COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

Dimai, Sanzio; Semmler, Lukas; Prabhu, Akshata; Stachelscheid, Harald; Huettemeister, Judith; Klaucke, Sandra C.; Lacour, Philipp; Blaschke, Florian; Kruse, Jan; Parwani, Abdul Shokor; Boldt, Leif‐Hendrik; Bullinger, Lars; Pieske, Burkert; Heinzel, Frank R.; Hohendanner, Felix

doi:10.1371/journal.pone.0255976

Cited by 11 publications

(6 citation statements)

References 34 publications

(32 reference statements)

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“…Beat irregularity and frequency changes were also observed in hiPSC-CM monolayers. Similarly, depressed Ca 2+ transient amplitude and increased spontaneous Ca 2+ release events were previously reported in hiPSC-CMs and rat ventricular myocytes exposed to serum from COVID-19 infected patients (90), possibly implicating cytokines as mediators of rhythm disturbances that could translate to higher organ level cardiac arrhythmias. Further studies are needed to discern which cytokine-receptor combinations might be critical to the CCS remodeling underlying the electrophysiological phenotype in COVID-19.…”

Section: Dsrna Activation Of Innate Immune Responses In the Absence O...supporting

confidence: 65%

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19

Ashok,

Liu,

Criscione

et al. 2024

Preprint

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BackgroundCardiac risk rises during acute SARS-CoV-2 infection and in long COVID syndrome in humans, but the mechanisms behind COVID-19-linked arrhythmias are unknown. This study explores the acute and long term effects of SARS-CoV-2 on the cardiac conduction system (CCS) in a hamster model of COVID-19.MethodsRadiotelemetry in conscious animals was used to non-invasively record electrocardiograms and subpleural pressures after intranasal SARS-CoV-2 infection. Cardiac cytokines, interferon-stimulated gene expression, and macrophage infiltration of the CCS, were assessed at 4 days and 4 weeks post-infection. A double-stranded RNA mimetic, polyinosinic:polycytidylic acid (PIC), was used in vivo and in vitro to activate viral pattern recognition receptors in the absence of SARS-CoV-2 infection.ResultsCOVID-19 induced pronounced tachypnea and severe cardiac conduction system (CCS) dysfunction, spanning from bradycardia to persistent atrioventricular block, although no viral protein expression was detected in the heart. Arrhythmias developed rapidly, partially reversed, and then redeveloped after the pulmonary infection was resolved, indicating persistent CCS injury. Increased cardiac cytokines, interferon-stimulated gene expression, and macrophage remodeling in the CCS accompanied the electrophysiological abnormalities. Interestingly, the arrhythmia phenotype was reproduced by cardiac injection of PIC in the absence of virus, indicating that innate immune activation was sufficient to drive the response. PIC also strongly induced cytokine secretion and robust interferon signaling in hearts, human iPSC-derived cardiomyocytes (hiPSC-CMs), and engineered heart tissues, accompanied by alterations in electrical and Ca2+handling properties. Importantly, the pulmonary and cardiac effects of COVID-19 were blunted by in vivo inhibition of JAK/STAT signaling or by a mitochondrially-targeted antioxidant.ConclusionsThe findings indicate that long term dysfunction and immune cell remodeling of the CCS is induced by COVID-19, arising indirectly from oxidative stress and excessive activation of cardiac innate immune responses during infection, with implications for long COVID Syndrome.

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Section: Dsrna Activation Of Innate Immune Responses In the Absence O...supporting

confidence: 65%

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19

Ashok,

Liu,

Criscione

et al. 2024

Preprint

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“…These small, spontaneous calcium release events are well known to be an underlying cause of DADs and ventricular arrhythmias in patients with underlying genetic heart disease such as catecholaminergic polymorphic ventricular tachycardia for example [29,30], and are therefore the likely cause of the DADs observed by patch clamp in CoV-2 S-mEm-induced syncytia. Interestingly, Dimai et al recently observed similar spontaneous calcium release events in otherwise normal hiPSC-CMs that were incubated in serum extracted from SARS-CoV-2 positive patients who were hospitalized for severe acute respiratory distress [31].…”

Section: Plos Onementioning

confidence: 77%

SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may contribute to increased arrhythmic risk in COVID-19

Clemens

Ye²,

Zhou³

et al. 2023

PLoS ONE

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Background SARS-CoV-2-mediated COVID-19 may cause sudden cardiac death (SCD). Factors contributing to this increased risk of potentially fatal arrhythmias include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs. However, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown. Objective To assess the cellular and electrophysiological effects of direct SARS-CoV-2 infection of the heart using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator. Results Transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; P<0.0001) consistent with increased cell size. The APD90 was prolonged significantly from 419±26 ms (n = 10) in untransfected hiPSC-CMs to 590±67 ms (n = 10; P<0.05) in CoV-2 S-mEm-transfected hiPSC-CMs. CoV-2 S-induced syncytia displayed delayed afterdepolarizations, erratic beating frequency, and calcium handling abnormalities including calcium sparks, large “tsunami”-like waves, and increased calcium transient amplitude. After furin protease inhibitor treatment or mutating the CoV-2 S furin cleavage site, cell-cell fusion was no longer evident and Ca2+ handling returned to normal. Conclusion The SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte’s repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic.

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“…While COVID-19 was the not the initial focus of our work, recent clinical studies highlighted correlations between elevated Activin A levels and disease severity in COVID-19 ( 10 , 11 ). In one preclinical study, hiPSC-CM treated with serum from patients with COVID-19 displayed marked arrhythmia ( 55 ). However, the arrhythmia was not abolished by adding the IL-1β inhibitor canakinumab to the culture.…”

Section: Discussionmentioning

confidence: 99%

Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development

MacDonnell

Megna

Ruan

et al. 2022

Front. Cardiovasc. Med.

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Activin A has been linked to cardiac dysfunction in aging and disease, with elevated circulating levels found in patients with hypertension, atherosclerosis, and heart failure. Here, we investigated whether Activin A directly impairs cardiomyocyte (CM) contractile function and kinetics utilizing cell, tissue, and animal models. Hydrodynamic gene delivery-mediated overexpression of Activin A in wild-type mice was sufficient to impair cardiac function, and resulted in increased cardiac stress markers (N-terminal pro-atrial natriuretic peptide) and cardiac atrophy. In human-induced pluripotent stem cell-derived (hiPSC) CMs, Activin A caused increased phosphorylation of SMAD2/3 and significantly upregulated SERPINE1 and FSTL3 (markers of SMAD2/3 activation and activin signaling, respectively). Activin A signaling in hiPSC-CMs resulted in impaired contractility, prolonged relaxation kinetics, and spontaneous beating in a dose-dependent manner. To identify the cardiac cellular source of Activin A, inflammatory cytokines were applied to human cardiac fibroblasts. Interleukin -1β induced a strong upregulation of Activin A. Mechanistically, we observed that Activin A-treated hiPSC-CMs exhibited impaired diastolic calcium handling with reduced expression of calcium regulatory genes (SERCA2, RYR2, CACNB2). Importantly, when Activin A was inhibited with an anti-Activin A antibody, maladaptive calcium handling and CM contractile dysfunction were abrogated. Therefore, inflammatory cytokines may play a key role by acting on cardiac fibroblasts, causing local upregulation of Activin A that directly acts on CMs to impair contractility. These findings demonstrate that Activin A acts directly on CMs, which may contribute to the cardiac dysfunction seen in aging populations and in patients with heart failure.

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COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

Cited by 11 publications

References 34 publications

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19

Innate Immune Activation and Mitochondrial ROS Invoke Persistent Cardiac Conduction System Dysfunction after COVID-19

SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may contribute to increased arrhythmic risk in COVID-19

Activin A directly impairs human cardiomyocyte contractile function indicating a potential role in heart failure development

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