Objectives The increased abnormal activity in heart failure is one of the major mechanisms of arrhythmogenesis which contributes directly to the sudden cardiac death. The current study is to explore the mechanisms underlying the increased abnormal impulses in heart failure (HF).
Methods Using the whole-cell patch clamp technique in current-clamp configuration, we studied freshly dissociated ventricular myocytes from a model of pressure-overload heart failure. In addition, we employed a unique coupling-clamp technique to electrically couple two isolated myocytes with a controlled value of coupling conductance (Gc). This method was also used to couple one cell to an invariable voltage source (-10mV) via various conductances (Gsac) designed to mimic the stretch-induced membrane depolarisation.
Results Action potential (AP) morphology was significantly altered in ventricular myocytes from failing heart compared with sham-operated controls, with significantly elevated plateau levels and prolonged APD30 and APD90. Increased pacing frequency (3Hz) significantly prolonged both APD30 and APD90 in failing myocytes but not in control myocytes. With rapid pacing, the critical Gc required for AP propagation decreased from 3.3 ± 0.1 to 2.7 ± 0.1 nS (n = 10, p < 0.01) demonstrating facilitated cell-cell conduction. In control cells, rapid pacing had no effect on Gc. Gsac-induced EADs and automaticity were significantly enhanced in failing myocytes (11/11) compared with sham-operated controls (4/31). To test whether EADs generated in one cell propagate to adjacent cells, we induced repetitive EADs from a failing myocyte by fast pacing and then coupled this cell to another cell. Interestingly, in failing myocytes, a Gc sufficient for propagation of EADs was insufficient for propagation of regular action potentials.
Conclusions These results demonstrate facilitation of electrical conduction and arrhythmia propagation in failing myocytes. Thus, in addition to its role in enhancing automaticity, AP remodelling contributes to arrhythmia development and antagonises diminished coupling that stems from fibrosis and down-regulated gap junctions.