SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Oudit G Y,Kassiri Z,Jiang C,Liu P P,Poutanen S M,Penninger J M,Butany J European journal of clinical investigation BACKGROUND:Angiotensin converting enzyme 2 (ACE2), a monocarboxylase that degrades angiotensin II to angiotensin 1-7, is also the functional receptor for severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and is highly expressed in the lungs and heart. Patients with SARS also suffered from cardiac disease including arrhythmias, sudden cardiac death, and systolic and diastolic dysfunction. MATERIALS AND METHODS:We studied mice infected with the human strain of the SARS-CoV and encephalomyocarditis virus and examined ACE2 mRNA and protein expression. Autopsy heart samples from patients who succumbed to the SARS crisis in Toronto (Canada) were used to investigate the impact of SARS on myocardial structure, inflammation and ACE2 protein expression. RESULTS:Pulmonary infection with the human SARS-CoV in mice led to an ACE2-dependent myocardial infection with a marked decrease in ACE2 expression confirming a critical role of ACE2 in mediating SARS-CoV infection in the heart. The SARS-CoV viral RNA was detected in 35% (7/20) of autopsied human heart samples obtained from patients who succumbed to the SARS crisis during the Toronto SARS outbreak. Macrophage-specific staining showed a marked increase in macrophage infiltration with evidence of myocardial damage in patients who had SARS-CoV in their hearts. The presence of SARS-CoV in the heart was also associated with marked reductions in ACE2 protein expression. CONCLUSIONS:Our data show that SARS-CoV can mediate myocardial inflammation and damage associated with down-regulation of myocardial ACE2 system, which may be responsible for the myocardial dysfunction and adverse cardiac outcomes in patients with SARS. 10.1111/j.1365-2362.2009.02153.x
    COVID-19 and Cardiovascular Disease. Clerkin Kevin J,Fried Justin A,Raikhelkar Jayant,Sayer Gabriel,Griffin Jan M,Masoumi Amirali,Jain Sneha S,Burkhoff Daniel,Kumaraiah Deepa,Rabbani LeRoy,Schwartz Allan,Uriel Nir Circulation Coronavirus disease 2019 (COVID-19) is a global pandemic affecting 185 countries and >3 000 000 patients worldwide as of April 28, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2, which invades cells through the angiotensin-converting enzyme 2 receptor. Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19. 10.1161/CIRCULATIONAHA.120.046941
    Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes. Kim Ye Seul,Lee Soo Yong,Yoon Jung Won,Kim Dasol,Yu Sangbin,Kim Jeong Su,Kim Jae Ho BMB reports Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].
    Mechanisms of COVID-19-induced heart failure: a short review. Adeghate Ernest A,Eid Nabil,Singh Jaipaul Heart failure reviews The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected more than 42.5 million people globally resulting in the death of over 1.15 million subjects. It has inflicted severe public health and economic hardships across the world. In addition to acute respiratory distress syndrome, respiratory failure, sepsis, and acute kidney injury, COVID-19 also causes heart failure (HF). COVID-19-induced HF is manifested via different mechanisms, including, but not limited to, (1) virus-induced infiltration of inflammatory cells, which could impair the function of the heart; (2) pro-inflammatory cytokines (monocyte chemoattractant protein-1, interleukin-1β; interleukin-6; tumor necrosis factor-α) that could cause necrosis and death of the myocardium; (3) endothelial injury coupled with micro-thrombosis which could damage the endocardium; and (4) acute respiratory distress syndrome and respiratory failure that could lead to heart failure due to severe hypoxia. It is concluded that the etiology of COVID-19-induced HF is multifactorial and mitigation of the development of HF in patients with COVID-19 will require different approaches such as social distancing, drug therapy, and the urgent development of a vaccine to eradicate the disease. 10.1007/s10741-020-10037-x
    COVID-19 cardiac injury and the use of colchicine. Anton-Vazquez Vanesa,Byrne Laura,Anderson Lisa,Hamzah Lisa BMJ case reports We report a case of cardiac injury in a 46-year-old man affected by COVID-19. The patient presented with shortness of breath and fever. ECG revealed sinus tachycardia with ventricular extrasystoles and T-wave inversion in anterior leads. Troponin T and N-terminal pro B-type natriuretic peptide were elevated. Transthoracic echocardiography showed severely reduced systolic function with an estimated left ventricle ejection fraction of 30%. A nasopharingeal swab was positive for SARS-CoV-2. On day 6, 11 days after onset of symptoms, the patient deteriorated clinically with new chest pain and type 1 respiratory failure. Treatment with colchicine 0.5 mg 8-hourly resulted in rapid clinical resolution. This case report highlights how cardiac injury can dominate the clinical picture in COVID-19 infection. The role of colchicine therapy should be further studied to determine its usefulness in reducing myocardial and possibly lung parenchymal inflammatory responses. 10.1136/bcr-2020-241047
    Is it all in the heart? Myocardial injury as major predictor of mortality among hospitalized COVID-19 patients. Harmouch Farah,Shah Kashyap,Hippen John T,Kumar Ashish,Goel Harsh Journal of medical virology Coronavirus disease 2019 (COVID-19) is an infection caused by the virus SARS-CoV-2, and has caused the most widespread global pandemic in over 100 years. Given the novelty of the disease, risk factors of mortality and adverse outcomes in hospitalized patients remain to be elucidated. We present the results of a retrospective cohort study including patients admitted to a large tertiary-care, academic university hospital with COVID-19. Patients were admitted with confirmed diagnosis of COVID-19 between 1 March and 15 April 2020. Baseline clinical characteristics and admission laboratory variables were retrospectively collected. Patients were grouped based on mortality, need for ICU care, and mechanical ventilation. Prevalence of clinical co-morbidities and laboratory abnormalities were compared between groups using descriptive statistics. Univariate analysis was performed to identify predictors of mortality, ICU care and mechanical ventilation. Predictors significant at P ≤ .10 were included in multivariate analysis. Five hundred and sixty patients were included in the analysis. Age and myocardial injury were only independent predictors of mortality, in patients with/without baseline co-morbidities. Body mass index, elevated ferritin, elevated d-dimer, and elevated procalcitonin predicted need for ICU care, and these along with vascular disease at baseline predicted need for mechanical ventilation. Hence, inflammatory markers (ferritin and d-dimer) predicted severe disease, but not death. 10.1002/jmv.26347
    Association of cardiac biomarkers and comorbidities with increased mortality, severity, and cardiac injury in COVID-19 patients: A meta-regression and decision tree analysis. Toraih Eman A,Elshazli Rami M,Hussein Mohammad H,Elgaml Abdelaziz,Amin Mohamed,El-Mowafy Mohammed,El-Mesery Mohamed,Ellythy Assem,Duchesne Juan,Killackey Mary T,Ferdinand Keith C,Kandil Emad,Fawzy Manal S Journal of medical virology BACKGROUND:Coronavirus disease-2019 (COVID-19) has a deleterious effect on several systems, including the cardiovascular system. We aim to systematically explore the association of COVID-19 severity and mortality rate with the history of cardiovascular diseases and/or other comorbidities and cardiac injury laboratory markers. METHODS:The standardized mean difference (SMD) or odds ratio (OR) and 95% confidence intervals (CIs) were applied to estimate pooled results from the 56 studies. The prognostic performance of cardiac markers for predicting adverse outcomes and to select the best cutoff threshold was estimated by receiver operating characteristic curve analysis. Decision tree analysis by combining cardiac markers with demographic and clinical features was applied to predict mortality and severity in patients with COVID-19. RESULTS:A meta-analysis of 17 794 patients showed patients with high cardiac troponin I (OR = 5.22, 95% CI = 3.73-7.31, P < .001) and aspartate aminotransferase (AST) levels (OR = 3.64, 95% CI = 2.84-4.66, P < .001) were more likely to develop adverse outcomes. High troponin I more than 13.75 ng/L combined with either advanced age more than 60 years or elevated AST level more than 27.72 U/L was the best model to predict poor outcomes. CONCLUSIONS:COVID-19 severity and mortality are complicated by myocardial injury. Assessment of cardiac injury biomarkers may improve the identification of those patients at the highest risk and potentially lead to improved therapeutic approaches. 10.1002/jmv.26166
    Cardiovascular manifestations of COVID-19: An evidence-based narrative review. Sharma Yash Paul,Agstam Sourabh,Yadav Ashutosh,Gupta Anunay,Gupta Ankur The Indian journal of medical research The recent outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization on March 11, 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, primarily involves the respiratory system with viral pneumonia as a predominant manifestation. In addition, SARS-CoV-2 has various cardiovascular manifestations which increase morbidity and mortality in COVID-19. Patients with underlying cardiovascular diseases and conventional cardiovascular risk factors are predisposed for COVID-19 with worse prognosis. The possible mechanisms of cardiovascular injury are endothelial dysfunction, diffuse microangiopathy with thrombosis and increased angiotensin II levels. Hyperinflammation in the myocardium can result in acute coronary syndrome, myocarditis, heart failure, cardiac arrhythmias and sudden death. The high level of cardiac troponins and natriuretic peptides in the early course of COVID-19 reflects an acute myocardial injury. The complex association between COVID-19 and cardiovascular manifestations requires an in-depth understanding for appropriate management of these patients. Till the time a specific antiviral drug is available for COVID-19, treatment remains symptomatic. This review provides information on the cardiovascular risk factors and cardiovascular manifestations of COVID-19. 10.4103/ijmr.IJMR_2450_20
    COVID-19, myocardial edema and dexamethasone. Rafiee Moezedin Javad,Babaki Fard Faranak,Friedrich Matthias G Medical hypotheses Severe acute respiratory syndrome corona virus 2(SARS-CoV-2), the cause of coronavirus disease- 2019 (COVID-19) after emerging in china in late 2019 is spreading rapidly across the world. The most common cause of death in patient with COVID-19 is the rapid progression of acute respiratory distress syndrome (ARDS) shortly after the beginning of dyspnea and hypoxemia. Patients with severe COVID-19 may also develop acute cardiac, kidney and liver injury that are associated with poor prognosis and can lead to high mortality rate. Numerous randomized trials are ongoing to find an effective, safe and widely available treatment. Remdisivir is the only FDA -approved antiviral agent for treatment of severe COVID-19. Glucocorticoids (GCs) have been used for treatment of cytokine storm syndrome and respiratory failure in hospitalized patient with severe covid-19. One of the therapeutic effects of GCs is stability of vascular endothelial barrier and decreasing tissue edema. In our opinion, the decreasing vascular permeability effect of glucocorticoids in the injured myocardium might has an important additional factor in reducing mortality in severe, hospitalized COVID-19 patients. 10.1016/j.mehy.2020.110307
    Gamut of cardiac manifestations and complications of COVID-19: a contemporary review. Cruz Rodriguez Jose Benjamin,Lange Richard A,Mukherjee Debabrata Journal of investigative medicine : the official publication of the American Federation for Clinical Research COVID-19 has posed an extraordinary burden on health and the economy worldwide. Patients with cardiovascular diseases are more likely to have severe illness due to COVID-19 and are at increased risk for complications and mortality. We performed a narrative literature review to assess the burden of COVID-19 and cardiovascular morbidity and mortality. Myocardial injury has been reported in 20%-30% of patients hospitalized due to COVID-19 and is associated with a worse prognosis and high mortality (~50%-60%). Proposed mechanisms of myocardial injury include inflammation within the myocardium (due to direct viral infection or cytokine storm), endotheliitis, coronary vasculitis, myocarditis, demand ischemia, plaque destabilization and right ventricular failure. The right ventricle is particularly vulnerable to injury and failure in COVID-19-infected patients, given the hypoxic pulmonary vasoconstriction, pulmonary microthrombi or pulmonary embolism. Echocardiography is an effective and accessible tool to evaluate left and right ventricular functions and risk stratify patients with COVID-19 infection. Cardiac MRI has detected and characterized myocardial injury, with changes compatible with other inflammatory cardiomyopathies. The long-term consequences of these inflammatory changes are unknown, but accumulating data will provide insight regarding the longitudinal impact of COVID-19 infection on cardiovascular morbidity and mortality. 10.1136/jim-2020-001592
    Cardiac Complications in COVID-19: A Systematic Review and Meta-analysis. Sahranavard Mehrdad,Akhavan Rezayat Arash,Zamiri Bidary Mohammad,Omranzadeh Alireza,Rohani Farahnaz,Hamidi Farahani Ramin,Hazrati Ebrahim,Mousavi Seyyed Hossein,Afshar Ardalan Mohamed,Soleiman-Meigooni Saeed,Hosseini-Shokouh Seyyed-Javad,Hejripour Zia,Nassireslami Ehsan,Laripour Reza,Salarian Amirahmad,Nourmohammadi Abbas,Mosaed Reza Archives of Iranian medicine BACKGROUND:The newly emerged coronavirus disease 2019 (COVID-19) seems to involve different organs, including the cardiovascular system. We systematically reviewed COVID-19 cardiac complications and calculated their pooled incidences. Secondarily, we compared the cardiac troponin I (cTnI) level between the surviving and expired patients. METHODS:A systematic search was conducted for manuscripts published from December 1, 2019 to April 16, 2020. Cardiovascular complications, along with the levels of cTnI, creatine kinase (CK), and creatine kinase MB (CK-MB) in hospitalized PCR-confirmed COVID-19 patients were extracted. The pooled incidences of the extracted data were calculated, and the unadjusted cTnI level was compared between the surviving and expired patients. RESULTS:Out of 1094 obtained records, 22 studies on a total of 4,157 patients were included. The pooled incidence rate of arrhythmia was 10.11%. Furthermore, myocardial injury had a pooled incidence of 17.85%, and finally, the pooled incidence for heart failure was 22.34%. The pooled incidence rates of cTnI, CK-MB, and CK elevations were also reported at 15.16%, 10.92%, and 12.99%, respectively. Moreover, the pooled level of unadjusted cTnI was significantly higher in expired cases compared with the surviving (mean difference = 31.818, 95% CI = 17.923-45.713, P value <0.001). CONCLUSION:COVID-19 can affect different parts of the heart; however, the myocardium is more involved. 10.34172/aim.2021.24
    COVID-19 in patients with cardiovascular diseases. Hulot Jean-Sébastien Archives of cardiovascular diseases 10.1016/j.acvd.2020.03.009
    Cardiac Involvement in Patients Recovered From COVID-2019 Identified Using Magnetic Resonance Imaging. Huang Lu,Zhao Peijun,Tang Dazhong,Zhu Tong,Han Rui,Zhan Chenao,Liu Weiyong,Zeng Hesong,Tao Qian,Xia Liming JACC. Cardiovascular imaging Objectives:This study evaluated cardiac involvement in patients recovered from coronavirus disease-2019 (COVID-19) using cardiac magnetic resonance (CMR). Background:Myocardial injury caused by COVID-19 was previously reported in hospitalized patients. It is unknown if there is sustained cardiac involvement after patients' recovery from COVID-19. Methods:Twenty-six patients recovered from COVID-19 who reported cardiac symptoms and underwent CMR examinations were retrospectively included. CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping). Edema ratio and LGE were assessed in post-COVID-19 patients. Cardiac function, native T1/T2, and ECV were quantitatively evaluated and compared with controls. Results:Fifteen patients (58%) had abnormal CMR findings on conventional CMR sequences: myocardial edema was found in 14 (54%) patients and LGE was found in 8 (31%) patients. Decreased right ventricle functional parameters including ejection fraction, cardiac index, and stroke volume/body surface area were found in patients with positive conventional CMR findings. Using quantitative mapping, global native T1, T2, and ECV were all found to be significantly elevated in patients with positive conventional CMR findings, compared with patients without positive findings and controls (median [interquartile range]: native T1 1,271 ms [1,243 to 1,298 ms] vs. 1,237 ms [1,216 to 1,262 ms] vs. 1,224 ms [1,217 to 1,245 ms]; mean ± SD: T2 42.7 ± 3.1 ms vs. 38.1 ms ± 2.4 vs. 39.1 ms ± 3.1; median [interquartile range]: 28.2% [24.8% to 36.2%] vs. 24.8% [23.1% to 25.4%] vs. 23.7% [22.2% to 25.2%]; p = 0.002; p < 0.001, and p = 0.002, respectively). Conclusions:Cardiac involvement was found in a proportion of patients recovered from COVID-19. CMR manifestation included myocardial edema, fibrosis, and impaired right ventricle function. Attention should be paid to the possible myocardial involvement in patients recovered from COVID-19 with cardiac symptoms. 10.1016/j.jcmg.2020.05.004
    Cardiac inflammation in COVID-19: Lessons from heart failure. Unudurthi Sathya D,Luthra Priya,Bose Rajendran J C,McCarthy Jason R,Kontaridis Maria Irene Life sciences Cardiovascular disease (CVD) is the most common co-morbidity associated with COVID-19 and the fatality rate in COVID-19 patients with CVD is higher compared to other comorbidities, such as hypertension and diabetes. Preliminary data suggest that COVID-19 may also cause or worsen cardiac injury in infected patients through multiple mechanisms such as 'cytokine storm', endotheliosis, thrombosis, lymphocytopenia etc. Autopsies of COVID-19 patients reveal an infiltration of inflammatory mononuclear cells in the myocardium, confirming the role of the immune system in mediating cardiovascular damage in response to COVID-19 infection and also suggesting potential causal mechanisms for the development of new cardiac pathologies and/or exacerbation of underlying CVDs in infected patients. In this review, we discuss the potential underlying molecular mechanisms that drive COVID-19-mediated cardiac damage, as well as the short term and expected long-term cardiovascular ramifications of COVID-19 infection in patients. 10.1016/j.lfs.2020.118482
    Cardiovascular aspects of COVID-19. Kurz David J.,Eberli Franz Robert Swiss medical weekly Coronavirus disease 2019 (COVID-19) is primarily a pulmonary disease, but also affects the cardiovascular system in multiple ways. In this review, we will summarise and put into perspective findings and debates relating to the diverse aspects of cardiovascular involvement of COVID-19. We will review evidence for the role of the renin-angiotensin-aldosterone system (RAAS), the risk of pre-existing cardiovascular disease in COVID-19 susceptibility and course, and the mechanism of acute and long-term myocardial injury. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses membrane-bound angiotensin converting-enzyme-2 (ACE2) as a receptor for cell entry. ACE2 is part of an important counter-regulatory circuit antagonising the harmful effects of angiotensin II on lung and heart. Modulation of ACE2 may therefore affect disease susceptibility and disease course. However, observational clinical studies and one randomised trial have so far not yielded evidence for harmful or beneficial effects of blockers of the RAAS during COVID-19. Age, gender, and multi-morbidity all increase susceptibility to SARS-CoV-2. In contrast, pre-existing cardiovascular diseases do so only minimally, but they may aggravate the disease course. Direct SARS-CoV-2 infection of the heart tissue and myocytes is rare. Nevertheless, COVID-19 may lead to myocarditis-like acute cardiac injury, characterised by myocardial oedema, but lacking extensive myocyte loss and lymphocytic infiltration. Independent of this, increases in cardiac biomarkers (troponin, N-terminal pro-brain natriuretic peptide, D-dimer) are frequent, especially in the phase of severe systemic inflammation and acute respiratory distress syndrome, and quantitatively associated with poor outcome. The pulmonary infection may result initially in right ventricular dysfunction, but in cases with severe systemic infection hypoxia, hyperinflammation and cytokine storm heart failure may eventually ensue. Unlike other infections and inflammatory states, COVID-19 does not appear to trigger acute coronary syndromes. In children, even mild COVID-19 can induce a multisystem inflammatory syndrome with Kawasaki-like symptoms frequently accompanied by cardiogenic shock. 10.4414/smw.2020.20417
    The Association of CT-measured Cardiac Indices with Lung Involvement and Clinical Outcome in Patients with COVID-19. Eslami Vahid,Abrishami Alireza,Zarei Ehsan,Khalili Nastaran,Baharvand Zahra,Sanei-Taheri Morteza Academic radiology RATIONALE AND OBJECTIVES:Cardiac indices can predict disease severity and survival in a multitude of respiratory and cardiovascular diseases. Herein, we hypothesized that CT-measured cardiac indices are correlated with severity of lung involvement and can predict survival in patients with COVID-19. MATERIALS AND METHODS:Eighty-seven patients with confirmed COVID-19 who underwent chest CT were enrolled. Cardiac indices including pulmonary artery-to-aorta ratio (PA/A), cardiothoracic ratio (CTR), epicardial adipose tissue (EAT) thickness and EAT density, inferior vena cava diameter, and transverse-to-anteroposterior trachea ratio were measured by non-enhanced CT. Logistic regression and Cox-regression analyses evaluated the association of cardiac indices with patients' outcome (death vs discharge). Linear regression analysis was used to assess the relationship between the extent of lung involvement (based on CT score) and cardiac indices. RESULTS:Mean (±SD) age of patients was 54.55 (±15.3) years old; 65.5% were male. Increased CTR (>0.49) was seen in 52.9% of patients and was significantly associated with increased odds and hazard of death (odds ratio [OR] = 12.5, p = 0.005; hazard ratio = 11.4, p = 0.006). PA/A >1 was present in 20.7% of patients and displayed a nonsignificant increase in odds of death (OR = 1.9, p = 0.36). Furthermore, extensive lung involvement was positively associated with elevated CTR and increased PA/A (p = 0.001). CONCLUSION:CT-measured cardiac indices might have predictive value regarding survival and extent of lung involvement in hospitalized patients with COVID-19 and could possibly be used for the risk stratification of these patients and for guiding therapy decision-making. In particular, increased CTR is prevalent in patients with COVID-19 and is a powerful predictor of mortality. 10.1016/j.acra.2020.09.012
    COVID-19 myocarditis and prospective heart failure burden. Shchendrygina Anastasia,Nagel Eike,Puntmann Valentina O,Valbuena-Lopez Silvia Expert review of cardiovascular therapy : COVID-19 is causing considerable morbidity and mortality worldwide. Serious respiratory complications aside, the heart is also frequently involved. The mechanisms and the extent of the myocardial injury, along with the short and long-term cardiovascular (CV) outcomes in COVID-19 survivors remain unclear. : myocardial injury has been found in a considerable proportion of hospitalized COVID-19 patients and is associated with a worse prognosis. The late onset of CV complications with myocarditis-like changes revealed by CMR has been reported in COVID-19 survivors. Previous observational studies on viral myocarditis provide evidence of a significant incomplete recovery with residual dysfunction and remodeling of left ventricle. Incomplete recovery is thought to be the result of persistent myocardial inflammation due to a post-viral autoimmune response. Considering the significant inflammatory nature of COVID-19, COVID-19 survivors may be at risk of developing persistent residual myocardial injury, the sequelae of which are unclear. : COVID-19 is an emerging threat for the heart. The extent of CV injury, along with the short and long-term sequelae, requires further investigation. The early detection of residual myocardial changes in COVID-19 survivors is of utmost importance in order to identify those patients at risk of CV complication development. 10.1080/14779072.2021.1844005
    A patient with rapid worsening dyspnoea during Covid-19 pandemic. Baggiano Andrea,Rizzo Stefania,Basso Cristina,Pontone Gianluca European heart journal 10.1093/eurheartj/ehaa988
    COVID-19 and the burning issue of drug interaction: never forget the ECG. Sciaccaluga Carlotta,Cameli Matteo,Menci Daniele,Mandoli Giulia Elena,Sisti Nicolò,Cameli Paolo,Franchi Federico,Mondillo Sergio,Valente Serafina Postgraduate medical journal The coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), has been rapidly escalating, becoming a relevant threat to global health. Being a recent virus outbreak, there are still no available therapeutic regimens that have been approved in large randomised trials and so patients are currently being treated with multiple drugs. This raises concerns regarding drug interaction and their implication in arrhythmic burden. In fact, two of the actually used drugs against SARS-CoV2, such as chloroquine and the combination lopinavir/ritonavir, might determine a QT (the time from the start of the Q wave to the end of the T wave) interval prolongation and they show several interactions with antiarrhythmic drugs and antipsychotic medications, making them prone to an increased risk of developing arrhythmias. This brief review focuses the attention on the most relevant drug interactions involving the currently used COVID-19 medications and their possible association with cardiac rhythm disorders, taking into account also pre-existing condition and precipitating factors that might additionally increase this risk. Furthermore, based on the available evidence and based on the knowledge of drug interaction, we propose a quick and simple algorithm that might help both cardiologists and non-cardiologists in the management of the arrhythmic risk before and during the treatment with the specific drugs used against SARS-CoV2. 10.1136/postgradmedj-2020-138093
    Myocardial injury in severe and critical coronavirus disease 2019 patients. Guo Huiqi,Shen Yunzhi,Wu Ning,Sun Xiaotian Journal of cardiac surgery BACKGROUND AND AIM OF THE STUDY:To investigate the effect of myocardial injury on the prognosis of patients with severe or critical coronavirus disease 2019 (COVID-19). METHODS:Between February 10, 2020 and March 31, 2020, data of severe and critical COVID-19 patients were collected and retrospectively analyzed. Admission data included age, heart rates, mean arterial pressure, and myocardial injury markers including creatine kinase isoenzyme-MB (CK-MB), myoglobin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and interleukin-6. The endpoints included mortality, the incidence of malignant arrhythmia, and mechanical ventilation time. Univariate regression analysis, multivariate linear regression analysis, and binary logistic analysis were performed to develop the risk predictors in myocardial injury to the prognosis of severe and critical COVID-19 patients. RESULTS:Seventy-four COVID-19 patients were included (mean age of 67.2 ± 14.6 years, male of 66.2%), including 42 severe and 32 critical cases. The mortality was 62.2% (n = 46). CK-MB (odds ratio = 5.895, p < .001, 95% confidence interval: 3.097-8.692) and interleukin-6 (odds ratio = 0.379; p = .005; 95% confidence interval: 1.051-1.769) were independent risk factors of increased mechanical ventilation time; myoglobin (odds ratio = 7.710; p = .045; 95% confidence interval: 1.051-56.571) were the independent predictor of incidence of malignant arrhythmia; age (odds ratio = 1.077; p = .009; 95% confidence interval: 1.019-1.139), myoglobin (odds ratio = 9.480; p = .032; 95% confidence interval: 1.211-78.188), and NT-proBNP (odds ratio = 4.852; p = .047; 95% confidence interval: 0.956-24.627) were the independent predictors of mortality. CONCLUSIONS:In severe and critical COVID-19 patients, the obvious myocardial injury was observed. Increases of CK-MB, myoglobin, NT-proBNP, interleukin-6, and age were independently associated with poor prognosis including increased ventilation duration, the incidence of malignant arrhythmia, and mortality. 10.1111/jocs.15164
    Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). Puntmann Valentina O,Carerj M Ludovica,Wieters Imke,Fahim Masia,Arendt Christophe,Hoffmann Jedrzej,Shchendrygina Anastasia,Escher Felicitas,Vasa-Nicotera Mariuca,Zeiher Andreas M,Vehreschild Maria,Nagel Eike JAMA cardiology Importance:Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown. Objective:To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness. Design, Setting, and Participants:In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020. Exposure:Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription-polymerase chain reaction on swab test of the upper respiratory tract. Main Outcomes and Measures:Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor-matched patients (n = 57). Results:Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%). Compared with healthy controls and risk factor-matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms; P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL; P = .002) but not for native T2 mapping. None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = -0.07; P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33; P < .001) and native T2 mapping (r = 0.18; P = .01). Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation. Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19-related myocardial pathology. Conclusions and Relevance:In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19. 10.1001/jamacardio.2020.3557
    Covid 19 and its cardiovascular effects. Rastogi Amit,Tewari Prabhat Annals of cardiac anaesthesia COVID-19 pandemic is mainly related with the pulmonary problems initially but now as the pandemic is growing it is observed that almost all organ systems of the body are affected. Up to 20-30% patients who are admitted in Covid hospitals are showing cardiovascular involvement. Severity of cardiovascular disease in a COVID-19 patient depends whether a patient is having pre-existing cardiac disease or not. Patients with pre-existing cardiac disease have more severe infection and associated mortality. Severe COVID-19 infection shows close association with myocardial damage and various arrythmias. The cardiovascular involvement occurs by either engagement directly with the angiotensin converting enzyme 2 or indirectly by the effect of inflammatory mediators which are generated as a result of viral-host response to infection. The COVID-19 disease is said to produce a wide spectrum of affliction ranging between even asymptomatic patient to Cardiovascular syndrome. Even after recovering from COVID-19 patients can reappear in the hospital with cardiomyopathies and arrythmias. 10.4103/aca.aca_237_20
    Sudden cardiogenic shock mimicking fulminant myocarditis in a surviving teenager affected by severe acute respiratory syndrome coronavirus 2 infection. Garau Giovanni,Joachim Sabrina,Duliere Guy-Loup,Melissopoulou Maria,Boccar Sandrine,Fraipont Vincent,Dugauquier Christophe,Troisfontaines Pierre,Hougrand Olivier,Delvenne Philippe,Hoffer Etienne ESC heart failure In the context of the coronavirus disease 2019 pandemic, myocardial injury is a relatively frequent finding. Progression to cardiogenic shock has been rarely described, especially in healthy young patients. The underlying mechanisms are to date controversial. A previously healthy 18-year-old female teenager affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) developed fulminant cardiogenic shock requiring a prompt extracorporeal membrane oxygenation support. Cardiac involvement was predominant compared with the pulmonary one. Myocardial biopsies were performed; and in order to clarify the pathophysiology of the acute heart failure, optical and transmission electron microscopy study was realized. Two additional immunohistology techniques were developed in order to (i) detect a SARS-CoV-2 recombinant fusion nucleoprotein by using a specific antibody and (ii) study fractalkine expression induced by activated endothelium because this molecule is well known to be elevated in patients with severe cytokine release syndrome. SARS-CoV-2 genome was not detected in the myocardium. Even if the clinical presentation, laboratory markers, and cardiac imaging techniques strongly suggested fulminant myocarditis, histology and immunohistology were not fully consistent with this diagnosis according to the Dallas criteria. Although rare suspected coronavirus particles were found by transmission electron microscopy in the cardiac endothelium, neither significant immunoreactivity for the viral nucleocapsid protein nor image suggestive of endotheliitis was detected. Intense endothelial immunoreactivity pattern for fractalkine expression was observed. From a clinical point of view, the left ventricular systolic function gradually improved, and the patient survived after a long stay in the intensive care unit. Our observations suggest that a massive cytokine storm induced by SARS-CoV-2 infection was the main cause of the cardiogenic shock, making a direct viral injury pathway very unlikely. 10.1002/ehf2.13049
    Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Basso Cristina,Leone Ornella,Rizzo Stefania,De Gaspari Monica,van der Wal Allard C,Aubry Marie-Christine,Bois Melanie C,Lin Peter T,Maleszewski Joseph J,Stone James R European heart journal AIMS: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. METHODS AND RESULTS: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. CONCLUSIONS: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. 10.1093/eurheartj/ehaa664
    Cardiac involvement in COVID-19 patients: mid-term follow up by cardiovascular magnetic resonance. Wang Hui,Li Ruili,Zhou Zhen,Jiang Hong,Yan Zixu,Tao Xinyan,Li Hongjun,Xu Lei Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance BACKGROUND:Coronavirus disease 2019 (COVID-19) induces myocardial injury, either direct myocarditis or indirect injury due to systemic inflammatory response. Myocardial involvement has been proved to be one of the primary manifestations of COVID-19 infection, according to laboratory test, autopsy, and cardiovascular magnetic resonance (CMR). However, the middle-term outcome of cardiac involvement after the patients were discharged from the hospital is yet unknown. The present study aimed to evaluate mid-term cardiac sequelae in recovered COVID-19 patients by CMR METHODS: A total of 47 recovered COVID-19 patients were prospectively recruited and underwent CMR examination. The CMR protocol consisted of black blood fat-suppressed T2 weighted imaging, T2 star mapping, left ventricle (LV) cine imaging, pre- and post-contrast T1 mapping, and late gadolinium enhancement (LGE). LGE were assessed in mixed both recovered COVID-19 patients and healthy controls. The LV and right ventricle (RV) function and LV mass were assessed and compared with healthy controls. RESULTS:A total of 44 recovered COVID-19 patients and 31 healthy controls were studied. LGE was found in 13 (30%) of COVID-19 patients. All LGE lesions were located in the mid myocardium and/or sub-epicardium with a scattered distribution. Further analysis showed that LGE-positive patients had significantly decreased LV peak global circumferential strain (GCS), RV peak GCS, RV peak global longitudinal strain (GLS) as compared to non-LGE patients (p < 0.05), while no difference was found between the non-LGE patients and healthy controls. CONCLUSION:Myocardium injury existed in 30% of COVID-19 patients. These patients have depressed LV GCS and peak RV strains at the 3-month follow-up. CMR can monitor the COVID-19-induced myocarditis progression, and CMR strain analysis is a sensitive tool to evaluate the recovery of LV and RV dysfunction. 10.1186/s12968-021-00710-x
    Cardiac Endotheliitis and Multisystem Inflammatory Syndrome After COVID-19. Fox Sharon E,Lameira Fernanda S,Rinker Elizabeth B,Vander Heide Richard S Annals of internal medicine 10.7326/L20-0882
    Association between myocardial injury and prognosis of COVID-19 hospitalized patients, with or without heart disease. CARDIOVID registry. López-Otero Diego,López-Pais Javier,Antúnez-Muiños Pablo José,Cacho-Antonio Carla,González-Ferrero Teba,González-Juanatey José Ramón Revista espanola de cardiologia (English ed.) 10.1016/j.rec.2020.08.005
    Myocardial Injury in Severe COVID-19 Compared With Non-COVID-19 Acute Respiratory Distress Syndrome. Metkus Thomas S,Sokoll Lori J,Barth Andreas S,Czarny Matthew J,Hays Allison G,Lowenstein Charles J,Michos Erin D,Nolley Eric P,Post Wendy S,Resar Jon R,Thiemann David R,Trost Jeffrey C,Hasan Rani K Circulation BACKGROUND:Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in coronavirus disease 2019 (COVID-19). We aimed to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared with acute respiratory distress syndrome (ARDS) unrelated to COVID-19. METHODS:We included intubated patients with COVID-19 from 5 hospitals between March 15 and June 11, 2020, with troponin levels assessed. We compared them with patients from a cohort study of myocardial injury in ARDS and performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. In addition, we performed linear regression to identify clinical factors associated with myocardial injury in COVID-19. RESULTS:Of 243 intubated patients with COVID-19, 51% had troponin levels above the upper limit of normal. Chronic kidney disease, lactate, ferritin, and fibrinogen were associated with myocardial injury. Mortality was 22.7% among patients with COVID-19 with troponin under the upper limit of normal and 61.5% for those with troponin levels >10 times the upper limit of normal (<0.001). The association of myocardial injury with mortality was not statistically significant after adjusting for age, sex, and multisystem organ dysfunction. Compared with patients with ARDS without COVID-19, patients with COVID-19 were older and had higher creatinine levels and less favorable vital signs. After adjustment, COVID-19-related ARDS was associated with lower odds of myocardial injury compared with non-COVID-19-related ARDS (odds ratio, 0.55 [95% CI, 0.36-0.84]; =0.005). CONCLUSIONS:Myocardial injury in severe COVID-19 is a function of baseline comorbidities, advanced age, and multisystem organ dysfunction, similar to traditional ARDS. The adverse prognosis of myocardial injury in COVID-19 relates largely to multisystem organ involvement and critical illness. 10.1161/CIRCULATIONAHA.120.050543
    COVID-19 Myocardial Pathology Evaluation in Athletes With Cardiac Magnetic Resonance (COMPETE CMR). Clark Daniel E,Parikh Amar,Dendy Jeffrey M,Diamond Alex B,George-Durrett Kristen,Fish Frank A,Slaughter James C,Fitch Warne,Hughes Sean G,Soslow Jonathan H Circulation 10.1161/CIRCULATIONAHA.120.052573
    Changes of Laboratory Cardiac Markers and Mechanisms of Cardiac Injury in Coronavirus Disease 2019. Li Lin,Zhou Qi,Xu Jiancheng BioMed research international Some patients with coronavirus disease 2019 (COVID-19) show abnormal changes in laboratory myocardial injury markers, suggesting that patients with myocardial injury have a higher mortality rate than those without myocardial injury. This article reviews the possible mechanism of myocardial injury in patients with COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the patients with COVID-19 in aspects of direct infection of myocardial injury, specific binding to functional receptors on cardiomyocytes, and immune-mediated myocardial injury. During hospitalization, the monitoring of laboratory myocardial injury markers in patients of COVID-19 should be strengthened. 10.1155/2020/7413673
    COVID-19 can affect the heart. Topol Eric J Science (New York, N.Y.) 10.1126/science.abe2813
    Cardiac considerations in patients with COVID-19. Calvillo-Argüelles Oscar,Ross Heather J CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 10.1503/cmaj.200562
    COVID-19 and multiorgan failure: A narrative review on potential mechanisms. Mokhtari Tahmineh,Hassani Fatemeh,Ghaffari Neda,Ebrahimi Babak,Yarahmadi Atousa,Hassanzadeh Ghomareza Journal of molecular histology The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in December 2019 form Wuhan, China leads to coronavirus disease 2019 (COVID-19) pandemic. While the common cold symptoms are observed in mild cases, COVID-19 is accompanied by multiorgan failure in severe patients. The involvement of different organs in severe patients results in lengthening the hospitalization duration and increasing the mortality rate. In this review, we aimed to investigate the involvement of different organs in COVID-19 patients, particularly in severe cases. Also, we tried to define the potential underlying mechanisms of SARS-CoV2 induced multiorgan failure. The multi-organ dysfunction is characterized by acute lung failure, acute liver failure, acute kidney injury, cardiovascular disease, and as well as a wide spectrum of hematological abnormalities and neurological disorders. The most important mechanisms are related to the direct and indirect pathogenic features of SARS-CoV2. Although the presence of angiotensin-converting enzyme 2, a receptor of SARS-CoV2 in the lung, heart, kidney, testis, liver, lymphocytes, and nervous system was confirmed, there are controversial findings to about the observation of SARS-CoV2 RNA in these organs. Moreover, the organ failure may be induced by the cytokine storm, a result of increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs. Therefore, further investigations are needed to detect the exact mechanisms of pathogenesis. Since the involvement of several organs in COVID-19 patients is important for clinicians, increasing their knowledge may help to improve the outcomes and decrease the rate of mortality and morbidity. 10.1007/s10735-020-09915-3
    COVID-19 and the cardiovascular system. Zheng Ying-Ying,Ma Yi-Tong,Zhang Jin-Ying,Xie Xiang Nature reviews. Cardiology 10.1038/s41569-020-0360-5
    Cardiovascular manifestations and treatment considerations in COVID-19. Kang Yu,Chen Tiffany,Mui David,Ferrari Victor,Jagasia Dinesh,Scherrer-Crosbie Marielle,Chen Yucheng,Han Yuchi Heart (British Cardiac Society) 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. 10.1136/heartjnl-2020-317056
    Myocardial injury in a patient with severe coronavirus disease: A case report. Nakamura Yuki,Shimizu Masaru,Yamaki Taeka,Kushimoto Kohsuke,Yamashita Ayahiro,Hayase Kazuma,Yamazaki Masaki,Hashimoto Satoru,Ohta Bon Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy INTRODUCTION:Coronavirus disease (COVID-19) can lead to severe disease or death and is characterized by a wide range of mild to severe symptoms. In addition to the lungs, studies have reported the involvement of the stomach, intestine, and angiotensin-converting enzyme 2 receptors in the heart. CASE REPORT:We present a case of a patient with COVID-19 who died soon after developing multi-organ failure and myocardial injury due to COVID-19-associated pneumonia. A 71-year-old man who contracted COVID-19 was admitted to the hospital after presenting with fever for 7 days and developed dyspnea. Following treatment, his respiratory status worsened. Thus, he was transferred to our hospital for intensive care on day 11. Physical examination revealed fever, dyspnea, respiratory distress, and no chest pain. Invasive positive pressure ventilation was initiated for acute respiratory distress syndrome on day 14. On day 15, we observed renal, liver, and coagulation dysfunction, indicating multi-organ failure. Chest radiography did not show clear signs of an increased cardiothoracic ratio or pulmonary congestion. An electrocardiogram (ECG) showed signs of myocardial infarction, which was confirmed by elevated troponin I and creatine kinase levels. The patient's circulatory dynamics did not improve on medication, and he died on day 16. CONCLUSIONS:We report the case of a patient with severe COVID-19 who died from an exacerbation of myocardial injury. Clinicians should not only evaluate respiration but also assess the heart by performing a 12-lead ECG, echocardiogram, and myocardial injury marker examination. Together, these tools can help predict which patients will develop severe COVID-19. 10.1016/j.jiac.2020.09.023
    Cardiac injury is associated with severe outcome and death in patients with Coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of observational studies. Parohan Mohammad,Yaghoubi Sajad,Seraji Asal European heart journal. Acute cardiovascular care 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, <0.001) and creatine kinase-MB (WMD=2.60 U/L, 95% CI=1.32-3.88, <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, <0.001), cardiac troponin I (WMD=26.35 pg/mL, 95% CI=14.54-38.15, <0.001), creatine kinase (WMD=48.10 U/L, 95% CI=0.27-95.94, = 0.049) and myoglobin (WMD=159.77 ng/mL, 95% CI=99.54-220.01, <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. 10.1177/2048872620937165
    [COVID-19 andcardiovascular diseases]. Haeck G,Ancion A,Marechal P,Oury C,Lancellotti P Revue medicale de Liege COVID-2019 disease mainly affects the respiratory tract and can progress in severe cases to pneumonia, acute respiratory distress syndrome and multi-organ failure. Patients with prior cardiovascular disease are at higher risk of developing an infection and progressing to a severe form of the disease. Also, due to the growing number of infected cases, it is clear that, in addition to the typical respiratory symptoms caused by the infection, some patients suffer from cardiovascular damage. This condition can, in fact, cause significant myocardial damage, which worsens the disease and affects the prognosis. Based on the results of currently published research, it seems important to discuss the manifestations and characteristics of myocardial damage induced by COVID-19 and its impact on patient prognosis.
    Fulminant COVID-19-related myocarditis in an infant. Kesici Selman,Aykan Hayrettin Hakan,Orhan Diclehan,Bayrakci Benan European heart journal 10.1093/eurheartj/ehaa515
    COVID-19: Myocardial Injury in Survivors. Knight Daniel S,Kotecha Tushar,Razvi Yousuf,Chacko Liza,Brown James T,Jeetley Paramjit S,Goldring James,Jacobs Michael,Lamb Lucy E,Negus Rupert,Wolff Anthony,Moon James C,Xue Hui,Kellman Peter,Patel Niket,Fontana Marianna Circulation 10.1161/CIRCULATIONAHA.120.049252
    Endomyocardial Biopsy in a Pediatric Patient With Cardiac Manifestations of COVID-19. Laurence Craig,Haini Mohammad,Thiruchelvam Timothy,Derrick Graham,Burch Michael,Yates Robert William Michael,Simmonds Jacob Circulation. Heart failure 10.1161/CIRCHEARTFAILURE.120.007384
    [COVID-19 coronavirus: what implications for Cardiology?] Di Pasquale Giuseppe Giornale italiano di cardiologia (2006) 10.1714/3328.32981
    [Analysis of myocardial injury in patients with COVID-19 and association between concomitant cardiovascular diseases and severity of COVID-19]. Chen C,Chen C,Yan J T,Zhou N,Zhao J P,Wang D W Zhonghua xin xue guan bing za zhi To evaluate the cardiovascular damage of patients with COVID-19, and determine the correlation of serum N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin-I (cTnI) with the severity of COVID-19, and the impact of concomitant cardiovascular disease on severity of COVID-19 was also evaluated. A cross-sectional study was designed on 150 consecutive patients with COVID-19 in the fever clinic of Tongji Hospital in Wuhan from January 19 to February 13 in 2020, including 126 mild cases and 24 cases in critical care. Both univariate and multivariate logistic regression were used to analyze the correlation of past medical history including hypertension, diabetes and coronary heart disease (CHD), as well as the levels of serum NT-proBNP and cTnI to the disease severity of COVID-19 patients. Age, hypersensitive C-reactive protein(hs-CRP) and serum creatinine levels of the patients were higher in critical care cases than in mild cases(all <0.05). Prevalence of male, elevated NT-proBNP and cTnI, hypertension and coronary heart disease were significantly higher in critical cases care patients than in the mild cases(all <0.05). Univariate logistic regression analysis showed that age, male, elevated NT-proBNP, elevated cTnI, elevated hs-CRP, elevated serum creatinine, hypertension, and CHD were significantly correlated with critical disease status(all <0.05). Multivariate logistic regression analysis showed that elevated cTnI(=26.909,95% 4.086-177.226,=0.001) and CHD (=16.609,95% 2.288-120.577,=0.005) were the independent risk factors of critical disease status. COVID-19 can significantly affect the heart function and lead to myocardial injury. The past medical history of CHD and increased level of cTnI are 2 independent determinants of clinical disease status in patients with COVID-19. 10.3760/cma.j.cn112148-20200225-00123
    Myocardial fibrosis detected by cardiovascular magnetic resonance in absence of myocardial oedema in a patient recovered from COVID-19. Jagia Priya,Ojha Vineeta,Naik Nitish,Sharma Sanjiv BMJ case reports 10.1136/bcr-2020-240193
    Cardiac Troponin as a Predictor of Myocardial Injury and Mortality from COVID-19. Nascimento Jorge Henrique Paiter,Gomes Bruno Ferraz de Oliveira,Oliveira Gláucia Maria Moraes de Arquivos brasileiros de cardiologia 10.36660/abc.20200862
    Microthrombi and ST-Segment-Elevation Myocardial Infarction in COVID-19. Guagliumi Giulio,Sonzogni Aurelio,Pescetelli Irene,Pellegrini Dario,Finn Aloke V Circulation 10.1161/CIRCULATIONAHA.120.049294
    Cardiac and Muscle Injury Might Partially Contribute to Elevated Aminotransferases in COVID-19 Patients. Xu Yongxing,Gu Jianwen Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 10.1016/j.cgh.2020.04.042
    Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response. Zhu Han,Rhee June-Wha,Cheng Paul,Waliany Sarah,Chang Amy,Witteles Ronald M,Maecker Holden,Davis Mark M,Nguyen Patricia K,Wu Sean M Current cardiology reports PURPOSE OF REVIEW:Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. RECENT FINDINGS:A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin-converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system. 10.1007/s11886-020-01292-3
    Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Tschöpe Carsten,Ammirati Enrico,Bozkurt Biykem,Caforio Alida L P,Cooper Leslie T,Felix Stephan B,Hare Joshua M,Heidecker Bettina,Heymans Stephane,Hübner Norbert,Kelle Sebastian,Klingel Karin,Maatz Henrike,Parwani Abdul S,Spillmann Frank,Starling Randall C,Tsutsui Hiroyuki,Seferovic Petar,Van Linthout Sophie Nature reviews. Cardiology 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. 10.1038/s41569-020-00435-x
    Unexpected Features of Cardiac Pathology in COVID-19 Infection. Fox Sharon E,Li Guang,Akmatbekov Aibek,Harbert Jack L,Lameira Fernanda S,Brown J Quincy,Vander Heide Richard S Circulation 10.1161/CIRCULATIONAHA.120.049465
    Characterization of Myocardial Injury in Patients With COVID-19. Giustino Gennaro,Croft Lori B,Stefanini Giulio G,Bragato Renato,Silbiger Jeffrey J,Vicenzi Marco,Danilov Tatyana,Kukar Nina,Shaban Nada,Kini Annapoorna,Camaj Anton,Bienstock Solomon W,Rashed Eman R,Rahman Karishma,Oates Connor P,Buckley Samantha,Elbaum Lindsay S,Arkonac Derya,Fiter Ryan,Singh Ranbir,Li Emily,Razuk Victor,Robinson Sam E,Miller Michael,Bier Benjamin,Donghi Valeria,Pisaniello Marco,Mantovani Riccardo,Pinto Giuseppe,Rota Irene,Baggio Sara,Chiarito Mauro,Fazzari Fabio,Cusmano Ignazio,Curzi Mirko,Ro Richard,Malick Waqas,Kamran Mazullah,Kohli-Seth Roopa,Bassily-Marcus Adel M,Neibart Eric,Serrao Gregory,Perk Gila,Mancini Donna,Reddy Vivek Y,Pinney Sean P,Dangas George,Blasi Francesco,Sharma Samin K,Mehran Roxana,Condorelli Gianluigi,Stone Gregg W,Fuster Valentin,Lerakis Stamatios,Goldman Martin E Journal of the American College of Cardiology BACKGROUND: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. OBJECTIVES:This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19. METHODS: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. RESULTS: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. CONCLUSIONS: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. 10.1016/j.jacc.2020.08.069
    COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis? Imazio Massimo,Klingel Karin,Kindermann Ingrid,Brucato Antonio,De Rosa Francesco Giuseppe,Adler Yehuda,De Ferrari Gaetano Maria Heart (British Cardiac Society) The initial mechanism for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is the binding of the virus to the membrane-bound form of ACE2, which is mainly expressed in the lung. Since the heart and the vessels also express ACE2, they both could become targets of the virus. However, at present the extent and importance of this potential involvement are unknown. Cardiac troponin levels are significantly higher in patients with more severe infections, patients admitted to intensive care units or in those who have died. In the setting of COVID-19, myocardial injury, defined by an increased troponin level, occurs especially due to non-ischaemic myocardial processes, including severe respiratory infection with hypoxia, sepsis, systemic inflammation, pulmonary thrombosis and embolism, cardiac adrenergic hyperstimulation during cytokine storm syndrome, and myocarditis. At present, there are limited reports on definite diagnosis of myocarditis caused by SARS-CoV-2 in humans and limited demonstration of the virus in the myocardium. In conclusion, although the heart and the vessels are potential targets in COVID-19, there is currently limited evidence on the direct infection of the myocardium by SARS-CoV-2. Additional pathological studies and autopsy series will be very helpful to clarify the potentiality of COVID-19 to directly infect the myocardium and cause myocarditis. 10.1136/heartjnl-2020-317186
    COVID-19 in patients with heart failure: the new and the old epidemic. Sisti Nicolò,Valente Serafina,Mandoli Giulia Elena,Santoro Ciro,Sciaccaluga Carlotta,Franchi Federico,Cameli Paolo,Mondillo Sergio,Cameli Matteo Postgraduate medical journal Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread in nearly 200 countries in less than 4 months since its first identification; accordingly, the coronavirus disease 2019 (COVID 2019) has affirmed itself as a clinical challenge. The prevalence of pre-existing cardiovascular diseases in patients with COVID19 is high and this dreadful combination dictates poor prognosis along with the higher risk of intensive care mortality. In the setting of chronic heart failure, SARS-CoV-2 can be responsible for myocardial injury and acute decompensation through various mechanisms. Given the clinical and epidemiological complexity of COVID-19, patiens with heart failure may require particular care since the viral infection has been identified, considering an adequate re-evaluation of medical therapy and a careful monitoring during ventilation. 10.1136/postgradmedj-2020-138080
    Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. Fox Sharon E,Akmatbekov Aibek,Harbert Jack L,Li Guang,Quincy Brown J,Vander Heide Richard S The Lancet. Respiratory medicine BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the USA, causing extensive morbidity and mortality, particularly in the African American community. Autopsy can considerably contribute to our understanding of many disease processes and could provide crucial information to guide management of patients with coronavirus disease 2019 (COVID-19). We report on the relevant cardiopulmonary findings in, to our knowledge, the first autopsy series of ten African American decedents, with the cause of death attributed to COVID-19. METHODS:Autopsies were performed on ten African American decedents aged 44-78 years with cause of death attributed to COVID-19, reflective of the dominant demographic of deaths following COVID-19 diagnosis in New Orleans. Autopsies were done with consent of the decedents' next of kin. Pulmonary and cardiac features were examined, with relevant immunostains to characterise the inflammatory response, and RNA labelling and electron microscopy on representative sections. FINDINGS:Important findings include the presence of thrombosis and microangiopathy in the small vessels and capillaries of the lungs, with associated haemorrhage, that significantly contributed to death. Features of diffuse alveolar damage, including hyaline membranes, were present, even in patients who had not been ventilated. Cardiac findings included individual cell necrosis without lymphocytic myocarditis. There was no evidence of secondary pulmonary infection by microorganisms. INTERPRETATION:We identify key pathological states, including thrombotic and microangiopathic pathology in the lungs, that contributed to death in patients with severe COVID-19 and decompensation in this demographic. Management of these patients should include treatment to target these pathological mechanisms. FUNDING:None. 10.1016/S2213-2600(20)30243-5
    Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease. Lebek Simon,Tafelmeier Maria,Messmann Rebecca,Provaznik Zdenek,Schmid Christof,Maier Lars S,Birner Christoph,Arzt Michael,Wagner Stefan European journal of heart failure AIMS:Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic. METHODS AND RESULTS:We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression. CONCLUSION:Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression. 10.1002/ejhf.2020
    Cardiorespiratory considerations for return-to-play in elite athletes after COVID-19 infection: a practical guide for sport and exercise medicine physicians. Wilson Mathew G,Hull James H,Rogers John,Pollock Noel,Dodd Miranda,Haines Jemma,Harris Sally,Loosemore Mike,Malhotra Aneil,Pieles Guido,Shah Anand,Taylor Lesley,Vyas Aashish,Haddad Fares S,Sharma Sanjay British journal of sports medicine SARS-CoV-2 is the causative virus responsible for the COVID-19 pandemic. This pandemic has necessitated that all professional and elite sport is either suspended, postponed or cancelled altogether to minimise the risk of viral spread. As infection rates drop and quarantine restrictions are lifted, the question how athletes can safely resume competitive sport is being asked. Given the rapidly evolving knowledge base about the virus and changing governmental and public health recommendations, a precise answer to this question is fraught with complexity and nuance. Without robust data to inform policy, return-to-play (RTP) decisions are especially difficult for elite athletes on the suspicion that the COVID-19 virus could result in significant cardiorespiratory compromise in a minority of afflicted athletes. There are now consistent reports of athletes reporting persistent and residual symptoms many weeks to months after initial COVID-19 infection. These symptoms include cough, tachycardia and extreme fatigue. To support safe RTP, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of COVID-19 in elite athletes who place high demand on their cardiorespiratory system. As new evidence emerges, guidance for a safe RTP should be updated. 10.1136/bjsports-2020-102710
    Microthrombi as a Major Cause of Cardiac Injury in COVID-19: A Pathologic Study. Pellegrini Dario,Kawakami Rika,Guagliumi Giulio,Sakamoto Atsushi,Kawai Kenji,Gianatti Andrea,Nasr Ahmed,Kutys Robert,Guo Liang,Cornelissen Anne,Faggi Lara,Mori Masayuki,Sato Yu,Pescetelli Irene,Brivio Matteo,Romero Maria,Virmani Renu,Finn Aloke V Circulation BACKGROUND:Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain uncertain. METHODS:We conducted a systematic pathological analysis of 40 hearts from hospitalized patients dying of COVID-19 in Bergamo, Italy, to determine the pathological mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury. RESULTS:Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. Compared with subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and have shorter symptom onset to admission. The incidence of severe coronary artery disease (ie, >75% cross-sectional narrowing) was not significantly different between those with and without necrosis. Three of 14 (21.4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction, defined as ≥1 cm area of necrosis, whereas 11 of 14 (78.6%) showed evidence of focal (>20 necrotic myocytes with an area of ≥0.05 mm but <1 cm) myocyte necrosis. Cardiac thrombi were present in 11 of 14 (78.6%) cases with necrosis, with 2 of 14 (14.2%) having epicardial coronary artery thrombi, whereas 9 of 14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19-positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19-infected patients presenting with ST-segment-elevation myocardial infarction. Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining compared with intramyocardial thromboemboli from COVID-19-negative subjects and with aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. CONCLUSIONS:The most common pathological cause of myocyte necrosis was microthrombi. Microthrombi were different in composition from intramyocardial thromboemboli from COVID-19-negative subjects and from coronary thrombi retrieved from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. Tailored antithrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection. 10.1161/CIRCULATIONAHA.120.051828
    Myocardial involvement in coronavirus disease 19. Saleh Ahmed,Matsumori Akira,Abdelrazek Sherif,Eltaweel Sara,Salous Amjad,Neumann Franz-Josef,Antz Matthias Herz BACKGROUND:In late 2019, a cohort of patients presenting with pneumonia of unclear etiology in Wuhan, China, heralded the outbreak of coronavirus disease 19 (COVID-19). Previous severe acute respiratory syndrome (SARS) beta-coronavirus infections have been associated with tachyarrhythmias and signs and symptoms of heart failure. The emergence of SARS coronavirus 2 (SARS-CoV-2), which causes COVID-19, has rapidly developed into a pandemic, and a large number of infected patients have been reported to have underlying cardiovascular disease. OBJECTIVE:Since there are only scant published data regarding cardiovascular burden in the wake of viral epidemics, this study aimed to evaluate cardiac involvement in COVID-19. MATERIAL AND METHODS:This prospective cohort study included 40 adult inpatients at two centers in Germany. Adult patients diagnosed with COVID-19 in accordance with World Health Organization (WHO) interim guidance were included in the study, which focused on the potential cardiac involvement of SARS-CoV‑2. It was based on laboratory parameters as well as electro- and echocardiographic values to determine the impact of SARS-CoV‑2 virus on heart tissues. RESULTS:The conducted investigations confirmed the relationship between the presence of acute cardiac injury and COVID-19. CONCLUSION:Myocardial injury and impaired myocardial function due to COVID-19 are common; however, no correlation was established between cardiac laboratory or echocardiographic values and mortality. Cardiovascular monitoring upon COVID-19 infection is crucial to determine the burden of cardiac involvement. 10.1007/s00059-020-05001-2
    COVID-19 associated viral myocarditis: does it exist? Verma Vaishali,Sondhi Sachin,Sharma Rajesh,Mahajan Kunal Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a lethal pandemic that has claimed millions of lives worldwide. While respiratory involvement is the most common and most virulent manifestation of COVID-19, there is enough data to suggest that myocardial injury reflected through elevated troponin levels is seen in around 7-28% of patients and is related with increased morbidity and mortality. 10.4081/monaldi.2020.1382
    Myocardial Injury Biomarkers and Cardiac Complications Associated with Mortality in Patients with COVID-19. Martins-Filho Paulo Ricardo,Barreto-Filho José Augusto Soares,Santos Victor Santana Arquivos brasileiros de cardiologia BACKGROUND:SARS-CoV-2 is an emerging RNA virus associated with a severe acute respiratory disease known as COVID-19. Although COVID-19 is predominantly a pulmonary disease, some patients have severe cardiovascular damage. We performed a quantitative evidence synthesis of clinical data, myocardial injury biomarkers, and cardiac complications associated with in-hospital death in patients with COVID-19. METHODS:We searched the databases PubMed, Embase, and Google Scholar to identify studies comparing clinical data, myocardial injury biomarkers, and cardiac complications between non-survivors and survivors of COVID-19. Effect sizes were reported as mean difference or standardized mean difference for continuous variables and risk ratio for dichotomous variables with 95% confidence intervals. A random effects model was used to pool the results. RESULTS:Six retrospective studies reporting data from 1,141 patients (832 survivors and 309 non-survivors) were included. We found that underlying cardiovascular conditions; elevation of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and creatine kinase-MB; and cardiac complications were associated with increased risk of death for patients with SARS-CoV-2 infection. CONCLUSIONS:The confirmation that underlying cardiovascular conditions, elevation of myocardial injury biomarkers during COVID-19 infection, and acute cardiovascular decompensation are predictors for mortality in SARS-CoV-2 infection must encourage new research to clarify potential mechanisms and test appropriate treatments. (Arq Bras Cardiol. 2020; 115(2):273-277). 10.36660/abc.20200372
    Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis: JACC Review Topic of the Week. Kawakami Rika,Sakamoto Atsushi,Kawai Kenji,Gianatti Andrea,Pellegrini Dario,Nasr Ahmed,Kutys Bob,Guo Liang,Cornelissen Anne,Mori Masayuki,Sato Yu,Pescetelli Irene,Brivio Matteo,Romero Maria,Guagliumi Giulio,Virmani Renu,Finn Aloke V Journal of the American College of Cardiology To investigate whether severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-induced myocarditis constitutes an important mechanism of cardiac injury, a review was conducted of the published data and the authors' experience was added from autopsy examination of 16 patients dying of SARS-CoV-2 infection. Myocarditis is an uncommon pathologic diagnosis occurring in 4.5% of highly selected cases undergoing autopsy or endomyocardial biopsy. Although polymerase chain reaction-detectable virus could be found in the lungs of most coronavirus disease-2019 (COVID-19)-infected subjects in our own autopsy registry, in only 2 cases was the virus detected in the heart. It should be appreciated that myocardial inflammation alone by macrophages and T cells can be seen in noninfectious deaths and COVID-19 cases, but the extent of each is different, and in neither case do such findings represent clinically relevant myocarditis. Given its extremely low frequency and unclear therapeutic implications, the authors do not advocate use of endomyocardial biopsy to diagnose myocarditis in the setting of COVID-19. 10.1016/j.jacc.2020.11.031
    A review of the main histopathological findings in coronavirus disease 2019. Vasquez-Bonilla Walter O,Orozco Roberto,Argueta Víctor,Sierra Manuel,Zambrano Lysien I,Muñoz-Lara Fausto,López-Molina Dennis Salomón,Arteaga-Livias Kovy,Grimes Zachary,Bryce Clare,Paniz-Mondolfi Alberto,Rodríguez-Morales Alfonso J Human pathology Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has been declared by the World Health Organization as an emerging public health problem of global importance and classified as a pandemic. SARS-CoV-2 infection can result in diverse, multiorgan pathology, the most significant being in the lungs (diffuse alveolar damage in its different phases, microthrombi, bronchopneumonia, necrotizing bronchiolitis, viral pneumonia), heart (lymphocytic myocarditis), kidney (acute tubular injury), central nervous system (microthrombi, ischemic necrosis, acute hemorrhagic infarction, congestion, and vascular edema), lymph nodes (hemophagocytosis and histiocytosis), bone marrow (hemophagocytosis), and vasculature (deep vein thrombosis). An understanding of the spectrum and frequency of histologic findings in COVID-19 is essential for gaining a better understanding of disease pathophysiology and its ongoing impact on public health. To this end, we conducted a systematic meta-analysis of histopathologic observations to date and review the reported findings. 10.1016/j.humpath.2020.07.023
    Parameters predicting COVID-19-induced myocardial injury and mortality. Duerr G D,Heine A,Hamiko M,Zimmer S,Luetkens J A,Nattermann J,Rieke G,Isaak A,Jehle J,Held S A E,Wasmuth J C,Wittmann M,Strassburg C P,Brossart P,Coburn M,Treede H,Nickenig G,Kurts C,Velten M Life sciences Clinical manifestations of COVID-19 affect many organs, including the heart. Cardiovascular disease is a dominant comorbidity and prognostic factors predicting risk for critical courses are highly needed. Moreover, immunomechanisms underlying COVID-induced myocardial damage are poorly understood. OBJECTIVE:To elucidate prognostic markers to identify patients at risk. RESULTS:Only patients with pericardial effusion (PE) developed a severe disease course, and those who died could be identified by a high CD8/Treg/monocyte ratio. Ten out of 19 COVID-19 patients presented with PE, 7 (78%) of these had elevated APACHE-II mortality risk-score, requiring mechanical ventilation. At admission, PE patients showed signs of systemic and cardiac inflammation in NMR and impaired cardiac function as detected by transthoracic echocardiography (TTE), whereas parameters of myocardial injury e.g. high sensitive troponin-t (hs-TnT) were not yet increased. During the course of disease, hs-TnT rose in 8 of the PE-patients above 16 ng/l, 7 had to undergo ventilatory therapy and 4 of them died. FACS at admission showed in PE patients elevated frequencies of CD3CD8 T cells among all CD3+ T-cells, and lower frequencies of Tregs and CD14HLADR-monocytes. A high CD8/Treg/monocyte ratio predicted a severe disease course in PE patients, and was associated with high serum levels of antiviral cytokines. By contrast, patients without PE and PE patients with a low CD8/Treg/monocyte ratio neither had to be intubated, nor died. CONCLUSIONS:PE predicts cardiac injury in COVID-19 patients. Therefore, TTE should be performed at admission. Immunological parameters for dysfunctional antiviral immunity, such as the CD8/Treg/monocyte ratio used here, supports risk assessment by predicting poor prognosis. 10.1016/j.lfs.2020.118400
    COVID-19-Associated Nonocclusive Fibrin Microthrombi in the Heart. Bois Melanie C,Boire Nicholas A,Layman Andrew J,Aubry Marie-Christine,Alexander Mariam P,Roden Anja C,Hagen Catherine E,Quinton Reade A,Larsen Christopher,Erben Young,Majumdar Ramanath,Jenkins Sarah M,Kipp Benjamin R,Lin Peter T,Maleszewski Joseph J Circulation BACKGROUND:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. METHODS:Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. RESULTS:Male sex was more common in the COVID-19 group (=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (=0.69, =1.00, =0.46, =0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. CONCLUSIONS:This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease. 10.1161/CIRCULATIONAHA.120.050754
    Myocardial injury and COVID-19: Possible mechanisms. Babapoor-Farrokhran Savalan,Gill Deanna,Walker Jackson,Rasekhi Roozbeh Tarighati,Bozorgnia Behnam,Amanullah Aman Life sciences Coronavirus Disease 2019 (COVID-19) has quickly progressed to a global health emergency. Respiratory illness is the major cause of morbidity and mortality in these patients with the disease spectrum ranging from asymptomatic subclinical infection, to severe pneumonia progressing to acute respiratory distress syndrome. There is growing evidence describing pathophysiological resemblance of SARS-CoV-2 infection with other coronavirus infections such as Severe Acute Respiratory Syndrome coronavirus and Middle East Respiratory Syndrome coronavirus (MERS-CoV). Angiotensin Converting Enzyme-2 receptors play a pivotal role in the pathogenesis of the virus. Disruption of this receptor leads to cardiomyopathy, cardiac dysfunction, and heart failure. Patients with cardiovascular disease are more likely to be infected with SARS-CoV-2 and they are more likely to develop severe symptoms. Hypertension, arrhythmia, cardiomyopathy and coronary heart disease are amongst major cardiovascular disease comorbidities seen in severe cases of COVID-19. There is growing literature exploring cardiac involvement in SARS-CoV-2. Myocardial injury is one of the important pathogenic features of COVID-19. As a surrogate for myocardial injury, multiple studies have shown increased cardiac biomarkers mainly cardiac troponins I and T in the infected patients especially those with severe disease. Myocarditis is depicted as another cause of morbidity amongst COVID-19 patients. The exact mechanisms of how SARS-CoV-2 can cause myocardial injury are not clearly understood. The proposed mechanisms of myocardial injury are direct damage to the cardiomyocytes, systemic inflammation, myocardial interstitial fibrosis, interferon mediated immune response, exaggerated cytokine response by Type 1 and 2 helper T cells, in addition to coronary plaque destabilization, and hypoxia. 10.1016/j.lfs.2020.117723
    Organ-specific manifestations of COVID-19 infection. Gavriatopoulou Maria,Korompoki Eleni,Fotiou Despina,Ntanasis-Stathopoulos Ioannis,Psaltopoulou Theodora,Kastritis Efstathios,Terpos Evangelos,Dimopoulos Meletios A Clinical and experimental medicine Although COVID-19 presents primarily as a lower respiratory tract infection transmitted via air droplets, increasing data suggest multiorgan involvement in patients that are infected. This systemic involvement is postulated to be mainly related to the SARS-CoV-2 virus binding on angiotensin-converting enzyme 2 (ACE2) receptors located on several different human cells. Lung involvement is the most common serious manifestation of the disease, ranging from asymptomatic disease or mild pneumonia, to severe disease associated with hypoxia, critical disease associated with shock, respiratory failure and multiorgan failure or death. Among patients with COVID-19, underlying cardiovascular comorbidities including hypertension, diabetes and especially cardiovascular disease, has been associated with adverse outcomes, whereas the emergence of cardiovascular complications, including myocardial injury, heart failure and arrhythmias, has been associated with poor survival. Gastrointestinal symptoms are also frequently encountered and may persist for several days. Haematological complications are frequent as well and have been associated with poor prognosis. Furthermore, recent studies have reported that over a third of infected patients develop a broad spectrum of neurological symptoms affecting the central nervous system, peripheral nervous system and skeletal muscles, including anosmia and ageusia. The skin, the kidneys, the liver, the endocrine organs and the eyes are also affected by the systemic COVID-19 disease. Herein, we provide a comprehensive overview of the organ-specific systemic manifestations of COVID-19. 10.1007/s10238-020-00648-x
    The Implication of Cardiac Injury Score on In-hospital Mortality of Coronavirus Disease 2019. Kim In Cheol,Song Jin Eun,Lee Hee Jung,Park Jeong Ho,Hyun Miri,Lee Ji Yeon,Kim Hyun Ah,Kwon Yong Shik,Park Jae Seok,Youn Jong Chan,Hwang Jongmin,Lee Cheol Hyun,Cho Yun Kyeong,Park Hyoung Seob,Yoon Hyuck Jun,Nam Chang Wook,Han Seongwook,Hur Seung Ho,Eisen Howard J,Kim Hyungseop Journal of Korean medical science BACKGROUNDS:The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has spread worldwide. Cardiac injury after SARS-CoV-2 infection is a major concern. The present study investigated impact of the biomarkers indicating cardiac injury in coronavirus disease 2019 (COVID-19) on patients' outcomes. METHODS:This study enrolled patients who were confirmed to have COVID-19 and admitted at a tertiary university referral hospital between February 19, 2020 and March 15, 2020. Cardiac injury was defined as an abnormality in one of the following result markers: 1) myocardial damage marker (creatine kinase-MB or troponin-I), 2) heart failure marker (N-terminal-pro B-type natriuretic peptide), and 3) electrical abnormality marker (electrocardiography). The relationship between each cardiac injury marker and mortality was evaluated. Survival analysis of mortality according to the scoring by numbers of cardiac injury markers was also performed. RESULTS:A total of 38 patients with COVID-19 were enrolled. Twenty-two patients (57.9%) had at least one of cardiac injury markers. The patients with cardiac injuries were older (69.6 ± 14.9 vs. 58.6 ± 13.9 years old, = 0.026), and were more male (59.1% vs. 18.8%, = 0.013). They showed lower initial oxygen saturation (92.8 vs. 97.1%, = 0.002) and a trend toward higher mortality (27.3 vs. 6.3%, = 0.099). The increased number of cardiac injury markers was significantly related to a higher incidence of in-hospital mortality which was also evidenced by Kaplan-Meier survival analysis ( = 0.008). CONCLUSION:The increased number of cardiac injury markers is related to in-hospital mortality in patients with COVID-19. 10.3346/jkms.2020.35.e349
    Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Tavazzi Guido,Pellegrini Carlo,Maurelli Marco,Belliato Mirko,Sciutti Fabio,Bottazzi Andrea,Sepe Paola Alessandra,Resasco Tullia,Camporotondo Rita,Bruno Raffaele,Baldanti Fausto,Paolucci Stefania,Pelenghi Stefano,Iotti Giorgio Antonio,Mojoli Francesco,Arbustini Eloisa European journal of heart failure 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. 10.1002/ejhf.1828
    Detection of viral RNA fragments in human iPSC cardiomyocytes following treatment with extracellular vesicles from SARS-CoV-2 coding sequence overexpressing lung epithelial cells. Kwon Youjeong,Nukala Sarath Babu,Srivastava Shubhi,Miyamoto Hiroe,Ismail Nur Izzah,Jousma Jordan,Rehman Jalees,Ong Sang-Bing,Lee Won Hee,Ong Sang-Ging Stem cell research & therapy Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic. The prevalence/severity of COVID-19 is higher among patients with cardiovascular risk factors. Despite the expression of angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 infection, in cardiomyocytes, there has been no conclusive evidence of direct viral infection although the presence of viral genome within COVID-19 patients' hearts has been reported. Here, we overexpressed SARS-CoV-2 genes in A549 lung epithelial cells. We then isolated extracellular vesicles (EVs) and detected the presence of viral RNA within these EVs. We observed that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are receptive to these EVs, and viral genes were detectable in the cardiomyocytes. Accordingly, the uptake of viral RNA-harboring EVs led to an upregulation of inflammation-related genes in hiPSC-CMs. Thus, our findings indicate that SARS-CoV-2 RNA containing EVs represents an indirect route of viral RNA entry into cardiomyocytes. 10.1186/s13287-020-02033-7
    Coronavirus Disease 2019 and the Myocardium. Figueiredo Neto José Albuquerque de,Marcondes-Braga Fabiana G,Moura Lidia Zytinski,Figueiredo André Melo E Silva de,Figueiredo Viviane Melo E Silva de,Mourilhe-Rocha Ricardo,Mesquita Evandro Tinoco Arquivos brasileiros de cardiologia Infection with the coronavirus known as COVID-19 has promoted growing interest on the part of cardiologists, emergency care specialists, intensive care specialists, and researchers, due to the study of myocardial involvement based on different clinical forms resulting from immunoinflammatory and neurohumoral demodulation.Myocardial involvement may be minimal and identifiable only by electrocardiographic changes, mainly increased cardiac troponins, or, on the other side of the spectrum, by forms of fulminant myocarditis and takotsubo syndrome.The description of probable acute myocarditis has been widely supported by the observation of increased troponin in association with dysfunction. Classical definition of myocarditis, supported by endomyocardial biopsy of inflammatory infiltrate, is rare; it has been observed in only one case report to date, and the virus has not been identified inside cardiomyocytes.Thus, the phenomenon that has been documented is acute myocardial injury, making it necessary to rule our obstructive coronary disease based on increased markers of myocardial necrosis, whether or not they are associated with ventricular dysfunction, likely associated with cytokine storms and other factors that may synergistically promote myocardial injury, such as sympathetic hyperactivation, hypoxemia, arterial hypotension, and microvascular thrombotic phenomena.Systemic inflammatory and myocardial phenomena following viral infection have been well documented, and they may progress to cardiac remodeling and myocardial dysfunction. Cardiac monitoring of these patients is, therefore, important in order to monitor the development of the phenotype of dilated myocardiopathy.This review presents the main etiological and physiopathological findings, a description of the taxonomy of these types of cardiac involvement, and their correlation with the main clinical forms of the myocardial component present in patients in the acute phase of COVID-19. 10.36660/abc.20200373
    Antiviral activity and safety of remdesivir against SARS-CoV-2 infection in human pluripotent stem cell-derived cardiomyocytes. Choi Seong Woo,Shin Jin Soo,Park Soon-Jung,Jung Eunhye,Park Yun-Gwi,Lee Jiho,Kim Sung Joon,Park Hun-Jun,Lee Jung-Hoon,Park Sung-Min,Moon Sung-Hwan,Ban Kiwon,Go Yun Young Antiviral research Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is considered as the most significant global public health crisis of the century. Several drug candidates have been suggested as potential therapeutic options for COVID-19, including remdesivir, currently the only authorized drug for use under an Emergency Use Authorization. However, there is only limited information regarding the safety profiles of the proposed drugs, in particular drug-induced cardiotoxicity. Here, we evaluated the antiviral activity and cardiotoxicity of remdesivir using cardiomyocytes-derived from human pluripotent stem cells (hPSC-CMs) as an alternative source of human primary cardiomyocytes (CMs). In this study, remdesivir exhibited up to 60-fold higher antiviral activity in hPSC-CMs compared to Vero E6 cells; however, it also induced moderate cardiotoxicity in these cells. To gain further insight into the drug-induced arrhythmogenic risk, we assessed QT interval prolongation and automaticity of remdesivir-treated hPSC-CMs using a multielectrode array (MEA). As a result, the data indicated a potential risk of QT prolongation when remdesivir is used at concentrations higher than the estimated peak plasma concentration. Therefore, we conclude that close monitoring of the electrocardiographic/QT interval should be advised in SARS-CoV-2-infected patients under remdesivir medication, in particular individuals with pre-existing heart conditions. 10.1016/j.antiviral.2020.104955
    SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes. Bojkova Denisa,Wagner Julian U G,Shumliakivska Mariana,Aslan Galip S,Saleem Umber,Hansen Arne,Luxán Guillermo,Günther Stefan,Pham Minh Duc,Krishnan Jaya,Harter Patrick N,Ermel Utz H,Frangakis Achilleas S,Milting Hendrik,Zeiher Andreas M,Klingel Karin,Cinatl Jindrich,Dendorfer Andreas,Eschenhagen Thomas,Tschöpe Carsten,Ciesek Sandra,Dimmeler Stefanie Cardiovascular research AIMS:Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. METHODS AND RESULTS:Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. CONCLUSION:This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir. 10.1093/cvr/cvaa267
    Mediators of SARS-CoV-2 entry are preferentially enriched in cardiomyocytes. Yang Jing,Chen Tan,Zhou Yafeng Hereditas BACKGROUND:The coronavirus disease 2019 (COVID-19) has spread rapidly around the world. In addition to common respiratory symptoms such as cough and fever, some patients also have cardiac injury, however, the mechanism of cardiac injury is not clear. In this study, we analyzed the RNA expression atlases of angiotensin-converting enzyme 2(ACE2), cathepsin B (CTSB) and cathepsin L (CTSL) in the human embryonic heart at single-cell resolution. RESULTS:The results showed that ACE2 was preferentially enriched in cardiomyocytes. Interestingly, serine protease transmembrane serine protease 2 (TMPRSS2) had less expression in cardiomyocytes, but CTSB and CTSL, which belonged to cell protease, could be found to be enriched in cardiomyocytes. The results of enrichment analysis showed that differentially expressed genes (DEGs) in ACE2-positive cardiomyocytes were mainly enriched in the processes of cardiac muscle contraction, regulation of cardiac conduction, mitochondrial respiratory chain, ion channel binding, adrenergic signaling in cardiomyocytes and viral transcription. CONCLUSIONS:Our study suggests that both atrial and ventricular cardiomyocytes are potentially susceptible to severe acute respiratory syndrome coronavirus-2(SARS-CoV-2), and SARS-CoV-2 may enter ventricular cardiomyocytes using CTSB/CTSL for S protein priming. This may be the partial cellular mechanism of cardiac injury in patients with COVID-19. 10.1186/s41065-020-00168-4
    Fatal Takotsubo syndrome in critical COVID-19 related pneumonia. Titi Luca,Magnanimi Eugenia,Mancone Massimo,Infusino Fabio,Coppola Giulia,Del Nonno Franca,Colombo Daniele,Nardacci Roberta,Falasca Laura,d'Amati Giulia,Tarsitano Maria Grazia,Merlino Lucia,Fedele Francesco,Pugliese Francesco Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology COVID-19 can involve several organs and systems, often with indirect and poorly clarified mechanisms. Different presentations of myocardial injury have been reported, with variable degrees of severity, often impacting on the prognosis of COVID-19 patients. The pathogenic mechanisms underlying cardiac damage in SARS-CoV-2 infection are under active investigation. We report the clinical and autopsy findings of a fatal case of Takotsubo Syndrome occurring in an 83-year-old patient with COVID-19 pneumonia. The patient was admitted to Emergency Department with dyspnea, fever and diarrhea. A naso-pharyngeal swab test for SARS-CoV-2 was positive. In the following week his conditions worsened, requiring intubation and deep sedation. While in the ICU, the patient suddenly showed ST segment elevation. Left ventricular angiography showed decreased with hypercontractile ventricular bases and mid-apical ballooning, consistent with diagnosis of Takotsubo syndrome. Shortly after the patient was pulseless. After extensive resuscitation maneuvers, the patient was declared dead. Autopsy revealed a subepicardial hematoma, in absence of myocardial rupture. On histology, the myocardium showed diffuse edema, multiple foci of contraction band necrosis in both ventricles and occasional coagulative necrosis of single cardiac myocytes. Abundant macrophages CD68+ were detected in the myocardial interstitium. The finding of diffuse contraction band necrosis supports the pathogenic role of increased catecholamine levels; the presence of a significant interstitial inflammatory infiltrate, made up by macrophages, remains of uncertain significance. 10.1016/j.carpath.2020.107314
    Direct SARS-CoV-2 infection of the heart potentiates the cardiovascular sequelae of COVID-19. Bose Rajendran J C,McCarthy Jason R Drug discovery today 10.1016/j.drudis.2020.06.021
    The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities. Buja Louis Maximilian,Wolf Dwayne A,Zhao Bihong,Akkanti Bindu,McDonald Michelle,Lelenwa Laura,Reilly Noah,Ottaviani Giulia,Elghetany M Tarek,Trujillo Daniel Ocazionez,Aisenberg Gabriel M,Madjid Mohammad,Kar Biswajit Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology This paper collates the pathological findings from initial published autopsy reports on 23 patients with coronavirus disease 2019 (COVID-19) from 5 centers in the United States of America, including 3 cases from Houston, Texas. Findings confirm that COVID-19 is a systemic disease with major involvement of the lungs and heart. Acute COVID-19 pneumonia has features of a distinctive acute interstitial pneumonia with a diffuse alveolar damage component, coupled with microvascular involvement with intra- and extravascular fibrin deposition and intravascular trapping of neutrophils, and, frequently, with formation of microthombi in arterioles. Major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage occurred in 5 of the 23 patients. Two of the Houston cases had interstitial pneumonia with diffuse alveolar damage pattern. One of the Houston cases had multiple bilateral segmental pulmonary thromboemboli with infarcts and hemorrhages coupled with, in nonhemorrhagic areas, a distinctive interstitial lymphocytic pneumonitis with intra-alveolar fibrin deposits and no hyaline membranes, possibly representing a transition form to acute fibrinous and organizing pneumonia. Multifocal acute injury of cardiac myocytes was frequently observed. Lymphocytic myocarditis was reported in 1 case. In addition to major pulmonary pathology, the 3 Houston cases had evidence of lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates, depletion of splenic white pulp, focal hepatocellular degeneration and rare glomerular capillary thrombosis. Each had evidence of chronic cardiac disease: hypertensive left ventricular hypertrophy (420 g heart), dilated cardiomyopathy (1070 g heart), and hypertrophic cardiomyopathy (670 g heart). All 3 subjects were obese (BMIs of 33.8, 51.65, and 35.2 Kg/m). Overall, the autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy. 10.1016/j.carpath.2020.107233
    Cardiovascular Manifestations of COVID-19 Infection. Magadum Ajit,Kishore Raj Cells SARS-CoV-2 induced the novel coronavirus disease (COVID-19) outbreak, the most significant medical challenge in the last century. COVID-19 is associated with notable increases in morbidity and death worldwide. Preexisting conditions, like cardiovascular disease (CVD), diabetes, hypertension, and obesity, are correlated with higher severity and a significant increase in the fatality rate of COVID-19. COVID-19 induces multiple cardiovascular complexities, such as cardiac arrest, myocarditis, acute myocardial injury, stress-induced cardiomyopathy, cardiogenic shock, arrhythmias and, subsequently, heart failure (HF). The precise mechanisms of how SARS-CoV-2 may cause myocardial complications are not clearly understood. The proposed mechanisms of myocardial injury based on current knowledge are the direct viral entry of the virus and damage to the myocardium, systemic inflammation, hypoxia, cytokine storm, interferon-mediated immune response, and plaque destabilization. The virus enters the cell through the angiotensin-converting enzyme-2 (ACE2) receptor and plays a central function in the virus's pathogenesis. A systematic understanding of cardiovascular effects of SARS-CoV2 is needed to develop novel therapeutic tools to target the virus-induced cardiac damage as a potential strategy to minimize permanent damage to the cardiovascular system and reduce the morbidity. In this review, we discuss our current understanding of COVID-19 mediated damage to the cardiovascular system. 10.3390/cells9112508
    Possible association between myocardial infarction with nonobstructed coronary arteries and SARS-CoV-2 infection. Agarwal Shubham,Al Hashimi Haitham,Agarwal Sanjeev Kumar,Albastaki Usama CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 10.1503/cmaj.202106
    Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Platform to Study SARS-CoV-2 Related Myocardial Injury. Wong Chun-Ka,Luk Hayes Kam-Hei,Lai Wing-Hon,Lau Yee-Man,Zhang Ricky Ruiqi,Wong Antonio Cheuk-Pui,Lo George Chi-Shing,Chan Kwok-Hung,Hung Ivan Fan-Ngai,Tse Hung-Fat,Woo Patrick Chiu-Yat,Lau Susanna Kar-Pui,Siu Chung-Wah Circulation journal : official journal of the Japanese Circulation Society BACKGROUND:SARS-CoV-2 infection is associated with myocardial injury, but there is a paucity of experimental platforms for the condition.Methods and Results:Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected by SARS-CoV-2 for 3 days ceased beating and exhibited cytopathogenic changes with reduced viability. Active viral replication was evidenced by an increase in supernatant SARS-CoV-2 and the presence of SARS-CoV-2 nucleocaspid protein within hiPSC-CMs. Expressions of BNP, CXCL1, CXCL2, IL-6, IL-8 and TNF-α were upregulated, while ACE2 was downregulated. CONCLUSIONS:Our hiPSC-CM-based in-vitro SARS-CoV-2 myocarditis model recapitulated the cytopathogenic effects and cytokine/chemokine response. It could be exploited as a drug screening platform. 10.1253/circj.CJ-20-0881
    MicroRNAs targeting the SARS-CoV-2 entry receptor ACE2 in cardiomyocytes. Lu Dongchao,Chatterjee Shambhabi,Xiao Ke,Riedel Isabelle,Wang Yibin,Foo Roger,Bär Christian,Thum Thomas Journal of molecular and cellular cardiology The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a public health emergency of international concern as more than 15 million cases were reported by 24th July 2020. Angiotensin-converting enzyme 2 (ACE2) is a COVID-19 entry receptor regulating host cell infection. A recent study reported that ACE2 is expressed in cardiomyocytes. In this study, we aimed to explore if there are microRNA (miRNA) molecules which target ACE2 and which may be exploited to regulate the SARS-CoV-2 receptor. Our data reveal that both Ace2 mRNA and Ace2 protein levels are inhibited by miR-200c in rat primary cardiomyocytes and importantly, in human iPSC-derived cardiomyocytes. We report the first miRNA candidate that can target ACE2 in cardiomyocytes and thus may be exploited as a preventive strategy to treat cardiovascular complications of COVID-19. 10.1016/j.yjmcc.2020.08.017
    Cardiovascular system and COVID-19: perspectives from a developing country. Kunal Shekhar,Gupta Kashish,Sharma Shashi Mohan,Pathak Vijay,Mittal Shruti,Tarke Chandrakant Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace A novel coronavirus, SARS-CoV-2, thought to have originated from bats causes COVID-19 infection which was first reported from Wuhan, China in December 2019. This virus has a high infectivity rate and has impacted a significant chunk of the population worldwide. The spectrum of disease ranges from mild to severe with respiratory system being the most commonly affected. Cardiovascular system often gets involved in later stages of the disease with acute cardiac injury, heart failure and arrhythmias being the common complications. In addition, the presence of cardiovascular co-morbidities such as hypertension, coronary artery disease in these patients are often associated with poor prognosis. It is still not clear regarding the exact mechanism explaining cardiovascular system involvement in COVID-19. Multiple theories have been put forward however, more robust studies are required to fully elucidate the "heart and virus" link. The disease has already made its presence felt on the global stage and its impact in the developing countries is going to be profound. These nations not only have a poorly developed healthcare system but there is also a huge burden of cardiovascular diseases. As a result, COVID-19 would adversely impact the already overburdened healthcare network leading to impaired cardiovascular care delivery especially for acute coronary syndrome and heart failure patients. 10.4081/monaldi.2020.1305
    Cardiovascular involvement in COVID-19: not to be missed. Rocco Isadora S,Gomes Walter J,Viceconte Marcela,Bolzan Douglas W,Moreira Rita Simone L,Arena Ross,Guizilini Solange Brazilian journal of cardiovascular surgery In December 2019, a striking appearance of new cases of viral pneumonia in Wuhan led to the detection of a novel coronavirus (SARS-CoV2). By analyzing patients with severe manifestations, it became apparent that 20 to 35% of patients who died had preexisting cardiovascular disease. This finding warrants the important need to discuss the influence of SARS-CoV2 infection on the cardiovascular system and hemodynamics in the context of clinical management, particularly during mechanical ventilation. The SARS-CoV2 enters human cells through the spike protein binding to angiotensin-converting enzyme 2 (ACE2), which is important to cardiovascular modulation and endothelial signaling. As ACE2 is highly expressed in lung tissue, patients have been progressing to acute respiratory injury at an alarming frequency during the Coronavirus Disease (COVID-19) pandemic. Moreover, COVID-19 leads to high D-dimer levels and prothrombin time, which indicates a substantial coagulation disorder. It seems that an overwhelming inflammatory and thrombogenic condition is responsible for a mismatching of ventilation and perfusion, with a somewhat near-normal static lung compliance, which describes two types of pulmonary conditions. As such, positive pressure during invasive mechanical ventilation (IMV) must be applied with caution. The authors of this review appeal to the necessity of paying closer attention to assess microhemodynamic repercussion, by monitoring central venous oxygen saturation during strategies of IMV. It is well known that a severe respiratory infection and a scattered inflammatory process can cause non-ischemic myocardial injury, including progression to myocarditis. Early strategies that guide clinical decisions can be lifesaving and prevent extended myocardial damage. Moreover, cardiopulmonary failure refractory to standard treatment may necessitate the use of extreme therapeutic strategies, such as extracorporeal membrane oxygenation. 10.21470/1678-9741-2020-0224
    Myocyte-Specific Upregulation of in Cardiovascular Disease: Implications for SARS-CoV-2-Mediated Myocarditis. Tucker Nathan R,Chaffin Mark,Bedi Kenneth C,Papangeli Irinna,Akkad Amer-Denis,Arduini Alessandro,Hayat Sikander,Eraslan Gökcen,Muus Christoph,Bhattacharyya Roby P,Stegmann Christian M, ,Margulies Kenneth B,Ellinor Patrick T, Circulation 10.1161/CIRCULATIONAHA.120.047911
    Marked Up-Regulation of ACE2 in Hearts of Patients With Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2-Mediated COVID-19. Bos J Martijn,Hebl Virginia B,Oberg Ann L,Sun Zhifu,Herman Daniel S,Teekakirikul Polakit,Seidman Jonathan G,Seidman Christine E,Dos Remedios Cristobal G,Maleszewski Joseph J,Schaff Hartzell V,Dearani Joseph A,Noseworthy Peter A,Friedman Paul A,Ommen Steve R,Brozovich Frank V,Ackerman Michael J Mayo Clinic proceedings OBJECTIVE:To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. PATIENTS AND METHODS:RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. RESULTS:Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10). CONCLUSION:More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart. 10.1016/j.mayocp.2020.04.028
    Letter to the Editor: Angiotensin-converting enzyme 2: an ally or a Trojan horse? Implications to SARS-CoV-2-related cardiovascular complications. Abassi Zaid,Assady Suheir,Khoury Emad E,Heyman Samuel N American journal of physiology. Heart and circulatory physiology 10.1152/ajpheart.00215.2020
    Proteome-wide data analysis reveals tissue-specific network associated with SARS-CoV-2 infection. Feng Li,Yin Yuan-Yuan,Liu Cong-Hui,Xu Ke-Ren,Li Qing-Run,Wu Jia-Rui,Zeng Rong Journal of molecular cell biology For patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the damages to multiple organs have been clinically observed. Since most of current investigations for virus-host interaction are based on cell level, there is an urgent demand to probe tissue-specific features associated with SARS-CoV-2 infection. Based on collected proteomic datasets from human lung, colon, kidney, liver, and heart, we constructed a virus-receptor network, a virus-interaction network, and a virus-perturbation network. In the tissue-specific networks associated with virus-host crosstalk, both common and different key hubs are revealed in diverse tissues. Ubiquitous hubs in multiple tissues such as BRD4 and RIPK1 would be promising drug targets to rescue multi-organ injury and deal with inflammation. Certain tissue-unique hubs such as REEP5 might mediate specific olfactory dysfunction. The present analysis implies that SARS-CoV-2 could affect multi-targets in diverse host tissues, and the treatment of COVID-19 would be a complex task. 10.1093/jmcb/mjaa033
    [Clinical feature changes of a COVID-19 patient from mild to critical condition and cardiopulmonary pathological results]. Jiang S W,Gao H,Wu L,Wang G W,Cen F L,Li J X,Feng C,Wen J M,Chen Y,He R L,Qiao K,Wang Y,Liu Y X,Wang Z Q Zhonghua xin xue guan bing za zhi To analyse the clinical history, laboratory tests and pathological data of a patient who suffered from novel coronavirus pneumonia(COVID-19) and provide reference for the clinical treatment of similar cases. Data of clinical manifestation, laboratory examination, bronchoscopy, echocardiography and cardiopulmonary pathological results were retrospectively reviewed in a case of COVID-19 with rapid exacerbation from mild to critical condition. This patient hospitalized at day 9 post 2019 novel coronavirus(2019-nCoV) infection, experienced progressive deterioration from mild to severe at day 12, severe to critical at day 18 and underwent extracorporeal membrane oxygenation(ECMO) and continuous renal replacement therapy(CRRT) as well as heart lung transplantation during day 28-45 post infection, and died at the second day post heart and lung transplantation. The patient had suffered from hypertension for 8 years. At the early stage of the disease, his symptoms were mild and the inflammatory indices increased and the lymphocyte count decreased continuously. The patient's condition exacerbated rapidly with multi-organ infections, and eventually developed pulmonary hemorrhage and consolidation, pulmonary hypertension, right heart failure, malignant ventricular arrhythmias, liver dysfunction, etc. His clinical manifestations could not be improved despite viral RNAs test results became negative. The patient underwent lung and heart transplantation and finally died of multi organ failure at the second day post lung and heart transplantation. Pathological examination indicated massive mucus, dark red secretions and blood clots in bronchus. The pathological changes were mainly diffused pulmonary hemorrhagic injuries and necrosis, fibrosis, small vessel disease with cardiac edema and lymphocyte infiltration. The clinical course of severe COVID-19 can exacerbate rapidly from mild to critical with lung, liver and heart injuries. 10.3760/cma.j.cn112148-20200304-00155
    Genes encoding ACE2, TMPRSS2 and related proteins mediating SARS-CoV-2 viral entry are upregulated with age in human cardiomyocytes. Robinson Emma L,Alkass Kanar,Bergmann Olaf,Maguire Janet J,Roderick H Llewelyn,Davenport Anthony P Journal of molecular and cellular cardiology 10.1016/j.yjmcc.2020.08.009
    ACE2 (Angiotensin-Converting Enzyme 2) and TMPRSS2 (Transmembrane Serine Protease 2) Expression and Localization of SARS-CoV-2 Infection in the Human Heart. Sakamoto Atsushi,Kawakami Rika,Kawai Kenji,Gianatti Andrea,Pellegrini Dario,Kutys Robert,Guo Liang,Mori Masayuki,Cornelissen Anne,Sato Yu,Bellasi Antonio,Faggi Lara,Hong Charles,Romero Maria,Guagliumi Giulio,Virmani Renu,Finn Aloke V Arteriosclerosis, thrombosis, and vascular biology 10.1161/ATVBAHA.120.315229
    SARS-Cov-2 fulminant myocarditis: an autopsy and histopathological case study. Gauchotte Guillaume,Venard Véronique,Segondy Michaël,Cadoz Cyril,Esposito-Fava Aude,Barraud Damien,Louis Guillaume International journal of legal medicine The coronavirus disease 2019 (COVID-19), due to SARS-CoV-2, is primarily a respiratory disease, causing in most severe cases life-threatening acute respiratory distress syndrome (ARDS). Cardiovascular involvement can also occur, such as thrombosis or myocarditis, generally associated with pulmonary lesions. Little is known about SARS-CoV-2-induced myocarditis. We report the case of a 69-year-old man suffering from a refractory cardiogenic shock, without significant lung involvement. Prior to death, several nasopharyngeal swabs and distal bronchoalveolar lavage were sampled in order to perform RT-PCR analyses for SARS-CoV-2-RNA, which all gave negative results. Autopsy showed coronary atherosclerosis, without acute complication. Microscopic examination of the heart revealed the existence of an intense multifocal inflammatory infiltration, in both ventricles and septum, composed in its majority of macrophages and CD8+ cytotoxic T lymphocytes (CD4/CD8 ratio: 0.11). Immunohistochemistry for anti-SARS nucleocapsid protein antibody was strongly positive in myocardial cells, but not in lung tissue. RT-PCR was realized on formalin-fixed paraffin-embedded lung and heart tissue blocks: only heart tissue was positive for SARS-CoV-2 RNA. In conclusion, this exhaustive post-mortem pathological case study of fulminant myocarditis demonstrates the presence of SARS-CoV-2 RNA in heart tissue, without significant lung involvement. Immunohistochemistry showed that the virus was specifically localized in cardiomyocytes and induced a strong cytotoxic T cells inflammatory response. This case report thus gives new insight in the pathogenesis of SARS-CoV-2-induced myocarditis and emphasizes on the importance and reliability of post-mortem analyses in order to better understand the physiopathology of this worldwide spreading new viral disease. 10.1007/s00414-020-02500-z
    Scientific and pharmacological rationale for the treatment of cardiac damage caused by COVID-19. Ferrara Francesco,Vitiello Antonio Discovery medicine SARS-CoV-2 is a novel coronavirus responsible for the global coronavirus 2019 pandemic (COVID-19), which started in early 2020 and is still ongoing today. COVID-19 has caused more than 1 million deaths worldwide and about 50 million infected. COVID-19 not only causes lung injury, but there may also be an involvement of other organs, including the cardiovascular system. SARS-CoV-2 penetrates host cells through the angiotensin 2 conversion enzyme (ACE-2). ACE-2 is expressed in the lungs, heart, testicles, liver, gastrointestinal tract, etc. Several studies have found that a sizeable percentage of patients with severe COVID-19 also have cardiac lesions, including myocardial fibrosis, edema, and pericarditis. Pathological remodeling of the extracellular matrix caused by SARS-CoV-2 leads to fibrotic lesions of myocardial tissue. These fibrotic lesions can cause cardiac dysfunction, reducing the ejection fraction caused by the presence of stiffened myocardial matrix and leading to heart failure, or cause an alteration in electrical conductance by creating cardiac arrhythmias. These cardiac dysfunctions can be fatal if left untreated and managed. It is therefore essential to identify cardiac involvement early in order to act with appropriate treatments to preserve the integrity of the heart. In this review, we describe what is known about cardiac damage from COVID-19, including the scientific rationale for effective therapeutic solutions to combat cardiac injury, and reduce or avoid cardiac damage from COVID-19.
    Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart. Liu Hanning,Gai Shujie,Wang Xiaoyi,Zeng Juntong,Sun Cheng,Zhao Yan,Zheng Zhe Cardiovascular research AIMS:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19. METHODS AND RESULTS:With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0-5%, I2 = 0%] in non-ICU patients to 59% (95% CI 48-71%, I2 = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P < 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P < 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19. CONCLUSION:Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2+/TMPRSS2+ cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart. 10.1093/cvr/cvaa191
    Pathogenesis of SARS-CoV-2 induced cardiac injury from the perspective of the virus. Knowlton Kirk U Journal of molecular and cellular cardiology 10.1016/j.yjmcc.2020.08.002
    Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. Lindner Diana,Fitzek Antonia,Bräuninger Hanna,Aleshcheva Ganna,Edler Caroline,Meissner Kira,Scherschel Katharina,Kirchhof Paulus,Escher Felicitas,Schultheiss Heinz-Peter,Blankenberg Stefan,Püschel Klaus,Westermann Dirk JAMA cardiology Importance:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown. Objective:To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection. Design, Setting, and Participants:This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests. Exposures:Patients who died of coronavirus disease 2019. Main Outcomes and Measures:Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3+, CD45+, and CD68+ cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18. Results:Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per μg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field. Conclusions and Relevance:In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement. 10.1001/jamacardio.2020.3551
    Histopathological findings in the advanced natural evolution of the SARS-CoV-2 infection. Cîrstea Andreea Elena,Buzulică Radu Lucian,Pirici Daniel,Ceauşu Mihail Constantin,Iman Radu Vasile,Gheorghe Ovidiu Mircea,Neamţu Simona Daniela,Stanca Liliana,Ene Răzvan,Kumar-Singh Samir,Mogoantă Laurenţiu Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie We are reporting a case of natural evolution and pathological data from a young person that was diagnosed with coronavirus disease 2019 (COVID-19). All data has been collected from the autopsy of a 30-year-old female, which was performed by the Department of Forensic Medicine from Emergency County Hospital, Drobeta Turnu Severin, Mehedinţi County, Romania. The infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed by reverse transcription polymerase chain reaction (RT-PCR) on the lung tissue which was obtained during autopsy. This case provides the opportunity to study the natural evolution of COVID-19 pneumonia in a young person with clinical signs of pneumonia but without associated comorbidities. The patient had not received any treatment. The histopathological examination of the lung revealed a process of productive proliferation, proteinaceous and fibrin-macrophagic interalveolar spaces exudate, and lesions consistent with vasculitis. In the heart, we identified a cardiac thrombus. These changes are likely to suggest an advanced natural evolution of SARS-CoV-2 virus infection. 10.47162/RJME.61.1.23
    Angiotensin-converting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes. Loganathan Sundareswaran,Kuppusamy Maheshkumar,Wankhar Wankupar,Gurugubelli Krishna Rao,Mahadevappa Vidyashree Hodagatta,Lepcha Lhakit,Choudhary Arbind Kumar Respiratory physiology & neurobiology BACKGROUND:Globally, the current medical emergency for novel coronavirus 2019 (COVID-19) leads to respiratory distress syndrome and death. PURPOSE:This review highlighted the effect of COVID-19 on systemic multiple organ failure syndromes. This review is intended to fill a gap in information about human physiological response to COVID-19 infections. This review may shed some light on other potential mechanisms and approaches in COVID -19 infections towards systemic multiorgan failure syndromes. FINDING:SARS-CoV-2 intervened mainly in the lung with progression to pneumonia and acute respiratory distress syndrome (ARDS) via the angiotensin-converting enzyme 2(ACE2) receptor. Depending on the viral load, infection spread through the ACE2 receptor further to various organs such as heart, liver, kidney, brain, endothelium, GIT, immune cell, and RBC (thromboembolism). This may be aggravated by cytokine storm with the extensive release of proinflammatory cytokines from the deregulating immune system. CONCLUSION:The widespread and vicious combinations of cytokines with organ crosstalk contribute to systemic hyper inflammation and ultimately lead to multiple organ dysfunction (Fig. 1). This comprehensive study comprises various manifestations of different organs in COVID-19 and may assist the clinicians and scientists pertaining to a broad approach to fight COVID 19. 10.1016/j.resp.2020.103548
    [A pathological report of three COVID-19 cases by minimal invasive autopsies]. Yao X H,Li T Y,He Z C,Ping Y F,Liu H W,Yu S C,Mou H M,Wang L H,Zhang H R,Fu W J,Luo T,Liu F,Guo Q N,Chen C,Xiao H L,Guo H T,Lin S,Xiang D F,Shi Y,Pan G Q,Li Q R,Huang X,Cui Y,Liu X Z,Tang W,Pan P F,Huang X Q,Ding Y Q,Bian X W Zhonghua bing li xue za zhi = Chinese journal of pathology To investigate the pathological characteristics and the clinical significance of novel coronavirus (2019-nCoV)-infected pneumonia (termed by WHO as coronavirus disease 2019, COVID-19). Minimally invasive autopsies from lung, heart, kidney, spleen, bone marrow, liver, pancreas, stomach, intestine, thyroid and skin were performed on three patients died of novel coronavirus pneumonia in Chongqing, China. Hematoxylin and eosin staining (HE), transmission electron microcopy, and histochemical staining were performed to investigate the pathological changes of indicated organs or tissues. Immunohistochemical staining was conducted to evaluate the infiltration of immune cells as well as the expression of 2019-nCoV proteins. Real time PCR was carried out to detect the RNA of 2019-nCoV. Various damages were observed in the alveolar structure, with minor serous exudation and fibrin exudation. Hyaline membrane formation was observed in some alveoli. The infiltrated immune cells in alveoli were majorly macrophages and monocytes. Moderate multinucleated giant cells, minimal lymphocytes, eosinophils and neutrophils were also observed. Most of infiltrated lymphocytes were CD4-positive T cells. Significant proliferation of type Ⅱ alveolar epithelia and focal desquamation of alveolar epithelia were also indicated. The blood vessels of alveolar septum were congested, edematous and widened, with modest infiltration of monocytes and lymphocytes. Hyaline thrombi were found in a minority of microvessels. Focal hemorrhage in lung tissue, organization of exudates in some alveolar cavities, and pulmonary interstitial fibrosis were observed. Part of the bronchial epithelia were exfoliated. Coronavirus particles in bronchial mucosal epithelia and type Ⅱ alveolar epithelia were observed under electron microscope. Immunohistochemical staining showed that part of the alveolar epithelia and macrophages were positive for 2019-nCoV antigen. Real time PCR analyses identified positive signals for 2019-nCoV nucleic acid. Decreased numbers of lymphocyte, cell degeneration and necrosis were observed in spleen. Furthermore, degeneration and necrosis of parenchymal cells, formation of hyaline thrombus in small vessels, and pathological changes of chronic diseases were observed in other organs and tissues, while no evidence of coronavirus infection was observed in these organs. The lungs from novel coronavirus pneumonia patients manifest significant pathological lesions, including the alveolar exudative inflammation and interstitial inflammation, alveolar epithelium proliferation and hyaline membrane formation. While the 2019-nCoV is mainly distributed in lung, the infection also involves in the damages of heart, vessels, liver, kidney and other organs. Further studies are warranted to investigate the mechanism underlying pathological changes of this disease. 10.3760/cma.j.cn112151-20200312-00193
    Imaging Diagnostics and Pathology in SARS-CoV-2-Related Diseases. Scimeca Manuel,Urbano Nicoletta,Bonfiglio Rita,Montanaro Manuela,Bonanno Elena,Schillaci Orazio,Mauriello Alessandro International journal of molecular sciences In December 2019, physicians reported numerous patients showing pneumonia of unknown origin in the Chinese region of Wuhan. Following the spreading of the infection over the world, The World Health Organization (WHO) on 11 March 2020 declared the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak a global pandemic. The scientific community is exerting an extraordinary effort to elucidate all aspects related to SARS-CoV-2, such as the structure, ultrastructure, invasion mechanisms, replication mechanisms, or drugs for treatment, mainly through in vitro studies. Thus, the clinical in vivo data can provide a test bench for new discoveries in the field of SARS-CoV-2, finding new solutions to fight the current pandemic. During this dramatic situation, the normal scientific protocols for the development of new diagnostic procedures or drugs are frequently not completely applied in order to speed up these processes. In this context, interdisciplinarity is fundamental. Specifically, a great contribution can be provided by the association and interpretation of data derived from medical disciplines based on the study of images, such as radiology, nuclear medicine, and pathology. Therefore, here, we highlighted the most recent histopathological and imaging data concerning the SARS-CoV-2 infection in lung and other human organs such as the kidney, heart, and vascular system. In addition, we evaluated the possible matches among data of radiology, nuclear medicine, and pathology departments in order to support the intense scientific work to address the SARS-CoV-2 pandemic. In this regard, the development of artificial intelligence algorithms that are capable of correlating these clinical data with the new scientific discoveries concerning SARS-CoV-2 might be the keystone to get out of the pandemic. 10.3390/ijms21186960
    Myocardium injury biomarkers predict prognosis of critically ill coronavirus disease 2019 (COVID-19) patients. Cao Liang,Zhang Sha,Luo Xi,Wang Enxin,Bai Yang,Li Zhe,Li Feng,Ma Jing,Liu Haitao Annals of palliative medicine BACKGROUND:The coronavirus disease 2019 (COVID-19) pandemic is a once-in-century crisis to public health. Although the pathogen for COVID-19, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been identified, the pandemic is still ongoing. The critically ill COVID-19 patients account for most disease-associated death; thus, there is an urgent need to identify prognostic factors that would help determine therapeutic approaches. METHODS:In this study, we retrospectively analyzed the clinical and laboratory findings in 100 critically ill COVID-19 patients in Hubei Women & Children Healthcare Hospital (Guanggu District), of whom 22 patients died in hospital, and 78 patients survived. RESULTS:We found that age, lymphocyte count, and total bilirubin concentration were an independent prognostic factor for critically ill COVID-19 patients. Of particular importance, we observed a significant elevation of myocardium injury biomarkers, including CK-MB, high-sensitivity cardiac troponini I (hs-cTnI), and Mb, in the non-survivor group. These myocardium injury biomarkers appeared to correlate with the time of survival, and two multivariate models have suggested hs-cTnI was a novel prognostic factor with a sensitivity of 75.0% and a specificity of 84.9%. CONCLUSIONS:Altogether, our study highlighted the prognostic significance of myocardium injury biomarkers in critically ill COVID-19 patients. Monitoring myocardium injury biomarkers would predict patient survival and guide therapeutic strategy. 10.21037/apm-20-2112
    Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Tian Sufang,Xiong Yong,Liu Huan,Niu Li,Guo Jianchun,Liao Meiyan,Xiao Shu-Yuan Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed postmortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients' ages ranged from 59 to 81, including three males and one female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the postmortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases. 10.1038/s41379-020-0536-x
    The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Chen Liang,Li Xiangjie,Chen Mingquan,Feng Yi,Xiong Chenglong Cardiovascular research 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. 10.1093/cvr/cvaa078