Recapitulation of respiratory sinus arrhythmia suppresses alternans in guinea pig ventricular myocytes

Abstract

Respiratory sinus arrhythmia (RSA) is an ancient physiological mechanism that is thought to maximise cardiac efficiency. It is the major component of short term heart rate variability (HRV), loss of which is associated with increased risk of sudden cardiac death (SCD), a major global health burden. The effect of recapitulating RSA on incidence of cardiac alternans, an arrhythmia mechanism associated with SCD was investigated, using a ‘short-short-long-long’ oscillatory pacing (OP) protocol of systematically varying stimulus cycle length (CL) in isolated guinea pig ventricular myocytes. Cells were enzymatically isolated and underwent whole-cell perforated patch clamp, including simultaneous recording of voltage, sarcomere shortening and intracellular calcium concentration ([Ca2+]i). While it was found that the use of Ca2+ fluorophores to monitor [Ca2+]i modified responses to changes in CL, sarcomere shortening proved a reliable proxy measure of the CaT. Cells paced in a metronomic fashion demonstrated a high burden of action potential (AP), mechanical and calcium transient (CaT) alternans which occurred more frequently at shorter CL and was associated with alternation of the maximum rate of sarcoplasmic reticulum (SR) Ca2+ release. In contrast, OP markedly suppressed AP, mechanical and CaT alternans, with the few episodes occurring of low duration. A similar effect of OP was also seen in rabbit ventricular myocytes. OP produced entrainment of APD90, sarcomere shortening, CaT and the maximum rate of SR Ca2+ release. Entrainment of sarcomere shortening and CaT was not dependent on variation in APD. There was a significant effect of not only the preceding (n-1) but also the anteceding (n-2) CL on sarcomere shortening and CaT in a manner reminiscent of post-extrasystolic potentiation (PESP), providing evidence of short-term cardiac memory. The dependence on anteceding CL and PESP-like behaviour was abolished following treatment with caffeine (50 µM), indicating the involvement of the SR in short-term memory. These novel findings suggest that OP pacing, recapitulating RSA, suppresses alternans by modulating short-term cardiac memory. The translational implications of improved risk prediction, and RSA recapitulation within cardiac devices, merit further investigation.

Date of Award	1 Oct 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jules C Hancox (Supervisor), Andrew F James (Supervisor) & Julian F.R Paton (Supervisor)