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Electrophysiological alterations in a murine model of chronic coxsackievirus B3 myocarditis
Sven Kaese1, Robert Larbig1, Matthias Rohrbeck2,3
1Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
Insights
Low-level Coxsackievirus B3 (CVB3) expression in mice did not alter cardiac electrophysiology or promote ventricular arrhythmias (VA). Prolonged ventricular refractoriness and hyperpolarized potentials were observed, suggesting other mechanisms cause arrhythmias in chronic enteroviral myocarditis.
Area of Science:
- Cardiology
- Virology
- Molecular Biology
Background:
- Coxsackievirus B3 (CVB3) infections can lead to myocarditis, ventricular arrhythmias (VA), and sudden cardiac death (SCD).
- CVB3-induced acute myocarditis can impair cardiac ion channel function, creating a proarrhythmic substrate.
- The effect of low-level CVB3 expression on cardiac electrophysiology and VA in chronic myocarditis is not well understood.
Purpose of the Study:
- To investigate whether low-level CVB3 expression in cardiomyocytes alters cardiac electrophysiology and leads to VA.
- To analyze the electrophysiological properties of cardiomyocytes and whole hearts from wildtype (WT) and transgenic CVB3+ mice.
Main Methods:
- Utilized cellular electrophysiology to assess action potentials (APs) and afterdepolarizations in isolated cardiomyocytes.
- Examined surface ECGs, monophasic APs, ventricular effective refractory period (VERP), and VA inducibility in Langendorff-perfused whole hearts.
- All experiments were conducted on male mice.
Main Results:
- No significant differences in action potential duration (APD) or afterdepolarizations were observed between WT and CVB3+ myocytes.
- CVB3+ myocytes exhibited significantly hyperpolarized resting membrane potentials (-114.1±3.0 mV) compared to WT (-90.0±2.2 mV).
- CVB3+ hearts showed significantly prolonged VERP (47.0±2.0 ms) compared to WT (36.0±2.7 ms), with no significant difference in resting heart rate or VA inducibility.
Conclusions:
- Low-level CVB3 expression in CVB3+ mice leads to prolonged ventricular refractoriness and hyperpolarized resting membrane potentials without altering APD.
- These electrophysiological changes do not promote VA, suggesting that CVB3 expression alone does not cause arrhythmias in this model.
- Chronic myocardial inflammation or fibrosis may be responsible for arrhythmias observed in patients with chronic enteroviral myocarditis.
Introduction:
Coxsackievirus 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.
Methods:
Cellular 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.
Results:
Cellular 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.
Conclusion:
In 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.
