Background and objective: Abnormal impulse is a major trigger for ventricular arrhythmias in heart failure (HF). In the heart, myocytes are electrically coupled and mechanically stretched, how cardiac stretch and electrical coupling affects abnormal impulse initiation and propagation is poorly understood. Here, we investigated the impact of β-adrenergic stimulation and CaMKII activation, the two major pathological changes in the setting of heart failure, on abnormal impulse initiation in the electrically stretched HF ventricular myocytes. The capability of abnormal impulse propagation was also determined in electrically coupled ventricular myocytes.
Methods and results: A stretch-activated current source was used to represent the activation of stretch activated channel (SAC) current in ventricular myocytes and a coupling conductance model (Gc) was used to assess the electrical coupling of ventricular myocytes in the heart. We found that activation of SAC current consistently induced abnormal impulses in HF ventricular myocytes and these abnormal impulses were no longer inducible under CaMKII inhibition. However, abnormal impulses were still inducible by adrenergic stimulation even CaMKII was inhibited. In addition, fast pacing itself steadily induced EADs in the isolated and the electrically coupled myocytes. Interestingly, the EADs propagated between ventricular myocytes more readily than the normal action potentials.
Conclusions: Our results suggest that stretch current is an important trigger of abnormal impulses in HF ventricular myocytes and that β-adrenergic activation may proceed in concert with CaMKII activation in promoting abnormal impulse induction. Furthermore, premature excitation promotes EAD induction and these abnormal impulses are easy to spread out, even more capable than the regular action potentials. This HF-related electrical remodelling may explain the increased propensity of ventricular arrhythmias in HF where the increased myocardial stretch, CaMKII activity and sympathetic tone coexist.
