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1.
Eur J Pediatr ; 181(1): 287-294, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1767496

ABSTRACT

Acute myocarditis is an inflammatory disease of the myocardium, and it can present as severe heart failure in children. Differential diagnosis with genetic cardiomyopathy can be difficult. The objective of this study is to identify patterns of clinical presentation and to assess invasive and non-invasive measures to differentiate patients with acute myocarditis from patients with dilated genetic cardiomyopathy. We performed a retrospective descriptive study of all paediatric patients (0-16 years old) that presented with new-onset heart failure with left ventricle ejection fraction < 35% in whom we performed an endomyocardial biopsy (EMB) during the period from April 2007 to December 2020. The patients were classified into two groups: Group 1 included 18 patients with myocarditis. Group 2 included 9 patients with genetic cardiomyopathy. Findings favouring a diagnosis of myocarditis included a fulminant or acute presentation (77.8% vs 33.3%, p = 0.01), higher degree of cardiac enzyme elevation (p = 0.011), lower left ventricular dimension z-score (2.2 vs 5.4, p = 0.03) increase of ventricular wall thickness (88.8% vs 33.3%, p = 0.03) and oedema in the EMB. Seven (77.8%) patients with genetic cardiomyopathy had inflammation in the endomyocardial biopsy fulfilling the diagnostic criteria of inflammatory cardiomyopathy.Conclusion: Differentiating patients with a myocarditis from those with genetic cardiomyopathy can be challenging, even performing an EMB. Some patients with genetic cardiomyopathy fulfil the diagnostic criteria of inflammatory cardiomyopathy. Using invasive and non-invasive measures may be useful to develop a predictive model to differentiate myocarditis from genetic cardiomyopathy. What is Known: • Acute myocarditis could present with cardiogenic shock in paediatric patients. • Parvovirus B19 is the main cause of myocarditis in this population. What is New: • Current diagnostic criteria for myocarditis have limited use in paediatric patients presenting with new-onset heart failure. • Some patients with a genetic cardiomyopathy and a new-onset heart failure fulfill the diagnostic criteria of inflammatory cardiomyopathy.


Subject(s)
Cardiomyopathy, Dilated , Myocarditis , Adolescent , Biopsy , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Myocarditis/diagnosis , Myocardium , Retrospective Studies , Stroke Volume
2.
BMJ Case Rep ; 15(3)2022 Mar 14.
Article in English | MEDLINE | ID: covidwho-1741597

ABSTRACT

A young man in his late 20s was presented with acute chest pain, concave ST elevation in lateral and inferior leads on ECG and elevated cardiac troponin. A thorough clinical history was notable for clenbuterol abuse. Transthoracic echocardiography revealed a small area of hypokinesia in the inferior wall and cardiac magnetic resonance supported the diagnosis of acute myocarditis revealing signs of myocardial oedema and subepicardial delayed enhancement. The patient was managed conservatively and had an uneventful clinical course. Awareness of the possibility of clenbuterol myocardial toxicity in young men admitted due to chest pain is essential to prompt diagnosis and management of this condition.


Subject(s)
Clenbuterol , Myocarditis , Clenbuterol/adverse effects , Humans , Magnetic Resonance Imaging , Male , Myocarditis/diagnosis , Myocarditis/diagnostic imaging , Myocardium/pathology , Weight Loss
3.
Front Endocrinol (Lausanne) ; 13: 801260, 2022.
Article in English | MEDLINE | ID: covidwho-1731767

ABSTRACT

Type 2 diabetes (T2D) patients with SARS-CoV-2 infection hospitalized develop an acute cardiovascular syndrome. It is urgent to elucidate underlying mechanisms associated with the acute cardiac injury in T2D hearts. We performed bioinformatic analysis on the expression profiles of public datasets to identify the pathogenic and prognostic genes in T2D hearts. Cardiac RNA-sequencing datasets from db/db or BKS mice (GSE161931) were updated to NCBI-Gene Expression Omnibus (NCBI-GEO), and used for the transcriptomics analyses with public datasets from NCBI-GEO of autopsy heart specimens with COVID-19 (5/6 with T2D, GSE150316), or dead healthy persons (GSE133054). Differentially expressed genes (DEGs) and overlapping homologous DEGs among the three datasets were identified using DESeq2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for event enrichment through clusterProfile. The protein-protein interaction (PPI) network of DEGs was established and visualized by Cytoscape. The transcriptions and functions of crucial genes were further validated in db/db hearts. In total, 542 up-regulated and 485 down-regulated DEGs in mice, and 811 up-regulated and 1399 down-regulated DEGs in human were identified, respectively. There were 74 overlapping homologous DEGs among all datasets. Mitochondria inner membrane and serine-type endopeptidase activity were further identified as the top-10 GO events for overlapping DEGs. Cardiac CAPNS1 (calpain small subunit 1) was the unique crucial gene shared by both enriched events. Its transcriptional level significantly increased in T2D mice, but surprisingly decreased in T2D patients with SARS-CoV-2 infection. PPI network was constructed with 30 interactions in overlapping DEGs, including CAPNS1. The substrates Junctophilin2 (Jp2), Tnni3, and Mybpc3 in cardiac calpain/CAPNS1 pathway showed less transcriptional change, although Capns1 increased in transcription in db/db mice. Instead, cytoplasmic JP2 significantly reduced and its hydrolyzed product JP2NT exhibited nuclear translocation in myocardium. This study suggests CAPNS1 is a crucial gene in T2D hearts. Its transcriptional upregulation leads to calpain/CAPNS1-associated JP2 hydrolysis and JP2NT nuclear translocation. Therefore, attenuated cardiac CAPNS1 transcription in T2D patients with SARS-CoV-2 infection highlights a novel target in adverse prognostics and comprehensive therapy. CAPNS1 can also be explored for the molecular signaling involving the onset, progression and prognostic in T2D patients with SARS-CoV-2 infection.


Subject(s)
COVID-19/epidemiology , Computational Biology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Diabetic Cardiomyopathies/epidemiology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Animals , Calpain/genetics , Calpain/physiology , Comorbidity , Diabetes Mellitus, Type 2/physiopathology , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/physiopathology , Humans , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Middle Aged , Mitochondria, Heart/ultrastructure , Muscle Proteins/metabolism , Myocardium/chemistry , Myocardium/metabolism , Myocardium/ultrastructure , Prognosis , Sequence Analysis, RNA , Transcriptome
4.
Front Immunol ; 13: 776861, 2022.
Article in English | MEDLINE | ID: covidwho-1701723

ABSTRACT

Cardiovascular dysfunction and disease are common and frequently fatal complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Indeed, from early on during the SARS-CoV-2 virus pandemic it was recognized that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection, and that these were associated with more severe disease and increased morbidity and mortality. The most common cardiac complication is acute cardiac injury, defined by significant elevation of cardiac troponins. The potential mechanisms of cardiovascular complications include direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability. This review is focused on the prevalence, risk factors and clinical course of COVID-19-related myocardial injury, as well as on current data with regard to disease pathogenesis, specifically the interaction of platelets with the vascular endothelium. The latter section includes consideration of the role of SARS-CoV-2 proteins in triggering development of a generalized endotheliitis that, in turn, drives intense activation of platelets. Most prominently, SARS-CoV-2-induced endotheliitis involves interaction of the viral spike protein with endothelial angiotensin-converting enzyme 2 (ACE2) together with alternative mechanisms that involve the nucleocapsid and viroporin. In addition, the mechanisms by which activated platelets intensify endothelial activation and dysfunction, seemingly driven by release of the platelet-derived calcium-binding proteins, SA100A8 and SA100A9, are described. These events create a SARS-CoV-2-driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease.


Subject(s)
Blood Platelets/metabolism , COVID-19/pathology , Cardiovascular Diseases/pathology , Endothelium, Vascular/metabolism , Platelet Activation/immunology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/mortality , Cardiovascular Diseases/virology , Coronavirus Nucleocapsid Proteins/immunology , Endothelial Cells/metabolism , Humans , Myocardium/pathology , Phosphoproteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
6.
Microcirculation ; 29(3): e12750, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1697657

ABSTRACT

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-c) is associated with severe cardiovascular impairment and eventually death. Pathophysiological mechanisms involved in myocardial injury were scarcely investigated, and cardiovascular outcomes are uncertain. Autopsy studies suggested that microvascular dysfunction may be relevant to LV impairment. OBJECTIVE: We aimed to evaluate segmental LV longitudinal strain by 2DST echocardiography and myocardial flow reserve (MFR) by 13 N-ammonia PET-CT, in six surviving MIS-c patients. METHODS: Each patient generated 34 LV segments for combined 2DST and MRF analysis. MFR was considered abnormal when <2, borderline when between 2 and 2.5 and normal when >2.5. RESULTS: From July 2020 to February 2021, six patients were admitted with MIS-c: three males, aged 9.3 (6.6-15.7) years. Time from admission to the follow-up visit was 6.05 (2-10.3) months. Although all patients were asymptomatic and LV EF was ≥55%, 43/102 (42.1%) LV segments showed MFR <2.5. There was a modest positive correlation between segmental peak systolic longitudinal strain and MFR: r = .36, p = .03 for basal segments; r = .41, p = .022 for mid segments; r = .42, p = .021 for apical segments. Median peak systolic longitudinal strain was different among MRF categories: 18% (12%-24%) for abnormal, 18.5% (11%-35%) for borderline, and 21% (12%-32%) for normal MFR (p = .006). CONCLUSION: We provided preliminary evidence that surviving MIS-c patients may present subclinical impairment of myocardial microcirculation. Segmental cardiac strain assessment 2DST seems useful for MIS-c cardiovascular follow-up, given its good correlation with 13 N-ammonia PET-CT derived MFR.


Subject(s)
Positron Emission Tomography Computed Tomography , Ventricular Dysfunction, Left , Ammonia , Child , Echocardiography/methods , Humans , Male , Microcirculation , Myocardium , Ventricular Dysfunction, Left/diagnostic imaging
7.
Diagn Pathol ; 17(1): 31, 2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1690905

ABSTRACT

BACKGROUND: Despite a reported cardiac injury in patients with new coronavirus infection, the possibility and specifics of genuine viral myocarditis in COVID-19 remains not fully clear. PURPOSE: To study the presence of SARS-CoV-2 in the myocardium and the morphological properties of myocarditis in patients with severe coronavirus infection (COVID-19). METHODS: Autopsy data of eight elderly patients (75.6 ± 7.4 years), four male and four female, with severe new coronavirus infection were studied. The lifetime diagnosis of COVID-19 is based on a positive result of the PCR study. The inclusion criterion was the presence of morphological signs of myocarditis according to the Dallas criteria. A standard histological examination included staining by hematoxylin and eosin, toluidin blue and Van Gieson. An immunohistochemical study was performed using antibodies to CD3, CD 68, CD20, perforin, toll-like receptor (TLR) types 4 and 9. PCR in real-time was performed to determine the viral RNA in the myocardium. RESULTS: All patients had severe bilateral viral pneumonia. In all cases, myocarditis was not clinically diagnosed. Morphological examination of the heart found signs of active lymphocytic myocarditis. PCR identified the SARS-Cov2 RNA in all cases. There were also signs of destructive coronaritis in all cases, thrombovasculitis, lymphocytic pericarditis (in 3 cases) and endocarditis (in 2 cases). The absence of neutrophils confirms the aseptic nature of inflammation. An immunohistochemical study showed the CD3-positive T lymphocytes in the infiltrates. Increased expression of TLR type 4 and less 9 was also detected. CONCLUSION: Morphological and immunohistochemical evidence of myocarditis in COVID-19 was presented. Lymphocytic infiltrations and positive PCR confirm the viral nature of inflammation. Myocarditis in COVID-19 is also characterized by coronaritis with microvascular thrombosis and associated with lymphocytic endo- and pericarditis.


Subject(s)
COVID-19/pathology , Myocarditis/pathology , Pneumonia, Viral/pathology , SARS-CoV-2/isolation & purification , Aged , Aged, 80 and over , Autopsy , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Female , Heart/virology , Humans , Immunohistochemistry , Inflammation , Lymphocytes/pathology , Male , Middle Aged , Myocarditis/complications , Myocarditis/diagnosis , Myocarditis/virology , Myocardium/pathology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2/genetics
8.
Cells ; 11(4)2022 02 10.
Article in English | MEDLINE | ID: covidwho-1690345

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an extremely contagious disease whereby the virus damages the host's respiratory tract via entering through the ACE2 receptor. Cardiovascular disorder is being recognized in the majority of COVID-19 patients; yet, the relationship between SARS-CoV-2 and heart failure has not been established. In the present study, SARS-CoV-2 infection was induced in the monkey model. Thereafter, heart tissue samples were collected, and pathological changes were analyzed in the left ventricular tissue by hematoxylin and eosin, trichrome, and immunohistochemical staining specific to T lymphocytes and macrophages. The findings revealed that SARS-CoV-2 infection induces several pathological changes in the heart, which cause cardiomyocyte disarray, mononuclear infiltrates of inflammatory cells, and hypertrophy. Furthermore, collagen-specific staining showed the development of cardiac fibrosis in the interstitial and perivascular regions in the hearts of infected primates. Moreover, the myocardial tissue samples displayed multiple foci of inflammatory cells positive for T lymphocytes and macrophages within the myocardium. These findings suggest the progression of the disease, which can lead to the development of severe complications, including heart failure. Additionally, SARS-CoV-2 antigen staining detected the presence of virus particles in the myocardium. Thus, we found that SARS-CoV-2 infection is characterized by an exaggerated inflammatory immune response in the heart, which possibly contributes to myocardial remodeling and subsequent fibrosis.


Subject(s)
COVID-19/immunology , Heart Failure/physiopathology , Heart/physiopathology , Animals , Chlorocebus aethiops , Heart/virology , Heart Failure/virology , Heart Ventricles/physiopathology , Heart Ventricles/virology , Immune System/pathology , Macaca mulatta , Myocarditis/virology , Myocardium/metabolism , SARS-CoV-2/pathogenicity
9.
J Card Surg ; 37(5): 1439-1443, 2022 May.
Article in English | MEDLINE | ID: covidwho-1685369

ABSTRACT

Emerging data suggest an association between severe acute respiratory syndrome coronavirus 2 and the development of acute myocarditis, with children and older adults being most at risk. We describe the clinical course of a previously healthy 12-year-old female who rapidly deteriorated into cardiogenic shock and arrest due to coronavirus disease 2019 induced fulminant myocarditis, necessitating venous-arterial extracorporeal membrane oxygenation as a bridge to full recovery. This case highlights the importance of early clinical recognition of myocardial involvement, and the benefits of taking a multidisciplinary approach in treating these patients.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Myocarditis , Adolescent , Aged , COVID-19/complications , COVID-19/therapy , Child , Female , Humans , Myocarditis/etiology , Myocarditis/therapy , Myocardium , Shock, Cardiogenic/etiology , Shock, Cardiogenic/therapy
12.
Am J Cardiol ; 168: 135-141, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1634616

ABSTRACT

Multisystem inflammatory syndrome (MIS) is a severe complication described in a minority of patients with COVID-19. Myocarditis has been reported in patients with COVID-19, including MIS. In this study, we compared the clinical characteristics and cardiac magnetic resonance (CMR) findings of COVID-19 myocarditis in patients with and without MIS. In the 330 patients with COVID-19 who were referred for CMR at our institution between July 24, 2020, to March 31, 2021, 40 patients were identified as having myocarditis, MIS myocarditis (n = 21) and non-MIS myocarditis (n = 19). MIS myocarditis was characterized by global myocardial inflammation/edema with significantly elevated native T1, whereas only regional inflammation, and edema were noted in the non-MIS group. Distinct late gadolinium enhancement (LGE) patterns-inferior myocardial involvement in non-MIS myocarditis and septal involvement in MIS myocarditis-were identified. The LGE burden was comparable between the 2 groups (5.9% vs 6.6%, MIS vs non-MIS group, p = 0.83). Myocarditis was diagnosed more frequently by CMR in the MIS group (70% vs 6.3%, MIS vs non-MIS, p <0.001). In the 20 patients with a sequential CMR study at a median 102-day follow-up, 25% had persistent myocardial edema. The LGE burden improved over time, from a median of 5.0% (interquartile range 3.4% to 7.3%) to 3.2% (interquartile range 2.0% to 3.8%; p <0.001). In conclusion, MIS and non-MIS myocarditis exhibit distinct characteristics by CMR. Persistent LGE and edema were common at follow-up CMR examination in both groups.


Subject(s)
COVID-19 , Myocarditis , COVID-19/complications , Contrast Media , Gadolinium , Humans , Magnetic Resonance Imaging , Magnetic Resonance Imaging, Cine , Myocarditis/diagnostic imaging , Myocarditis/pathology , Myocardium/pathology , Predictive Value of Tests
13.
Bioengineered ; 13(2): 2486-2497, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625949

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can target cardiomyocytes (CMs) to directly invade the heart resulting in high mortality. This study aims to explore the biological characteristics of SARS-CoV-2 infected myocardium based on omics by collecting transcriptome data and analyzing them with a series of bioinformatics tools. Totally, 86 differentially expressed genes (DEGs) were discovered in SARS-CoV-2 infected CMs, and 15 miRNAs were discovered to target 60 genes. Functional enrichment analysis indicated that these DEGs were mainly enriched in the inflammatory signaling pathway. After the protein-protein interaction (PPI) network was constructed, several genes including CCL2 and CXCL8 were regarded as the hub genes. SRC inhibitor saracatinib was predicted to potentially act against the cardiac dysfunction induced by SARS-CoV-2. Among the 86 DEGs, 28 were validated to be dysregulated in SARS-CoV-2 infected hearts. Gene Set Enrichment Analysis (GSEA) analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that malaria, IL-17 signaling pathway, and complement and coagulation cascades were significantly enriched. Immune infiltration analysis indicated that 'naive B cells' was significantly increased in the SARS-CoV-2 infected heart. The above results may help to improve the prognosis of patients with COVID-19.


Subject(s)
COVID-19/immunology , COVID-19/virology , Heart/physiopathology , Heart/virology , Myocardium/pathology , SARS-CoV-2 , Blood Coagulation , Chemokine CCL2/biosynthesis , Complement System Proteins , Computational Biology , Gene Expression Profiling , Gene Expression Regulation, Viral , Genome, Human , Humans , Inflammation , Interleukin-17/blood , Interleukin-8/biosynthesis , MicroRNAs/metabolism , Prognosis , Protein Interaction Mapping , Signal Transduction
14.
Sci Rep ; 12(1): 298, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1612205

ABSTRACT

Inappropriate sinus tachycardia (IST) is a common observation in patients with post-COVID-19 syndrome (PCS) but has not yet been fully described to date. To investigate the prevalence and the mechanisms underlying IST in a prospective population of PCS patients. Consecutive patients admitted to the PCS Unit between June and December 2020 with a resting sinus rhythm rate ≥ 100 bpm were prospectively enrolled in this study and further examined by an orthostatic test, 2D echocardiography, 24-h ECG monitoring (heart rate variability was a surrogate for cardiac autonomic activity), quality-of-life and exercise capacity testing, and blood sampling. To assess cardiac autonomic function, a 2:1:1 comparative sub-analysis was conducted against both fully recovered patients with previous SARS-CoV-2 infection and individuals without prior SARS-CoV-2 infection. Among 200 PCS patients, 40 (20%) fulfilled the diagnostic criteria for IST (average age of 40.1 ± 10 years, 85% women, 83% mild COVID-19). No underlying structural heart disease, pro-inflammatory state, myocyte injury, or hypoxia were identified. IST was accompanied by a decrease in most heart rate variability parameters, especially those related to cardiovagal tone: pNN50 (cases 3.2 ± 3 vs. recovered 10.5 ± 8 vs. non-infected 17.3 ± 10; p < 0.001) and HF band (246 ± 179 vs. 463 ± 295 vs. 1048 ± 570, respectively; p < 0.001). IST is prevalent condition among PCS patients. Cardiac autonomic nervous system imbalance with decreased parasympathetic activity may explain this phenomenon.


Subject(s)
COVID-19/complications , Tachycardia, Sinus/etiology , Adult , COVID-19/diagnosis , COVID-19/pathology , COVID-19/physiopathology , Female , Heart Rate , Humans , Male , Middle Aged , Myocardium/pathology , Prevalence , Prospective Studies , SARS-CoV-2/isolation & purification , Tachycardia, Sinus/diagnosis , Tachycardia, Sinus/pathology , Tachycardia, Sinus/physiopathology
15.
Elife ; 102021 12 21.
Article in English | MEDLINE | ID: covidwho-1597375

ABSTRACT

For the first time, we have used phase-contrast X-ray tomography to characterize the three-dimensional (3d) structure of cardiac tissue from patients who succumbed to Covid-19. By extending conventional histopathological examination by a third dimension, the delicate pathological changes of the vascular system of severe Covid-19 progressions can be analyzed, fully quantified and compared to other types of viral myocarditis and controls. To this end, cardiac samples with a cross-section of 3.5mm were scanned at a laboratory setup as well as at a parallel beam setup at a synchrotron radiation facility the synchrotron in a parallel beam configuration. The vascular network was segmented by a deep learning architecture suitable for 3d datasets (V-net), trained by sparse manual annotations. Pathological alterations of vessels, concerning the variation of diameters and the amount of small holes, were observed, indicative of elevated occurrence of intussusceptive angiogenesis, also confirmed by high-resolution cone beam X-ray tomography and scanning electron microscopy. Furthermore, we implemented a fully automated analysis of the tissue structure in the form of shape measures based on the structure tensor. The corresponding distributions show that the histopathology of Covid-19 differs from both influenza and typical coxsackie virus myocarditis.


Subject(s)
COVID-19/complications , Myocarditis/pathology , Myocarditis/virology , Myocardium/pathology , SARS-CoV-2/isolation & purification , Artificial Intelligence , COVID-19/pathology , Heart/diagnostic imaging , Heart/virology , Humans , Imaging, Three-Dimensional , Myocarditis/diagnostic imaging , Myocarditis/etiology , Synchrotrons , Tomography, X-Ray Computed
16.
Int J Mol Sci ; 22(24)2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1580692

ABSTRACT

Although blood-heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.


Subject(s)
COVID-19/complications , Heart Failure/metabolism , Heart/virology , Animals , Blood/virology , Blood Physiological Phenomena/immunology , COVID-19/physiopathology , Cardiomegaly/metabolism , Cardiovascular Diseases/metabolism , Cardiovascular Physiological Phenomena/immunology , Disease Models, Animal , Endothelium/metabolism , Heart/physiopathology , Heart Failure/virology , Hydroxychloroquine/pharmacology , Male , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Muscle Cells/metabolism , Myocardium/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Ventricular Remodeling/physiology
17.
Clin Sci (Lond) ; 135(24): 2667-2689, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1585742

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Basigin/metabolism , Myocardium/enzymology , Pericytes/enzymology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/blood , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/blood , Caco-2 Cells , Cell Death , Child , Child, Preschool , Cytokines/metabolism , Female , Host-Pathogen Interactions , Humans , Infant , Infant, Newborn , Male , Middle Aged , Myocardium/cytology , Pericytes/virology , Primary Cell Culture , Young Adult
18.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1571524

ABSTRACT

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.


Subject(s)
COVID-19 , Heart Injuries , RNA-Seq , SARS-CoV-2/metabolism , Thrombosis , Adult , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/metabolism , COVID-19/pathology , Female , Heart Injuries/genetics , Heart Injuries/metabolism , Heart Injuries/pathology , Humans , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , Prospective Studies , Thrombosis/genetics , Thrombosis/metabolism , Thrombosis/pathology
19.
Biomed Pharmacother ; 146: 112518, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1562447

ABSTRACT

SARS-CoV-2 causes respiratory illness with a spectrum of systemic complications. However, the mechanism for cardiac infection and cardiomyocyte injury in COVID-19 patients remains unclear. The current literature supports the notion that SARS-CoV-2 particles access the heart either by the circulating blood cells or by extracellular vesicles, originating from the inflamed lungs, and encapsulating the virus along with its receptor (ACE2). Both cardiomyocytes and pericytes (coronary arteries) express the necessary accessory proteins for access of SARS-CoV-2 particles (i.e. ACE2, NRP-1, TMPRSS2, CD147, integrin α5ß1, and CTSB/L). These proteins facilitate the SARS-CoV-2 interaction and entry into the pericytes and cardiomyocytes thus leading to cardiac manifestations. Subsequently, various signaling pathways are altered in the infected cardiomyocytes (i.e. increased ROS production, reduced contraction, impaired calcium homeostasis), causing cardiac dysfunction. The currently adopted pharmacotherapy in severe COVID-19 subjects exhibited side effects on the heart, often manifested by electrical abnormalities. Nonetheless, cardiovascular adverse repercussions have been associated with the advent of some of the SARS-CoV-2 vaccines with no clear mechanisms underlining these complications. We provide herein an overview of the pathways involved with cardiomyocyte in COVID-19 subjects to help promoting pharmacotherapies that can protect against SARS-CoV-2-induced cardiac injuries.


Subject(s)
COVID-19/metabolism , Heart Diseases/metabolism , Myocardium/metabolism , Myocytes, Cardiac/metabolism , SARS-CoV-2/metabolism , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/metabolism , Heart Diseases/drug therapy , Heart Diseases/epidemiology , Humans , Myocytes, Cardiac/drug effects , SARS-CoV-2/drug effects
20.
J Pathol ; 256(3): 256-261, 2022 03.
Article in English | MEDLINE | ID: covidwho-1549277

ABSTRACT

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
Brain/enzymology , COVID-19/enzymology , Indoleamine-Pyrrole 2,3,-Dioxygenase/analysis , Lung/enzymology , Myocardium/enzymology , 3-Hydroxyanthranilic Acid/analysis , Adult , Aged , Apoptosis , Autopsy , Brain/pathology , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Humans , Kynurenine/analysis , Lung/pathology , Middle Aged , Myocardium/pathology , Prospective Studies , Quinolinic Acid/analysis , Severity of Illness Index , Tryptophan/analysis
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