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1.
Viruses ; 14(2)2022 01 28.
Article in English | MEDLINE | ID: covidwho-1667343

ABSTRACT

Cardiomyocyte injury and troponin T elevation has been reported within COVID-19 patients and are associated with a worse prognosis. Limited data report this association among COVID-19 pregnant patients. OBJECTIVE: We aimed to analyze the association between troponin T levels in severe COVID-19 pregnant women and risk of viral sepsis, intensive care unit (ICU) admission, or maternal death. METHODS: We performed a prospective cohort of all obstetrics emergency admissions from a Mexican National Institute. All pregnant women diagnosed by reverse transcription-polymerase chain reaction (RT-qPCR) for SARS-CoV-2 infection between October 2020 and May 2021 were included. Clinical data were collected, and routine blood samples were obtained at hospital admission. Seric troponin T was measured at admission. RESULTS: From 87 included patients, 31 (35.63%) had severe COVID-19 pneumonia, and 6 (6.89%) maternal deaths. ROC showed a significant relationship between troponin T and maternal death (AUC 0.979, CI 0.500-1.000). At a cutoff point of 7 ng/mL the detection rate for severe pneumonia was 83.3% (95%CI: 0.500-0.100) at 10% false-positive rate. CONCLUSION: COVID-19 pregnant women with elevated levels of troponin T present a higher risk of death and severe pneumonia.


Subject(s)
COVID-19/complications , COVID-19/mortality , Maternal Mortality , Pneumonia/mortality , Pregnancy Complications, Infectious/mortality , Pregnancy Complications, Infectious/virology , Troponin T/blood , Adult , COVID-19/epidemiology , Female , Hospitalization , Humans , Mexico/epidemiology , Myocytes, Cardiac/pathology , Myocytes, Cardiac/virology , Pneumonia/epidemiology , Pneumonia/virology , Pregnancy , Pregnancy Complications, Infectious/epidemiology , Prospective Studies , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index
2.
Sci Rep ; 12(1): 965, 2022 01 19.
Article in English | MEDLINE | ID: covidwho-1638855

ABSTRACT

Hospitalized patients who die from Covid-19 often have pre-existing heart disease. The SARS-CoV-2 virus is dependent on the ACE2 receptor to be able to infect cells. It is possible that the strong link between cardiovascular comorbidities and a poor outcome following a SARS-CoV-2 infection is sometimes due to viral myocarditis. The aim was to examine the expression of ACE2 in normal hearts and hearts from patients with terminal heart failure. The ACE2 expression was measured by global quantitative proteomics and RT-qPCR in left ventricular (LV) tissue from explanted hearts. Immunohistochemistry was used to examine ACE2 expression in cardiomyocytes, fibroblasts and endothelial cells. In total, tissue from 14 organ donors and 11 patients with terminal heart failure were included. ACE2 expression was 2.6 times higher in 4 hearts from patients with terminal heart failure compared with 6 healthy donor hearts. The results were confirmed by immunohistochemistry where more than half of cardiomyocytes or fibroblasts showed expression of ACE2 in hearts from patients with terminal heart failure. In healthy donor hearts ACE2 was not expressed or found in few fibroblasts. A small subpopulation of endothelial cells expressed ACE2 in both groups. Upregulated ACE2 expression in cardiomyocytes may increase the risk of SARS-CoV-2 myocarditis in patients with heart failure.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Endothelial Cells/pathology , Fibroblasts/pathology , Heart Failure/pathology , Myocytes, Cardiac/pathology , Tissue Donors/supply & distribution , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Case-Control Studies , Endothelial Cells/metabolism , Female , Fibroblasts/metabolism , Heart Failure/genetics , Heart Failure/metabolism , Heart Failure/therapy , Heart Transplantation/methods , Humans , Male , Middle Aged , Myocytes, Cardiac/metabolism , Young Adult
3.
J Virol ; 96(2): e0106321, 2022 01 26.
Article in English | MEDLINE | ID: covidwho-1476388

ABSTRACT

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1ß. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19.


Subject(s)
COVID-19/immunology , Induced Pluripotent Stem Cells , Interleukin-10/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Myocytes, Cardiac , Cells, Cultured , Humans , Induced Pluripotent Stem Cells/immunology , Induced Pluripotent Stem Cells/pathology , Induced Pluripotent Stem Cells/virology , Myocytes, Cardiac/immunology , Myocytes, Cardiac/pathology , Myocytes, Cardiac/virology
4.
PLoS One ; 16(8): e0255976, 2021.
Article in English | MEDLINE | ID: covidwho-1365424

ABSTRACT

BACKGROUND: Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. AIMS AND METHODS: We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1ß antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. RESULTS: Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. CONCLUSION: Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Arrhythmias, Cardiac , COVID-19 , Calcium Signaling/drug effects , Myocytes, Cardiac , SARS-CoV-2/metabolism , Adult , Aged , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/pathology , COVID-19/complications , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , Calcium/metabolism , Drug Evaluation, Preclinical , Female , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Male , Middle Aged , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Rats , Rats, Sprague-Dawley , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/metabolism , Ventricular Dysfunction, Left/pathology
5.
Cardiovasc Res ; 117(10): 2148-2160, 2021 08 29.
Article in English | MEDLINE | ID: covidwho-1266112

ABSTRACT

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.


Subject(s)
COVID-19/virology , Heart Diseases/virology , Heart/virology , Myocytes, Cardiac/virology , SARS-CoV-2/pathogenicity , Animals , Biomarkers/metabolism , Blood Coagulation , COVID-19/complications , Fibrosis , Heart/physiopathology , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Diseases/physiopathology , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Ventricular Remodeling
6.
Cardiovasc Res ; 117(10): 2161-2174, 2021 08 29.
Article in English | MEDLINE | ID: covidwho-1266111

ABSTRACT

We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.


Subject(s)
Biomedical Research , Cardiology , Cell Proliferation , Heart Failure/pathology , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/pathology , Myocytes, Cardiac/pathology , Regeneration , Animals , COVID-19/pathology , COVID-19/virology , Cell Communication , Cellular Microenvironment , Exosomes/metabolism , Exosomes/pathology , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/physiopathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/virology , Phenotype , RNA, Untranslated/metabolism , SARS-CoV-2/pathogenicity
7.
Cardiovasc Diabetol ; 20(1): 99, 2021 05 07.
Article in English | MEDLINE | ID: covidwho-1219133

ABSTRACT

RATIONALE: About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. METHODS AND RESULTS: We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. CONCLUSIONS: The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/metabolism , Diabetes Mellitus/metabolism , Myocytes, Cardiac/metabolism , SARS-CoV-2/metabolism , Aged , Amino Acid Sequence , Autopsy , COVID-19/epidemiology , COVID-19/pathology , Cohort Studies , Diabetes Mellitus/pathology , Female , Humans , Italy/epidemiology , Male , Middle Aged , Myocytes, Cardiac/pathology , Protein Binding/physiology , Protein Structure, Secondary
9.
Comput Biol Med ; 131: 104293, 2021 04.
Article in English | MEDLINE | ID: covidwho-1101164

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 20%-30% of patients hospitalized with COVID-19 have evidence of cardiac dysfunction. Xuebijing injection is a compound injection containing five traditional Chinese medicine ingredients, which can protect cells from SARS-CoV-2-induced cell death and improve cardiac function. However, the specific protective mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction remains unclear. METHODS: The therapeutic effect of Xuebijing injection on COVID-19 was validated by the TCM Anti COVID-19 (TCMATCOV) platform. RNA-sequencing (RNA-seq) data from GSE150392 was used to find differentially expressed genes (DEGs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. Data from GSE151879 was used to verify the expression of Angiotensin I Converting Enzyme 2 (ACE2) and central hub genes in both human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) and adult human CMs with SARS-CoV-2 infection. RESULTS: A total of 97 proteins were identified as the therapeutic targets of Xuebijing injection for COVID-19. There were 22 DEGs in SARS-CoV-2 infected hiPSC-CMs overlapped with the 97 therapeutic targets, which might be the therapeutic targets of Xuebijing injection on COVID-19-induced cardiac dysfunction. Based on the bioinformatics analysis, 7 genes (CCL2, CXCL8, FOS, IFNB1, IL-1A, IL-1B, SERPINE1) were identified as central hub genes and enriched in pathways including cytokines, inflammation, cell senescence and oxidative stress. ACE2, the receptor of SARS-CoV-2, and the 7 central hub genes were differentially expressed in at least two kinds of SARS-CoV-2 infected CMs. Besides, FOS and quercetin exhibited the tightest binding by molecular docking analysis. CONCLUSION: Our study indicated the underlying protective effect of Xuebijing injection on COVID-19, especially on COVID19-induced cardiac dysfunction, which provided the theoretical basis for exploring the potential protective mechanism of Xuebijing injection on COVID19-induced cardiac dysfunction.


Subject(s)
COVID-19/metabolism , Drugs, Chinese Herbal/pharmacology , Gene Expression Regulation/drug effects , Myocytes, Cardiac/metabolism , RNA-Seq , SARS-CoV-2/metabolism , COVID-19/drug therapy , Cell Line , Human Embryonic Stem Cells/metabolism , Human Embryonic Stem Cells/pathology , Human Embryonic Stem Cells/virology , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Induced Pluripotent Stem Cells/virology , Myocytes, Cardiac/pathology , Myocytes, Cardiac/virology
10.
Cardiovasc Res ; 116(14): 2207-2215, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1048209

ABSTRACT

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.


Subject(s)
Apoptosis , COVID-19/virology , Heart Diseases/virology , Myocytes, Cardiac/virology , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Apoptosis/drug effects , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , Caco-2 Cells , Cathepsins/metabolism , Heart Diseases/drug therapy , Heart Diseases/metabolism , Heart Diseases/pathology , Host-Pathogen Interactions , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Reactive Oxygen Species/metabolism , SARS-CoV-2/drug effects , Signal Transduction
11.
Am J Forensic Med Pathol ; 42(2): 164-169, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1035550

ABSTRACT

ABSTRACT: As of August 23, 2020, the 2019 novel coronavirus disease (COVID-19) has infected more than 23,518,340 people and caused more than 810,492 deaths worldwide including 4,717 deaths in China. We present a case of a 53-year-old woman who was admitted to the hospital because of dry coughs and high fever on January 26, 2020, in Wuhan, China. She was not tested for SARS-CoV-2 RNA until on hospital day 11 (illness day 21) because of a significant shortage of test kits at the local hospital. Then, her test was positive for COVID-19 on hospital day 20. Despite intensive medical treatments, she developed respiratory failure with secondary bacterial infection and expired on hospital day 23 (3 days after she was tested positive for SARS-CoV-2 RNA). A systemic autopsy examination, including immunohistochemistry and ultrastructural studies, demonstrates that SARS-CoV-2 can infect multiple organs with profound adverse effect on the immune system, and the lung pathology is characterized by diffuse alveolar damage. Extrapulmonary SARS-CoV-2 RNA was detected in several organs postmortem. The detailed pathological features are described. In addition, this report highlights the value of forensic autopsy in studying SARS-CoV-2 infection and the importance of clinicopathological correlation in better understanding the pathogenesis of COVID-19.


Subject(s)
COVID-19/diagnosis , Autopsy , Epiglottitis/pathology , Female , Fibroblasts/pathology , Humans , Infarction/pathology , Intracranial Thrombosis/pathology , Kidney/blood supply , Kidney/pathology , Lung/pathology , Lymph Nodes/pathology , Lymphocytes/pathology , Middle Aged , Myocytes, Cardiac/pathology , Myofibroblasts/pathology , Necrosis , RNA, Viral/analysis , Splenic Infarction/pathology , Subarachnoid Hemorrhage/pathology , Thromboembolism/pathology , Thrombosis/pathology , Thyroiditis, Autoimmune/pathology , Urinary Bladder/pathology
12.
Life Sci ; 253: 117723, 2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-1023706

ABSTRACT

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.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/pathology , Myocardium/pathology , Pneumonia, Viral/pathology , COVID-19 , Coronavirus Infections/immunology , Humans , Myocarditis/virology , Myocytes, Cardiac/pathology , Myocytes, Cardiac/virology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2
13.
J Mol Cell Cardiol ; 153: 106-110, 2021 04.
Article in English | MEDLINE | ID: covidwho-989436

ABSTRACT

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. Direct effects of these drugs on the human heart remain very poorly defined. To better understand the mechanisms of action of HCQ +/- AZM, we employed bioengineered human ventricular cardiac tissue strip (hvCTS) and anisotropic sheet (hvCAS) assays, made with human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCMs), which have been designed for measuring cardiac contractility and electrophysiology, respectively. Our hvCTS experiments showed that AZM induced a dose-dependent negative inotropic effect which could be aggravated by HCQ; electrophysiologically, as revealed by the hvCAS platform, AZM prolonged action potentials and induced spiral wave formations. Collectively, our data were consistent with reported clinical risks of HCQ and AZM on QTc prolongation/ventricular arrhythmias and development of heart failure. In conclusion, our study exposed the risks of HCQ/AZM administration while providing mechanistic insights for their toxicity. Our bioengineered human cardiac tissue constructs therefore provide a useful platform for screening cardiac safety and efficacy when developing therapeutics against COVID-19.


Subject(s)
Arrhythmias, Cardiac/pathology , Azithromycin/adverse effects , Chloroquine/adverse effects , Drug-Related Side Effects and Adverse Reactions/pathology , Myocardial Contraction , Myocytes, Cardiac/pathology , Ventricular Function/drug effects , Anti-Bacterial Agents/adverse effects , Antimalarials/adverse effects , Arrhythmias, Cardiac/chemically induced , COVID-19/drug therapy , Drug-Related Side Effects and Adverse Reactions/etiology , Humans , Myocytes, Cardiac/drug effects , Pluripotent Stem Cells/drug effects , Pluripotent Stem Cells/pathology , Tissue Engineering/methods
14.
Curr Cardiol Rep ; 22(5): 32, 2020 04 21.
Article in English | MEDLINE | ID: covidwho-100111

ABSTRACT

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.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/immunology , Heart Diseases/complications , Heart Diseases/immunology , Heart Diseases/virology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/therapy , Cytokines/immunology , Humans , Hypoxia/pathology , Myocytes, Cardiac/pathology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/therapy , SARS-CoV-2
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