence of the COVID‐19 pandemic on the occurrence of multisystem inflammatory syndrome in children (MIS‐C) and compared the main characteristics of MIS‐C and Kawasaki disease (KD).,We included patients aged up to 18 years of age who were diagnosed with MIS‐C or KD in a paediatric university hospital in Paris from 1 January 2018 to 15 July 2020.,Clinical, laboratory and imaging characteristics were compared, and new French COVID‐19 cases were correlated with MIS‐C cases in our hospital.,There were seven children with MIS‐C, from 6 months to 12 years of age, who were all positive for the virus that causes COVID‐19, and 40 virus‐negative children with KD.,Their respective characteristics were as follows: under 5 years of age (14.3% vs.,85.0%), paediatric intensive care unit admission (100% vs.,10.0%), abdominal pain (71.4% vs.,12.5%), myocardial dysfunction (85.7% vs.,5.0%), shock syndrome (85.7% vs.,2.5%) and mean and standard deviation C‐reactive protein (339 ± 131 vs.,153 ± 87).,There was a strong lagged correlation between the rise and fall in MIS‐C patients and COVID‐19 cases.,The rise and fall of COVID‐19 first wave mirrored the MIS‐C cases.,There were important differences between MIS‐C and KD. | 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. | 1 |
•COVID-19 disease is associated with stroke•All strokes subtypes are seen in association with COVID-19, with ischemic stroke being most prevalent•The most common etiology for ischemic stroke in SARS-CoV2 infection is cryptogenic•Sex plays an important role in stroke outcomes in patients with COVID-19 disease•Males have higher rates of ICU admission, in-hospital complications and more likely to have worse outcome at hospital discharge compare with females,COVID-19 disease is associated with stroke,All strokes subtypes are seen in association with COVID-19, with ischemic stroke being most prevalent,The most common etiology for ischemic stroke in SARS-CoV2 infection is cryptogenic,Sex plays an important role in stroke outcomes in patients with COVID-19 disease,Males have higher rates of ICU admission, in-hospital complications and more likely to have worse outcome at hospital discharge compare with females,Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with stroke.,The role of sex on stroke outcome has not been investigated.,To objective of this paper is to describe the characteristics of a diverse cohort of acute stroke patients with COVID-19 disease and determine the role of sex on outcome.,This is a retrospective study of patients with acute stroke and SARS-CoV-2 infection admitted between March 15 to May 15, 2020 to one of the six participating comprehensive stroke centers.,Baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage or median and interquartile range.,Outcome at discharge was determined by the modified Rankin Scale Score (mRS).,Variables and outcomes were compared for males and females using univariate and multivariate analysis.,The study included 83 patients, 47% of which were Black, 28% Hispanics/Latinos, and 16% whites.,Median age was 64 years.,Approximately 89% had at least one preexisting vascular risk factor (VRF).,The most common complications were respiratory failure (59%) and septic shock (34%).,Compared with females, a higher proportion of males experienced severe SARS-CoV-2 symptoms requiring ICU hospitalization (73% vs. 49%; p = 0.04).,When divided by stroke subtype, there were 77% ischemic, 19% intracerebral hemorrhage and 3% subarachnoid hemorrhage.,The most common ischemic stroke etiologies were cryptogenic (39%) and cardioembolic (27%).,Compared with females, males had higher mortality (38% vs. 13%; p = 0.02) and were less likely to be discharged home (12% vs. 33%; p = 0.04).,After adjustment for age, race/ethnicity, and number of VRFs, mRS was higher in males than in females (OR = 1.47, 95% CI = 1.03-2.09).,In this cohort of SARS-CoV-2 stroke patients, most had clinical evidence of coronavirus infection on admission and preexisting VRFs.,Severe in-hospital complications and worse outcomes after ischemic strokes were higher in males, than females. | The purpose of the study is to analyze how the coronavirus disease 2019 (COVID-19) pandemic affected acute stroke care in a Comprehensive Stroke Center.,On February 28, 2020, contingency plans were implemented at Hospital Clinic of Barcelona to contain the COVID-19 pandemic.,Among them, the decision to refrain from reallocating the Stroke Team and Stroke Unit to the care of patients with COVID-19.,From March 1 to March 31, 2020, we measured the number of emergency calls to the Emergency Medical System in Catalonia (7.5 million inhabitants), and the Stroke Codes dispatched to Hospital Clinic of Barcelona.,We recorded all stroke admissions, and the adequacy of acute care measures, including the number of thrombectomies, workflow metrics, angiographic results, and clinical outcomes.,Data were compared with March 2019 using parametric or nonparametric methods as appropriate.,At Hospital Clinic of Barcelona, 1232 patients with COVID-19 were admitted in March 2020, demanding 60% of the hospital bed capacity.,Relative to March 2019, the Emergency Medical System had a 330% mean increment in the number of calls (158 005 versus 679 569), but fewer Stroke Code activations (517 versus 426).,Stroke admissions (108 versus 83) and the number of thrombectomies (21 versus 16) declined at Hospital Clinic of Barcelona, particularly after lockdown of the population.,Younger age was found in stroke admissions during the pandemic (median [interquartile range] 69 [64-73] versus 75 [73-80] years, P=0.009).,In-hospital, there were no differences in workflow metrics, angiographic results, complications, or outcomes at discharge.,The COVID-19 pandemic reduced by a quarter the stroke admissions and thrombectomies performed at a Comprehensive Stroke Center but did not affect the quality of care metrics.,During the lockdown, there was an overload of emergency calls but fewer Stroke Code activations, particularly in elderly patients.,Hospital contingency plans, patient transport systems, and population-targeted alerts must act concertedly to better protect the chain of stroke care in times of pandemic. | 1 |
In December 2019, the world started to face a new pandemic situation, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2).,Although coronavirus disease (COVID‐19) clinical manifestations are mainly respiratory, major cardiac complications are being reported.,Cardiac manifestations etiology seems to be multifactorial, comprising direct viral myocardial damage, hypoxia, hypotension, enhanced inflammatory status, ACE2‐receptors downregulation, drug toxicity, endogenous catecholamine adrenergic status, among others.,Studies evaluating patients with COVID‐19 presenting cardiac injury markers show that it is associated with poorer outcomes, and arrhythmic events are not uncommon.,Besides, drugs currently used to treat the COVID‐19 are known to prolong the QT interval and can have a proarrhythmic propensity.,This review focus on COVID‐19 cardiac and arrhythmic manifestations and, in parallel, makes an appraisal of other virus epidemics as SARS‐CoV, Middle East respiratory syndrome coronavirus, and H1N1 influenza. | Evidence about COVID-19 on cardiac injury is inconsistent.,We aimed to summarize available data on severity differences in acute cardiac injury and acute cardiac injury with mortality during the COVID-19 outbreak.,We performed a systematic literature search across Pubmed, Embase and pre-print from December 1, 2019 to March 27, 2020, to identify all observational studies that reported cardiac specific biomarkers (troponin, creatine kinase-MB fraction, myoglobin, or NT-proBNP) during COVID-19 infection.,We extracted data on patient demographics, infection severity, comorbidity history, and biomarkers during COVID-19 infection.,Where possible, data were pooled for meta-analysis with standard (SMD) or weighted (WMD) mean difference and corresponding 95% confidence intervals (CI).,We included 4189 confirmed COVID-19 infected patients from 28 studies.,More severe COVID-19 infection is associated with higher mean troponin (SMD 0.53, 95% CI 0.30 to 0.75, p < 0.001), with a similar trend for creatine kinase-MB, myoglobin, and NT-proBNP.,Acute cardiac injury was more frequent in those with severe, compared to milder, disease (risk ratio 5.99, 3.04 to 11.80; p < 0.001).,Meta regression suggested that cardiac injury biomarker differences of severity are related to history of hypertension (p = 0.030).,Also COVID19-related cardiac injury is associated with higher mortality (summary risk ratio 3.85, 2.13 to 6.96; p < 0.001). hsTnI and NT-proBNP levels increased during the course of hospitalization only in non-survivors.,The severity of COVID-19 is associated with acute cardiac injury, and acute cardiac injury is associated with death.,Cardiac injury biomarkers mainly increase in non-survivors.,This highlights the need to effectively monitor heart health to prevent myocarditis in patients infected with COVID-19.,Unlabelled Image | 1 |
Since the appearance of the first case of coronavirus disease 2019 (COVID-19) a pandemic has emerged affecting millions of people worldwide.,Although the main clinical manifestations are respiratory, an increase in neurological conditions, specifically acute cerebrovascular disease, has been detected.,We present cerebrovascular disease case incidence in hospitalized patients with SARS-CoV-2 infection.,Patients were confirmed by microbiological/serological testing, or on chest CT semiology.,Available data on comorbidity, laboratory parameters, treatment administered, neuroimaging, neuropathological studies and clinical evolution during hospitalization, measured by the modified Rankin scale, were analysed.,A bivariate study was also designed to identify differences between ischaemic and haemorrhagic subtypes.,A statistical model of binary logistic regression and sensitivity analysis was designed to study the influence of independent variables over prognosis.,In our centre, there were 1683 admissions of patients with COVID-19 over 50 days, of which 23 (1.4%) developed cerebrovascular disease.,Within this group of patients, cerebral and chest CT scans were performed in all cases, and MRI in six (26.1%).,Histological samples were obtained in 6/23 cases (two brain biopsies, and four arterial thrombi).,Seventeen patients were classified as cerebral ischaemia (73.9%, with two arterial dissections), five as intracerebral haemorrhage (21.7%), and one leukoencephalopathy of posterior reversible encephalopathy type.,Haemorrhagic patients had higher ferritin levels at the time of stroke (1554.3 versus 519.2, P = 0.004).,Ischaemic strokes were unexpectedly frequent in the vertebrobasilar territory (6/17, 35.3%).,In the haemorrhagic group, a characteristic radiological pattern was identified showing subarachnoid haemorrhage, parieto-occipital leukoencephalopathy, microbleeds and single or multiple focal haematomas.,Brain biopsies performed showed signs of thrombotic microangiopathy and endothelial injury, with no evidence of vasculitis or necrotizing encephalitis.,The functional prognosis during the hospital period was unfavourable in 73.9% (17/23 modified Rankin scale 4-6), and age was the main predictive variable (odds ratio = 1.5; 95% confidence interval 1.012-2.225; P = 0.043).,Our series shows cerebrovascular disease incidence of 1.4% in patients with COVID-19 with high morbidity and mortality.,We describe pathological and radiological data consistent with thrombotic microangiopathy caused by endotheliopathy with a haemorrhagic predisposition. | Patients with the Coronavirus Disease of 2019 (COVID-19) are at increased risk for thrombotic events and mortality.,Various anticoagulation regimens are now being considered for these patients.,Anticoagulation is known to increase the risk for adverse bleeding events, of which intracranial hemorrhage (ICH) is one of the most feared.,We present a retrospective study of 33 patients positive for COVID-19 with neuroimaging-documented ICH and examine anticoagulation use in this population.,Patients over the age of 18 with confirmed COVID-19 and radiographic evidence of ICH were included in this study.,Evidence of hemorrhage was confirmed and categorized by a fellowship trained neuroradiologist.,Electronic health records were analyzed for patient information including demographic data, medical history, hospital course, laboratory values, and medications.,We identified 33 COVID-19 positive patients with ICH, mean age 61.6 years (range 37-83 years), 21.2% of whom were female.,Parenchymal hemorrhages with mass effect and herniation occurred in 5 (15.2%) patients, with a 100% mortality rate.,Of the remaining 28 patients with ICH, 7 (25%) had punctate hemorrhages, 17 (60.7%) had small- moderate size hemorrhages, and 4 (14.3%) had a large single site of hemorrhage without evidence of herniation.,Almost all patients received either therapeutic dose anticoagulation (in 22 [66.7%] patients) or prophylactic dose (in 3 [9.1] patients) prior to ICH discovery.,Anticoagulation therapy may be considered in patients with COVID-19 though the risk of ICH should be taken into account when developing a treatment regimen. | 1 |
A substantial proportion of critically ill COVID-19 patients develop thromboembolic complications, but it is unclear whether higher doses of thromboprophylaxis are associated with lower mortality rates.,The purpose of the study was to evaluate the association between initial dosing strategy of thromboprophylaxis in critically ill COVID-19 patients and the risk of death, thromboembolism, and bleeding.,In this retrospective study, all critically ill COVID-19 patients admitted to two intensive care units in March and April 2020 were eligible.,Patients were categorized into three groups according to initial daily dose of thromboprophylaxis: low (2500-4500 IU tinzaparin or 2500-5000 IU dalteparin), medium (> 4500 IU but < 175 IU/kilogram, kg, of body weight tinzaparin or > 5000 IU but < 200 IU/kg of body weight dalteparin), and high dose (≥ 175 IU/kg of body weight tinzaparin or ≥ 200 IU/kg of body weight dalteparin).,Thromboprophylaxis dosage was based on local standardized recommendations, not on degree of critical illness or risk of thrombosis.,Cox proportional hazards regression was used to estimate hazard ratios with corresponding 95% confidence intervals of death within 28 days from ICU admission.,Multivariable models were adjusted for sex, age, body mass index, Simplified Acute Physiology Score III, invasive respiratory support, and initial dosing strategy of thromboprophylaxis.,A total of 152 patients were included: 67 received low-, 48 medium-, and 37 high-dose thromboprophylaxis.,Baseline characteristics did not differ between groups.,For patients who received high-dose prophylaxis, mortality was lower (13.5%) compared to those who received medium dose (25.0%) or low dose (38.8%), p = 0.02.,The hazard ratio of death was 0.33 (95% confidence intervals 0.13-0.87) among those who received high dose, and 0.88 (95% confidence intervals 0.43-1.83) among those who received medium dose, as compared to those who received low-dose thromboprophylaxis.,There were fewer thromboembolic events in the high (2.7%) vs medium (18.8%) and low-dose thromboprophylaxis (17.9%) groups, p = 0.04.,Among critically ill COVID-19 patients with respiratory failure, high-dose thromboprophylaxis was associated with a lower risk of death and a lower cumulative incidence of thromboembolic events compared with lower doses.,Clinicaltrials.gov NCT04412304 June 2, 2020, retrospectively registered. | 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. | 1 |
Supplemental Digital Content is available in the text.,Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories.,However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation.,Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM.,We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines.,We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis.,Truncating variants in TTN and DSP were associated with DCM in all comparisons.,Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM.,Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM.,Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal.,In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing.,The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present.,This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing. | 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. | 1 |
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. | 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. | 1 |
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. | 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. | 1 |
The ongoing COVID-19 pandemic has caused significant morbidity and mortality worldwide, as well as profound effects on society.,COVID-19 patients have an increased risk of thromboembolic (TE) complications, which develop despite pharmacological thromboprophylaxis.,The mechanism behind COVID-19-associated coagulopathy remains unclear.,Mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, has been suggested as a potential amplifier of blood coagulation during thromboinflammation.,Here we describe data from a cohort of critically ill COVID-19 patients ( n = 65) treated at a tertiary hospital center intensive care unit (ICU).,A subset of patients had strongly elevated MBL plasma levels, and activity upon ICU admission, and patients who developed symptomatic TE (14%) had significantly higher MBL levels than patients without TE.,MBL was strongly correlated to plasma D-dimer levels, a marker of COVID-19 coagulopathy, but showed no relationship to degree of inflammation or other organ dysfunction.,In conclusion, we have identified complement activation through the MBL pathway as a novel amplification mechanism that contributes to pathological thrombosis in critically ill COVID-19 patients.,Pharmacological targeting of the MBL pathway could be a novel treatment option for thrombosis in COVID-19.,Laboratory testing of MBL levels could be of value for identifying COVID-19 patients at risk for TE events. | •SARS-CoV-2 may impair host antiviral response, causing subsequent hyperinflammation.,•SARS-CoV-2 likely deranges the renin angiotensin aldosterone system (RAAS).,•Hyperinflammation and RAAS imbalance may drive acute lung injury and coagulopathy.,•RAAS imbalance impairs fibrinolysis, which can result in relative hypofibrinolysis.,•This can lead widespread immunothrombosis, contributing to multi-organ damage.,SARS-CoV-2 may impair host antiviral response, causing subsequent hyperinflammation.,SARS-CoV-2 likely deranges the renin angiotensin aldosterone system (RAAS).,Hyperinflammation and RAAS imbalance may drive acute lung injury and coagulopathy.,RAAS imbalance impairs fibrinolysis, which can result in relative hypofibrinolysis.,This can lead widespread immunothrombosis, contributing to multi-organ damage.,Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy.,In this paper, we present an immunothrombosis model of COVID-19.,We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients. | 1 |
In December 2019, the world started to face a new pandemic situation, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2).,Although coronavirus disease (COVID‐19) clinical manifestations are mainly respiratory, major cardiac complications are being reported.,Cardiac manifestations etiology seems to be multifactorial, comprising direct viral myocardial damage, hypoxia, hypotension, enhanced inflammatory status, ACE2‐receptors downregulation, drug toxicity, endogenous catecholamine adrenergic status, among others.,Studies evaluating patients with COVID‐19 presenting cardiac injury markers show that it is associated with poorer outcomes, and arrhythmic events are not uncommon.,Besides, drugs currently used to treat the COVID‐19 are known to prolong the QT interval and can have a proarrhythmic propensity.,This review focus on COVID‐19 cardiac and arrhythmic manifestations and, in parallel, makes an appraisal of other virus epidemics as SARS‐CoV, Middle East respiratory syndrome coronavirus, and H1N1 influenza. | 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. | 1 |
Hydrogen sulfide (H2S) has anti-inflammatory and anti-hypertensive effects, and connexins (Cxs) are involved in regulation of immune homeostasis.,In this study, we explored whether exogenous H2S prevents hypertensive inflammation by regulating Cxs expression of T lymphocytes in spontaneously hypertensive rats (SHR).,We treated SHR with sodium hydrosulfide (NaHS) for 9 weeks.,Vehicle-treated Wistar-Kyoto rats (WKYs) were used as a control.,The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography.,Hematoxylin and eosin staining was used to show vascular remodeling and renal injury.,The percentage of T cell subtypes in peripheral blood, surface expressions of Cx40/Cx43 on T cell subtypes, and serum cytokines level were determined by flow cytometry or ELISA.,Expression of Cx40/Cx43 proteins in peripheral blood lymphocytes was analyzed by Western blot.,Chronic NaHS treatment significantly attenuated blood pressure elevation, and inhibited inflammation of target organs, vascular remodeling, and renal injury in SHR.,Exogenous NaHS also improved vascular function by attenuating KCl-stimulated vasoconstrictor response in basilar arteries of SHR.,In addition, chronic NaHS administration significantly suppressed inflammation of peripheral blood in SHR, as evidenced by the decreased serum levels of IL-2, IL-6, and CD4/CD8 ratio and the increased IL-10 level and percentage of regulatory T cells.,NaHS treatment decreased hypertension-induced Cx40/Cx43 expressions in T lymphocytes from SHR.,Our data demonstrate that H2S reduces hypertensive inflammation, at least partly due to regulation of T cell subsets balance by Cx40/Cx43 expressions inhibition. | Inflammation has been shown to play an important role in the mechanisms involved in the pathogenesis of hypertension.,Connexins (Cxs)-based gap junction channels (GJCs) or hemichannels (HCs) are involved in the maintenance of homeostasis in the immune system.,However, the role of Cx43-based channels in T-lymphocytes in mediating the immune response in essential hypertension is not fully understand.,The present study was designed to investigate the role of Cxs-based channels in T lymphocytes in the regulation of hypertension-mediated inflammation.,The surface expressions of T lymphocyte subtypes, Cx40/Cx43, and inflammatory cytokines (IFN-γ (interferon-gamma) and TNF-ɑ (tumor necrosis factor alpha)) in T cells, as well as gap junction communication of peripheral blood lymphocytes from essential hypertensive patients (EHs) and normotensive healthy subjects (NTs) were detected by flow cytometry.,Expression levels and phosphorylation of Cx43 protein in peripheral blood lymphocytes of EHs and NTs were analyzed by Western blot.,The proliferation rate of peripheral blood mononuclear cells (PBMCs) after treatment with a Cxs inhibitor was examined by a CCK-8 assay.,The levels of inflammatory cytokines were detected using ELISA.,Within the CD3+ T cell subsets, we found a significant trend toward an increase in the percentage of CD4+ T cells and CD4+/CD8+ ratio as well as in serum levels of IFN-γ and TNF-ɑ in the peripheral blood of EHs compared with those in NTs.,Moreover, the peripheral blood lymphocytes of EH patients exhibited enhanced GJCs formation, increased Cx43 protein level and Cx43 phosphorylation at Ser368, and a significant increase in Cx40/Cx43 surface expressions levels in CD4+ or CD8+ T lymphocytes.,Cx43-based channel inhibition by a mimetic peptide greatly reduced the exchange of dye between lymphocytes, proliferation of stimulated lymphocytes and the pro-inflammatory cytokine levels of EHs and NTs.,Our data suggest that Cx40/Cx43-based channels in lymphocytes may be involved in the regulation of T lymphocyte proliferation and the production of pro-inflammatory cytokines, which contribute to the hypertensive inflammatory response. | 1 |
Implantable-cardioverter defibrillators (ICD) detect and terminate life-threatening ventricular tachyarrhythmia with electric shocks after they occur.,This puts patients at risk if they are driving or in a situation where they can fall.,ICD’s shocks are also very painful and affect a patient’s quality of life.,It would be ideal if ICDs can accurately predict the occurrence of ventricular tachyarrhythmia and then issue a warning or provide preventive therapy.,Our study explores the use of ICD data to automatically predict ventricular arrhythmia using heart rate variability (HRV).,A 5 minute and a 10 second warning system are both developed and compared.,The participants for this study consist of 788 patients who were enrolled in the ICD arm of the Sudden Cardiac Death-Heart Failure Trial (SCD-HeFT).,Two groups of patient rhythms, regular heart rhythms and pre-ventricular-tachyarrhythmic rhythms, are analyzed and different HRV features are extracted.,Machine learning algorithms, including random forests (RF) and support vector machines (SVM), are trained on these features to classify the two groups of rhythms in a subset of the data comprising the training set.,These algorithms are then used to classify rhythms in a separate test set.,This performance is quantified by the area under the curve (AUC) of the ROC curve.,Both RF and SVM methods achieve a mean AUC of 0.81 for 5-minute prediction and mean AUC of 0.87-0.88 for 10-second prediction; an AUC over 0.8 typically warrants further clinical investigation.,Our work shows that moderate classification accuracy can be achieved to predict ventricular tachyarrhythmia with machine learning algorithms using HRV features from ICD data.,These results provide a realistic view of the practical challenges facing implementation of machine learning algorithms to predict ventricular tachyarrhythmia using HRV data, motivating continued research on improved algorithms and additional features with higher predictive power. | In‐hospital cardiac arrest is a major burden to public health, which affects patient safety.,Although traditional track‐and‐trigger systems are used to predict cardiac arrest early, they have limitations, with low sensitivity and high false‐alarm rates.,We propose a deep learning-based early warning system that shows higher performance than the existing track‐and‐trigger systems.,This retrospective cohort study reviewed patients who were admitted to 2 hospitals from June 2010 to July 2017.,A total of 52 131 patients were included.,Specifically, a recurrent neural network was trained using data from June 2010 to January 2017.,The result was tested using the data from February to July 2017.,The primary outcome was cardiac arrest, and the secondary outcome was death without attempted resuscitation.,As comparative measures, we used the area under the receiver operating characteristic curve (AUROC), the area under the precision-recall curve (AUPRC), and the net reclassification index.,Furthermore, we evaluated sensitivity while varying the number of alarms.,The deep learning-based early warning system (AUROC: 0.850; AUPRC: 0.044) significantly outperformed a modified early warning score (AUROC: 0.603; AUPRC: 0.003), a random forest algorithm (AUROC: 0.780; AUPRC: 0.014), and logistic regression (AUROC: 0.613; AUPRC: 0.007).,Furthermore, the deep learning-based early warning system reduced the number of alarms by 82.2%, 13.5%, and 42.1% compared with the modified early warning system, random forest, and logistic regression, respectively, at the same sensitivity.,An algorithm based on deep learning had high sensitivity and a low false‐alarm rate for detection of patients with cardiac arrest in the multicenter study. | 1 |
Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology.,Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases.,Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis.,At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear.,The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders.,As a consequence, treatment strategies are not well established.,In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis.,Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field.,The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed.,This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.,In this Review, Tschöpe and colleagues summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with special focus on virus-induced and virus-associated myocarditis.,The authors also identify knowledge gaps, appraise available experimental models and propose future directions for the field.,The role of specific viruses, immune cells and autoimmunity in the pathogenesis of myocarditis and inflammatory cardiomyopathy is still incompletely understood, and advanced animal and cell models are required for future research.Advanced animal models that take into account immune experience and exposure to environmental factors and in vitro models with immune cell interactions are needed to facilitate better clinical translation of the findings.Improved standardization of available invasive and noninvasive diagnostic tools and a consensus on their specific use are needed to allow specific diagnosis and stratification of patient cohorts for the implementation of aetiology-based therapies.To develop aetiology-based therapies, the efficacy of many existing, repurposed or emerging therapies needs to be evaluated in large, controlled, randomized trials.,The role of specific viruses, immune cells and autoimmunity in the pathogenesis of myocarditis and inflammatory cardiomyopathy is still incompletely understood, and advanced animal and cell models are required for future research.,Advanced animal models that take into account immune experience and exposure to environmental factors and in vitro models with immune cell interactions are needed to facilitate better clinical translation of the findings.,Improved standardization of available invasive and noninvasive diagnostic tools and a consensus on their specific use are needed to allow specific diagnosis and stratification of patient cohorts for the implementation of aetiology-based therapies.,To develop aetiology-based therapies, the efficacy of many existing, repurposed or emerging therapies needs to be evaluated in large, controlled, randomized trials. | Since December 2019, the novel coronavirus SARS‐CoV‐2 has spread rapidly throughout China and keeps the world in suspense.,Cardiovascular complications with myocarditis and embolism due to COVID‐19 have been reported.,SARS‐CoV‐2 genome detection in the heart muscle has not been demonstrated so far, and the underlying pathophysiological mechanisms remain to be investigated.,Endomyocardial biopsies (EMBs) of 104 patients (mean age: 57.90 ± 16.37 years; left ventricular ejection fraction: 33.7 ± 14.6%, sex: n = 79 male/25 female) with suspected myocarditis or unexplained heart failure were analysed.,EMB analysis included histology, immunohistochemistry, and detection of SARS‐CoV‐2 genomes by real‐time reverse transcription polymerase chain reaction in the IKDT Berlin, Germany.,Among 104 EMBs investigated, five were confirmed with SARS‐CoV‐2 infected by reverse real‐time transcriptase polymerase chain reaction.,We describe patients of different history of symptoms and time duration.,Additionally, we investigated histopathological changes in myocardial tissue showing that the inflammatory process in EMBs seemed to permeate vascular wall leading to small arterial obliteration and damage.,This is the first report that established the evidence of SARS‐CoV‐2 genomes detection in EMBs.,In these patients, myocardial injury ischaemia may play a role, which could explain the ubiquitous troponin increases.,EMB‐based identification of the cause of myocardial injury may contribute to explain the different evolution of complicated SARS‐CoV‐2‐infection and to design future specific and personalized treatment strategies. | 1 |
There are concerns that the coronavirus disease 2019 (COVID-19) outbreak negatively affects the quality of care for acute cardiovascular conditions.,We assessed the impact of the COVID-19 outbreak on trends in hospital admissions and workflow parameters of acute stroke care in Amsterdam, The Netherlands.,We used data from the three hospitals that provide acute stroke care for the Amsterdam region.,We compared two 7-week periods: one during the peak of the COVID-19 outbreak (March 16th-May 3th 2020) and one prior to the outbreak (October 21st-December 8th 2019).,We included consecutive patients who presented to the emergency departments with a suspected stroke and assessed the change in number of patients as an incidence-rate ratio (IRR) using a Poisson regression analysis.,Other outcomes were the IRR for stroke subtypes, change in use of reperfusion therapy, treatment times, and in-hospital complications.,During the COVID-19 period, 309 patients presented with a suspected stroke compared to 407 patients in the pre-COVID-19 period (IRR 0.76 95%CI 0.65-0.88).,The proportion of men was higher during the COVID-19 period (59% vs. 47%, p < 0.001).,There was no change in the proportion of stroke patients treated with intravenous thrombolysis (28% vs. 30%, p = 0.58) or endovascular thrombectomy (11% vs 12%, p = 0.82) or associated treatment times.,Seven patients (all ischemic strokes) were diagnosed with COVID-19.,We observed a 24% decrease in suspected stroke presentations during the COVID-19 outbreak, but no evidence for a decrease in quality of acute stroke care. | While the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spreads all over the world, the healthcare systems are facing the dramatic challenge of simultaneously fight against the outbreak and life-threating emergencies.,In this biological setting, emergency departments and neurovascular teams are exposed to high risk of infection and should therefore be prepared to deal with neurological emergencies safely.,The purpose of this article is to analyze the current evidence on COVID-19 in the context of acute ischemic stroke and to describe the model of behavior we are putting into action to maintain the stroke pathway both rapid for the patient and safe for the healthcare professionals.,We reserve a specific focus on personal protection equipment, dress code and healthcare professional behavior. | 1 |
Emerging evidence shows that severe coronavirus disease 2019 (COVID‐19) can be complicated with coagulopathy, namely disseminated intravascular coagulation, which has a rather prothrombotic character with high risk of venous thromboembolism.,The incidence of venous thromboembolism among COVID‐19 patients in intensive care units appears to be somewhat higher compared to that reported in other studies including such patients with other disease conditions.,D‐dimer might help in early recognition of these high‐risk patients and also predict outcome.,Preliminary data show that in patients with severe COVID‐19, anticoagulant therapy appears to be associated with lower mortality in the subpopulation meeting sepsis‐induced coagulopathy criteria or with markedly elevated d‐dimer.,Recent recommendations suggest that all hospitalized COVID‐19 patients should receive thromboprophylaxis, or full therapeutic‐intensity anticoagulation if such an indication is present. | Venous thromboembolism (VTE) is a well-known complication in hospitalised patients [1-5].,Risk factors include older age, obesity, immobilisation, active malignancy, systemic inflammatory response syndrome (SIRS), (major) surgery, thrombophilia and a history of thromboembolism [2, 5].,In 1884, Rudolph Virchow first described the underlying pathophysiological mechanisms, which consist of endothelial cell dysfunction/inflammation, low blood flow and blood hypercoagulability.,Current guidelines recommend the use of thromboprophylaxis in acutely ill medical patients who are at high risk for VTE (Padua score ≥4, IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) score ≥2) [6].,However, in medical practice, less than half of the patients at risk receive adequate thromboprophylaxis [4].,Insidiousvenous thromboembolism (VTE) is mainly a problem in ICU-ventilated SARS-CoV-2 patients, while patients in the general ward, treated with thromboprophylaxis (0.5 mg·kg−1), had a low incidence of insidious VTEhttps://bit.ly/2Yl8jft | 1 |
Ischemic heart disease still represents a large burden on individuals and health care resources worldwide.,By conventions, it is equated with atherosclerotic plaque due to flow-limiting obstruction in large-medium sized coronary arteries.,However, clinical, angiographic and autoptic findings suggest a multifaceted pathophysiology for ischemic heart disease and just some cases are caused by severe or complicated atherosclerotic plaques.,Currently there is no well-defined assessment of ischemic heart disease pathophysiology that satisfies all the observations and sometimes the underlying mechanism to everyday ischemic heart disease ward cases is misleading.,In order to better examine this complicated disease and to provide future perspectives, it is important to know and analyze the pathophysiological mechanisms that underline it, because ischemic heart disease is not always determined by atherosclerotic plaque complication.,Therefore, in order to have a more complete comprehension of ischemic heart disease we propose an overview of the available pathophysiological paradigms, from plaque activation to microvascular dysfunction. | Remote monitoring (RM) has significantly transformed the standard of care for patients with cardiac electronic implantable devices.,It provides easy access to valuable information, such as arrhythmic events, acute decompensation manifestations and device‐related issues, without the need of in‐person visits.,Starting March 1st, 332 patients were introduced to an RM program during the Italian lockdown to limit the risk of in‐hospital exposure to severe acute respiratory syndrome‐coronavirus‐2.,Patients were categorized into two groups based on the modality of RM delivery (home [n = 229] vs. office [n = 103] delivered).,The study aimed at assessing the efficacy of the new follow‐up protocol, assessed as mean RM activation time (AT), and the need for technical support.,In addition, patients' acceptance and anxiety status were quantified via the Home Monitoring Acceptance and Satisfaction Questionnaire and the Generalized Anxiety Disorder 7‐item scale.,AT time was less than 48 h in 93% of patients and 7% of them required further technical support.,Despite a higher number of trans‐telephonic technical support in the home‐delivered RM group, mean AT was similar between groups (1.33 ± 0.83 days in home‐delivered vs 1.28 ± 0.81 days in office‐delivered patients; p = .60).,A total of 28 (2.5%) urgent/emergent in‐person examinations were required.,A high degree of patient satisfaction was reached in both groups whereas anxiety status was higher in the office‐delivered group.,The adoption of RM resulted in high patient satisfaction, regardless of the modality of modem delivery; nonetheless, in‐office modem delivery was associated with a higher prevalence of anxiety symptoms. | 1 |
Supplemental Digital Content is available in the text,Pulmonary embolism (PE) is a devastating diagnosis which carries a high mortality risk.,Echocardiography is often performed to risk stratify patients diagnosed with PE, and guide management strategies.,Trends in the performance of echocardiography among patients with PE and its role in influencing outcomes is unknown.,We analyzed the 2005 to 2014 National Inpatient Sample Database to identify patients with primary diagnosis of PE or secondary diagnosis of PE and ≥1 of the following diagnoses: syncope, thrombolysis, acute deep vein thrombosis, acute cardiorespiratory failure, and secondary pulmonary hypertension.,Trends in the performance of echocardiography and in-hospital mortality were analyzed.,The admissions were divided into 2 groups with echocardiography, and without echocardiography, and 1:2 propensity score matching (PSM) was performed for comparison.,The primary end-point was in-hospital mortality.,The secondary endpoints were length of stay and total hospitalization costs.,Odd ratios (OR) with confidence intervals (CI) were reported.,A total of 299,536 unweighted PE cases were studied.,Performance of echocardiography among patients with PE patients increased from 3.5% to 5.6%, whereas in-hospital mortality decreased from 4.2% to 3.7% between years 2005 and 2014.,Before matching, patients who received an echocardiogram were more likely to be younger, African American, admitted to a large, urban teaching institute, and had higher rates of concurrent acute deep vein thrombosis, and acute respiratory failure.,Post-PSM, patients who received echocardiography during hospitalization had lower in-hospital mortality (odds ratio 0.75, 95% confidence intervals (CI) 0.68-0.83; P < 0.001), longer length of stay (median 6 days vs 5 days; P < .001) and higher mean hospitalization costs ($34,379 vs $27,803; P < .001) compared to those without echocardiography.,Performance of echocardiography among patients with a PE is increasing and is associated with lower in-hospital mortality. | Right ventricular (RV) function is a significantly important factor in the determination of the prognosis of chronic thromboembolic pulmonary hypertension (CTEPH) patients.,Speckle-tracking echocardiography (STE) is an angle-independent new technique for quantifying myocardial deformation that is capable of providing data on multiple parameters including longitudinal and transverse information of the myocardium.,In the present study, we aimed to study the advantages of STE-derived parameters in identifying RV dysfunction in CTEPH patients.,Sixty CTEPH patients (mean age: 55 years ± 13 years; 25 males) and 30 normal controls (mean age: 54 years ± 14 years; 14 males) were enrolled in this study.,RV free wall (RVFW) systolic peak longitudinal strain (LS) including the basal, mid-, and apical-segments and the basal longitudinal and transverse displacement (basal-DL and basal-DT) were measured by STE.,Global LS (GLS) of the RV was calculated by averaging the LS value of the 3 segments of RVFW.,Clinical data of CTEPH patients were collected.,CTEPH patients were divided into 2 subgroups according to the World Health Organization function classification.,Clinical right heart failure (RHF) was defined as the presence of symptoms of heart failure and signs of systemic circulation congestion during hospitalization.,The apical segment LS of the RVFW was lower than that in the basal and mid-segments in the control group (P < 0.001), but no significant difference was found among the 3 segments of LS in the CTEPH group (P = 0.263).,When we used the cutoff value recommended by the American Society of Echocardiography guidelines to identify abnormal RV function, 30 CTEPH patients (50%) by tricuspid annular plane systolic excursion (TAPSE), 42 patients (70%) by fractional area change (FAC), 20 patients (33.33%) by RV index of myocardial performance (RVIMP), and 46 patients (77%) patients by GLS were determined to have abnormal RV function, respectively.,Among multiple RV function indicators, TAPSE, FAC, GLS, basal-DL, and N-terminal pronatriuretic B-type natriuretic peptide showed significant differences between CTEPH patients with mild (WHO II) and severe symptoms (WHO III/IV) (all P < 0.001), while RVIMP and basal-DT showed no significant difference (P = 0.188 and P = 0.394, respectively).,Pearson correlation analysis showed that GLS has no correlation with sPAP as evaluated by echocardiography in CTEPH patients (r = − 0.079, P = 0.574), and a weak to moderate correlation with RA area (r = 0.488, P = 0.000), the RV diameter (r = 0.429, P = 0.001), and the RVFW thickness (r = 0.344, P = 0.009).,On receiver operating characteristic analysis, GLS has the largest area under the curve to identify RHF when the cutoff value was − 13.45%, the sensitivity was 78.2%, and the specificity was 84.6%, separately.,Our study demonstrated that the depression of regional LS of RVFW is more pronounced in the basal and middle segments in CTEPH patients.,Also, the longitudinal movement is much more important than the transverse movement when evaluating RV systolic function.,As compared with conventional parameters, RVFW GLS showed more sensitivity to identify abnormal RV function and had the largest AUC for identifying RHF.,Additionally, GLS showed no correlation with sPAP and a weak correlation with right heart morphological parameters in our CTEPH cohort. | 1 |
Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability.,This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019.,GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019.,Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019.,The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period.,The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019.,The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019.,Cardiovascular diseases remain the leading cause of disease burden in the world.,CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries.,There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.,•The burden of CVD, in number of DALYs and deaths, continues to increase globally.,•CVD burden attributable to modifiable risk factors continues to increase globally.,•Countries should invest in existing cost-effective public health programs and clinical interventions to target modifiable risks, promote healthy aging across the lifespan, and reduce disability and premature death due to CVD.,The burden of CVD, in number of DALYs and deaths, continues to increase globally.,CVD burden attributable to modifiable risk factors continues to increase globally.,Countries should invest in existing cost-effective public health programs and clinical interventions to target modifiable risks, promote healthy aging across the lifespan, and reduce disability and premature death due to CVD. | Cardiovascular disease (CVD) is a common comorbidity in type 2 diabetes (T2DM).,CVD’s prevalence has been growing over time.,To estimate the current prevalence of CVD among adults with T2DM by reviewing literature published within the last 10 years (2007-March 2017).,We searched Medline, Embase, and proceedings of major scientific meetings for original research documenting the prevalence of CVD in T2DM.,CVD included stroke, myocardial infarction, angina pectoris, heart failure, ischemic heart disease, cardiovascular disease, coronary heart disease, atherosclerosis, and cardiovascular death.,No restrictions were placed on country of origin or publication language.,Two reviewers independently searched for articles and extracted data, adjudicating results through consensus.,Data were summarized descriptively.,Risk of bias was examined by applying the STROBE checklist.,We analyzed data from 57 articles with 4,549,481 persons having T2DM.,Europe produced the most articles (46%), followed by the Western Pacific/China (21%), and North America (13%).,Overall in 4,549,481 persons with T2DM, 52.0% were male, 47.0% were obese, aged 63.6 ± 6.9 years old, with T2DM duration of 10.4 ± 3.7 years.,CVD affected 32.2% overall (53 studies, N = 4,289,140); 29.1% had atherosclerosis (4 studies, N = 1153), 21.2% had coronary heart disease (42 articles, N = 3,833,200), 14.9% heart failure (14 studies, N = 601,154), 14.6% angina (4 studies, N = 354,743), 10.0% myocardial infarction (13 studies, N = 3,518,833) and 7.6% stroke (39 studies, N = 3,901,505).,CVD was the cause of death in 9.9% of T2DM patients (representing 50.3% of all deaths).,Risk of bias was low; 80 ± 12% of STROBE checklist items were adequately addressed.,Globally, overall CVD affects approximately 32.2% of all persons with T2DM.,CVD is a major cause of mortality among people with T2DM, accounting for approximately half of all deaths over the study period.,Coronary artery disease and stroke were the major contributors. | 1 |
Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19).,We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.,In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care.,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.,The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation.,Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis).,The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%).,The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11).,Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.,In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis.,(REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.) | Coronavirus disease of 2019 (COVID-19) is the respiratory viral infection caused by the coronavirus SARS-CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2).,Despite being a respiratory illness, COVID-19 is found to increase the risk of venous and arterial thromboembolic events.,Indeed, the link between COVID-19 and thrombosis is attracting attention from the broad scientific community.,In this review we will analyze the current available knowledge of the association between COVID-19 and thrombosis.,We will highlight mechanisms at both molecular and cellular levels that may explain this association.,In addition, the article will review the antithrombotic properties of agents currently utilized or being studied in COVID-19 management.,Finally, we will discuss current professional association guidance on prevention and treatment of thromboembolism associated with COVID-19. | 1 |
Multiple myeloma (MM) is characterized by bone destruction due to increased bone resorption and decreased bone formation.,Semaphorin 4D (CD100, Sema4D) is expressed by osteoclasts, binds to its receptor Plexin-B1, and acts as a mediator of osteoclast-osteoblast interaction that ultimately inhibits osteoblastic bone formation.,Preclinical data suggest that Sema4D/Plexin-B1 pathway is implicated in MM-induced bone disease.,However, there is no information on the role of Sema4D in MM patients.,Thus, we evaluated Sema4D and Plexin-B1 in six myeloma cells lines in vitro; in the bone marrow plasma (BMP) and serum of 72 newly diagnosed symptomatic MM (NDMM) patients and in 25 healthy controls.,Only one myeloma cell line produced high Sema4D.,BMP and circulating Sema4D and Plexin-B1 levels were significantly higher in MM patients compared to controls (p < 0.01).,Sema4D correlated with serum calcium levels (p < 0.001), increased bone resorption (as assessed by CTX; p < 0.01), and ISS (p < 0.001).,There was a trend for higher Sema4D levels in patients with osteolysis (p = 0.07), while patients with diffuse MRI pattern had higher BMP Sema4D levels (p = 0.02).,Our data suggest that Sema4D is elevated in MM patients and correlate with adverse myeloma features and increased bone resorption, providing a possible target for novel therapeutic approaches in MM. | Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality.,The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process.,The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss.,Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process.,During the last years, osteocytes have emerged as key regulators of bone loss in myeloma through direct interactions with the myeloma cells.,The myeloma-induced crosstalk among the molecular pathways establishes a positive feedback that sustains myeloma cell survival and continuous bone destruction, even when a plateau phase of the disease has been achieved.,Targeted therapies, based on the better knowledge of the biology, constitute a promising approach in the management of myeloma-related bone disease and several novel agents are currently under investigation.,Herein, we provide an insight into the underlying pathogenesis of bone disease and discuss possible directions for future studies. | 1 |
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. | 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. | 1 |
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. | 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. | 1 |
Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe.,The aim of this two part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular (CV) disease in association with COVID-19.,A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts.,The first, which was reported previously, focused on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19.,This second part addresses the topics of: care pathways and triage systems and management and treatment pathways, both of the most commonly encountered CV conditions and of COVID-19; and information that may be considered useful to help patients with CV disease (CVD) to avoid exposure to COVID-19.,This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19.,The recommendations are mainly the result of observations and personal experience from healthcare providers.,Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic.,Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.,Graphical Abstract | 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. | 1 |
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. | Recent studies have reported a high prevalence of thrombotic events in coronavirus disease 2019.,However, the significance of thromboembolic complications has not been widely appreciated.,The purpose of this review is to provide current knowledge of this serious problem.,Narrative review.,Online search of published medical literature through PubMed using the term “COVID-19,” “SARS,” “acute respiratory distress syndrome,” “coronavirus,” “coagulopathy,” “thrombus,” and “anticoagulants.”,Articles were chosen for inclusion based on their relevance to coagulopathy and thrombosis in coronavirus disease 2019, and anticoagulant therapy.,Reference lists were reviewed to identify additional relevant articles.,Coronavirus disease 2019 is associated with a strikingly high prevalence of coagulopathy and venous thromboembolism that may contribute to respiratory deterioration.,Monitoring coagulation variables is important, as abnormal coagulation tests are related to adverse outcomes and may necessitate adjuvant antithrombotic interventions.,In the initial phase of the infection, d-dimer and fibrinogen levels are increased, while activated partial prothrombin time, prothrombin time, and platelet counts are often relatively normal.,Increased d-dimer levels three times the upper limit of normal may trigger screening for venous thromboembolism.,In all hospitalized patients, thromboprophylaxis using low-molecular-weight heparin is currently recommended.,The etiology of the procoagulant responses is complex and thought to be a result of specific interactions between host defense mechanisms and the coagulation system.,Although the coagulopathy is reminiscent of disseminated intravascular coagulation and thrombotic microangiopathy, it has features that are markedly distinct from these entities.,Severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019 frequently induces hypercoagulability with both microangiopathy and local thrombus formation, and a systemic coagulation defect that leads to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism in critically ill hospitalized patients. d-dimers and fibrinogen levels should be monitored, and all hospitalized patients should undergo thromboembolism prophylaxis with an increase in therapeutic anticoagulation in certain clinical situations. | 1 |
The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies.,There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3 in endothelium.,Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication.,It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as endothelial expression of cytokines that produce the cytokine storm.,The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response. | COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support.,Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis.,We studied the connection between NETs and COVID-19 severity and progression.,We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17).,We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines.,Three COVID-19 lung autopsies were examined for NETs and platelet involvement.,We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma.,We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma.,Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome.,Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340).,Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration.,Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF.,Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.,•NETs contribute to microthrombi through platelet-neutrophil interactions in COVID-19 ARDS.•nNIF blocks NETs induced by COVID-19 plasma and represents a potential therapeutic intervention in COVID-19.,NETs contribute to microthrombi through platelet-neutrophil interactions in COVID-19 ARDS.,nNIF blocks NETs induced by COVID-19 plasma and represents a potential therapeutic intervention in COVID-19. | 1 |
In our registry, 90-day postdischarge VTE, ATE, and ACM rates were 1.55%, 1.71%, and 4.83%, respectively.Discharge anticoagulants, mostly prophylactic doses, were associated with 46% decrease in major thromboembolism or ACM composite end point.,In our registry, 90-day postdischarge VTE, ATE, and ACM rates were 1.55%, 1.71%, and 4.83%, respectively.,Discharge anticoagulants, mostly prophylactic doses, were associated with 46% decrease in major thromboembolism or ACM composite end point.,Thromboembolic events, including venous thromboembolism (VTE) and arterial thromboembolism (ATE), and mortality from subclinical thrombotic events occur frequently in coronavirus disease 2019 (COVID-19) inpatients.,Whether the risk extends postdischarge has been controversial.,Our prospective registry included consecutive patients with COVID-19 hospitalized within our multihospital system from 1 March to 31 May 2020.,We captured demographics, comorbidities, laboratory parameters, medications, postdischarge thromboprophylaxis, and 90-day outcomes.,Data from electronic health records, health informatics exchange, radiology database, and telephonic follow-up were merged.,Primary outcome was a composite of adjudicated VTE, ATE, and all-cause mortality (ACM).,Principal safety outcome was major bleeding (MB).,Among 4906 patients (53.7% male), mean age was 61.7 years.,Comorbidities included hypertension (38.6%), diabetes (25.1%), obesity (18.9%), and cancer history (13.1%).,Postdischarge thromboprophylaxis was prescribed in 13.2%.,VTE rate was 1.55%; ATE, 1.71%; ΑCM, 4.83%; and MB, 1.73%.,Composite primary outcome rate was 7.13% and significantly associated with advanced age (odds ratio [OR], 3.66; 95% CI, 2.84-4.71), prior VTE (OR, 2.99; 95% CI, 2.00-4.47), intensive care unit (ICU) stay (OR, 2.22; 95% CI, 1.78-2.93), chronic kidney disease (CKD; OR, 2.10; 95% CI, 1.47-3.0), peripheral arterial disease (OR, 2.04; 95% CI, 1.10-3.80), carotid occlusive disease (OR, 2.02; 95% CI, 1.30-3.14), IMPROVE-DD VTE score ≥4 (OR, 1.51; 95% CI, 1.06-2.14), and coronary artery disease (OR, 1.50; 95% CI, 1.04-2.17).,Postdischarge anticoagulation was significantly associated with reduction in primary outcome (OR, 0.54; 95% CI, 0.47-0.81).,Postdischarge VTE, ATE, and ACM occurred frequently after COVID-19 hospitalization.,Advanced age, cardiovascular risk factors, CKD, IMPROVE-DD VTE score ≥4, and ICU stay increased risk.,Postdischarge anticoagulation reduced risk by 46%. | 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. | 1 |
Supplemental Digital Content is available in the text.,The pandemic caused by the novel coronavirus disease 2019 (COVID-19) has led to an unprecedented paradigm shift in medical care.,We sought to evaluate whether the COVID-19 pandemic may have contributed to delays in acute stroke management at comprehensive stroke centers.,Pooled clinical data of consecutive adult stroke patients from 14 US comprehensive stroke centers (January 1, 2019, to July 31, 2020) were queried.,The rate of thrombolysis for nontransferred patients within the Target: Stroke goal of 60 minutes was compared between patients admitted from March 1, 2019, and July 31, 2019 (pre-COVID-19), and March 1, 2020, to July 31, 2020 (COVID-19).,The time from arrival to imaging and treatment with thrombolysis or thrombectomy, as continuous variables, were also assessed.,Of the 2955 patients who met inclusion criteria, 1491 were admitted during the pre-COVID-19 period and 1464 were admitted during COVID-19, 15% of whom underwent intravenous thrombolysis.,Patients treated during COVID-19 were at lower odds of receiving thrombolysis within 60 minutes of arrival (odds ratio, 0.61 [95% CI, 0.38-0.98]; P=0.04), with a median delay in door-to-needle time of 4 minutes (P=0.03).,The lower odds of achieving treatment in the Target: Stroke goal persisted after adjustment for all variables associated with earlier treatment (adjusted odds ratio, 0.55 [95% CI, 0.35-0.85]; P<0.01).,The delay in thrombolysis appeared driven by the longer delay from imaging to bolus (median, 29 [interquartile range, 18-41] versus 22 [interquartile range, 13-37] minutes; P=0.02).,There was no significant delay in door-to-groin puncture for patients who underwent thrombectomy (median, 83 [interquartile range, 63-133] versus 90 [interquartile range, 73-129] minutes; P=0.30).,Delays in thrombolysis were observed in the months of June and July.,Evaluation for acute ischemic stroke during the COVID-19 period was associated with a small but significant delay in intravenous thrombolysis but no significant delay in thrombectomy time metrics.,Taking steps to reduce delays from imaging to bolus time has the potential to attenuate this collateral effect of the pandemic. | Higher rates of strokes have been observed in patients with coronavirus disease 2019 (COVID-19), but data regarding the outcomes of COVID-19 patients suffering from acute ischemic stroke due to large vessel occlusion (LVO) are lacking.,We report our initial experience in the treatment of acute ischemic stroke with LVO in patients with COVID-19.,All consecutive patients with COVID-19 with acute ischemic stroke due to LVO treated in our institution during the 6 first weeks of the COVID-19 outbreak were included.,Baseline clinical and radiological findings, treatment, and short-term outcomes are reported.,We identified 10 patients with confirmed COVID-19 treated for an acute ischemic stroke due to LVO.,Eight were men, with a median age of 59.5 years.,Seven had none or mild symptoms of COVID-19 at stroke onset.,Median time from COVID-19 symptoms to stroke onset was 6 days.,All patients had brain imaging within 3 hours from symptoms onset.,Five patients had multi-territory LVO.,Five received intravenous alteplase.,All patients had mechanical thrombectomy.,Nine patients achieved successful recanalization (mTICI2B-3), none experienced early neurological improvement, 4 had early cerebral reocclusion, and a total of 6 patients (60%) died in the hospital.,Best medical care including early intravenous thrombolysis, and successful and prompt recanalization achieved with mechanical thrombectomy, resulted in poor outcomes in patients with COVID-19.,Although our results require further confirmation, a different pharmacological approach (antiplatelet or other) should be investigated to take in account inflammatory and coagulation disorders associated with COVID-19. | 1 |
Although originally described as a survival mechanism, it is unknown whether and to what extent autophagy is implicated in the terminal stages of heart failure.,Here, we studied magnitude and evolution of autophagy in patients with intractable heart failure.,Myocardial samples were obtained from 22 patients with ischemic cardiomyopathy and idiopathic dilated cardiomyopathy who were undergoing cardiac transplantation.,Hearts from 11 patients who died from non-cardiac causes were used as control samples.,Autophagy was evaluated by immunostaining with a monoclonal microtubule associated protein light chain 3 (LC3)-II antibody, while the relationship of autophagy with apoptosis and oncosis was assessed by double staining with TUNEL (terminal deoxynucleotidyl transferase - mediated deoxyuridine triphosphate nick end labeling) assay and complement 9 (C9) immunological staining, respectively.,In addition, several necroptotic markers, including RIP1 and RIP3 (receptor interacting protein kinase 1 and 3), anti-C3 (cleaved-caspase-3), and anti-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) were assessed by immunohistochemistry.,Anti-LC3-II staining was detected in 8.7±1.6% of the heart failure patient heart samples and in 1.2±0.3% of control patient heart samples.,Vacuole formation started at one nuclear pole, before becoming bipolar and involving the cytosol.,Subsequently, the autophagic process extended also to the nuclei, which underwent a progressive vacuolization and disintegration, assuming a peculiar “strawberry like appearance”.,Myocytes with extensive vacuole formation exhibited nuclear degeneration, which was associated with TUNEL, C3, C9, RIP1, and RIP3 positive staining.,Conversely, myocytes with less extensive vacuole formation showed RIP1 and NF-κB positive staining, though not positivity for other cell death markers.,Autophagy was extensively detected in end-stage heart failure and its progression, resulted in secondary cell death, with occurrence of oncosis and necroptosis exceeding that of apoptosis.,Conversely, activation of the RIP1/NF-κB pathway was associated with cell survival. | Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF).,While apoptosis has been investigated as a participant in the progression of HF, it is unlikely that it accounts for the total amount of non-functional tissue.,In addition, there is evidence for the presence of necrotic cardiomyocytes in HF.,Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF.,Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied.,Immunoblotting for necroptotic and apoptotic markers was performed.,Triton X-114 fractionated samples were analyzed to study differences in subcellular localization.,Elevated expression of RIP1 (receptor-interacting protein), pSer227-RIP3 and its total levels were observed in HF groups compared to controls.,On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling.,Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls.,Interestingly, pThr357-MLKL unlike pSer358-MLKL, was higher in DCM than CAD.,In HF, the subcellular localization of both RIP3 and pThr357-MLKL was consistent with activation of necroptosis signaling.,Expression of main apoptotic markers has not indicated importance of apoptosis.,This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.,The online version of this article (doi:10.1186/s12967-017-1189-5) contains supplementary material, which is available to authorized users. | 1 |
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. | 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. | 1 |
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