Correlation of ventricular arrhythmogenesis with neuronal remodeling in cardiac postganglionic parasympathetic neurons during the progression of heart failure after myocardial infarction

Abstract

Lethal ventricular arrhythmia has been a major cause of sudden cardiac death in patients with chronic heart failure (CHF). Autonomic dysfunction has been defined as a negative prognostic indicator for high mortality associated with lethal ventricular arrhythmia during the progression of CHF. Our previous study has demonstrated that expression and ion currents of N‐type Ca2+ channels in cardiac postganglionic parasympathetic (CPP) neurons located in intracardiac ganglia (ICG) are decreased in late stage of CHF rats. However, it is unclear whether electrical remodeling in CPP neurons contributes to ventricular arrhythmogenesis during the development of CHF. Here, we investigated relationship between ventricular arrhythmogenesis and neuronal remodeling in CPP neurons in coronary arterial ligation‐induced CHF rats. ECG data obtained from continuous telemetry recording in conscious rats showed that ventricular tachycardia/fibrillation (VT/VF) occurred in 1–3 and 12–14 weeks after coronary arterial ligation (60 % and 80%, respectively), whereas VT/VF did not occurred in 6–8 weeks after coronary arterial ligation. Additionally, as an index of ventricular vagal tone, the change of left ventricular pressure in response to vagal efferent nerve stimulation was blunted in 12 –14 weeks but not 1–3 weeks or 6–8 weeks after coronary arterial ligation. More importantly, the results from whole‐cell patch clamp recording demonstrated that N‐type Ca2+ currents in CPP neurons began to decrease in 6–8 weeks after coronary arterial ligation, and had a significant decrease in 12–14 weeks after coronary arterial ligation. Based on above results, we concluded that lethal ventricular arrhythmia mainly occurred in both early stage and late stage of CHF after myocardial infarction. Electrical remodeling in CPP neurons highly correlated with the occurrence of fatal ventricular arrhythmia in late stage of CHF. However, lethal ventricular arrhythmia in early stage of CHF was not attributed to N‐type Ca2+ currents in CPP neurons. These new findings suggest that improving ventricular vagal tone at late stage of CHF might be a potential therapeutic target for prevention of fatal ventricular arrhythmia and sudden cardiac death in patients with CHF.Support or Funding InformationThis study was supported by AHA Grant‐in‐Aid (15GRANT24970002)