Electrophysiological alterations in a murine model of chronic coxsackievirus B3 myocarditis

Abstract

IntroductionCoxsackievirus B3 (CVB3) is known to induce acute and chronic myocarditis. Most infections are clinically unapparent but some patients suffer from ventricular arrhythmias (VA) and sudden cardiac death (SCD). Studies showed that acute CVB3 infection may cause impaired function of cardiac ion channels, creating a proarrhythmic substrate. However, it is unknown whether low level CVB3+ expression in myocytes may cause altered cardiac electrophysiology leading to VA.MethodsCellular electrophysiology was used to analyze cellular action potentials (APs) and occurrence of afterdepolarizations from isolated cardiomyocytes of wildtype (WT) and transgenic CVB3ΔVP0 (CVB3+) mice. Further, we studied surface ECGs, monophasic APs, ventricular effective refractory period (VERP) and inducibility of VAs in Langendorff-perfused whole hearts. All used cardiomyocytes and whole hearts originated from male mice.ResultsCellular action potential duration (APD) in WT and CVB3+ myocytes was unchanged. No difference in mean occurrence or amplitude of afterdepolarizations in WT and CVB3+ myocytes was found. Interestingly, resting membrane potential in CVB3+ myocytes was significantly hyperpolarized (WT: -90.0±2.2 mV, n = 7; CVB3+: -114.1±3.0 mV, n = 14; p<0.005). Consistently, in Langendorff-perfused hearts, APDs were also not different between WT and CVB3+ whole hearts. Within both groups, we found a heart rate dependent shortening of ADP90 with increasing heart rate in Langendorff-perfused hearts. VERP was significantly prolonged in CVB3+ hearts compared to WT (WT: 36.0±2.7 ms, n = 5; CVB3+: 47.0±2.0 ms, n = 7; p = 0.018). Resting heart rate (HR) in Langendorff-perfused hearts was not significantly different between both genotypes. Electrical pacing protocols induced no VA in WT and CVB3+ hearts.ConclusionIn CVB3+ mice, prolonged ventricular refractoriness and hyperpolarized resting membrane potentials in presence of unchanged APD were observed, suggesting that low level CVB3 expression does not promote VA by altered cardiac electrophysiology in this type of chronic myocarditis. These findings may suggest that other mechanisms such as chronic myocardial inflammation or fibrosis may account for arrhythmias observed in patients with chronic enteroviral myocarditis.

Extracellular SPARC increases cardiomyocyte contraction during health and disease

“…So far, research and development of novel therapeutic strategies for viral myocarditis has focused on processes targeting inflammation, cardiomyocyte degeneration, and fibrosis [7–9], whilst only a few studies have addressed the direct effect of viral infection on cardiomyocyte function. Importantly, viruses can also directly cause defective cardiomyocyte contraction, by time-dependently modulating numerous cardiac ion-channels, leading to alterations in action potential duration and resting membrane potential, as well as alterations in calcium loading which may contribute to viral-induced cardiac dysfunction [10–12]. Furthermore, non-structural matrix proteins in the heart can influence a myriad of processes during cardiac stress, such as inflammation, fibrosis and myocyte survival.…”

The first versatile human iPSC-based model of ectopic virus induction allows new insights in RNA-virus disease

“…With this tool in hand, it is now possible to observe changes in excitation spreading and contraction propagation if a signal passes CVB3 expressing cell clusters embedded in a non-induced control cell layer. As CVB3 is known to modulate cardiac ion-channels in membrane localization and function, the effects of CVB3-infected cell clusters in a non-infected monolayer are a valuable object for quantitative and qualitative analysis 16,17 . Moreover, completely new experimental setups can be designed and the pathophysiology of RNA-virus infections can be studied in more detail than ever before, especially when it comes to high-speed life cell imaging or in the use of voltage-dependent dyes.…”

The First Viral Expression Model in Human Induced Pluripotent Stem Cells to Observe Enteroviral Infections In vitro

“…Little is known about viral influences on electrical signal generation, while just a few studies address this question. A study by Seebohm et al could show that the expression of CVB3 in Xenopus laevis oocytes changes the distribution of ion channels and so potentially leads to changes in action potential generation and propagation [22]. This could be verified in the viral expression system by Peischard et al with multielectrode array measurements.…”