Heart rate variability and alternans formation in the heart: The role of feedback in cardiac dynamics.

A beat-to-beat alternation in the action potential duration (APD) of myocytes, i.e. alternans, is believed to be a direct precursor of ventricular fibrillation in the whole heart. A common approach for the prediction of alternans is to construct the restitution curve, which is the nonlinear functional relationship between the APD and the preceding diastolic interval (DI). It was proposed that alternans appears when the magnitude of the slope of the restitution curve exceeds one, known as the restitution hypothesis. However, this restitution hypothesis was derived under the assumption of periodic stimulation, when there is a dependence of the DI on the immediate preceding APD (i.e. feedback). However, under physiological conditions, the heart rate exhibits substantial variations in time, known as heart rate variability (HRV), which introduces deviations from periodic stimulation in the system. In this manuscript, we investigated the role of HRV on alternans formation in isolated cardiac myocytes using numerical simulations of an ionic model of the cardiac action potential. We used this model with two different pacing protocols: a periodic pacing protocol with feedback and a protocol without feedback. We show that when HRV is incorporated in the periodic pacing protocol, it facilitated alternans formation in the isolated cell, but did not significantly change the magnitude of alternans. On the other hand, in the case of the pacing protocol without feedback, alternans formation was prevented, even in the presence of HRV.

Spatiotemporal evolution and prediction of [Ca(2+) ]i and APD alternans in isolated rabbit hearts.

INTRODUCTION: Action potential duration (APD) alternans can be accompanied by alternans in intracellular calcium transients ([Ca(2+) ]i ), leading to electromechanical alternans. Electromechanical alternans is considered a substrate for ventricular fibrillation. Although some techniques have been developed to predict APD alternans, the onset of [Ca(2+) ]i alternans has never been predicted. METHODS AND RESULTS: Simultaneous mapping of voltage and calcium was performed in 8 Langendorff-perfused rabbit hearts. APD, [Ca(2+) ]i amplitude (CaA) and duration (CaD) alternans were induced using a perturbed downsweep protocol. Local onset of alternans (B(onset) ) was defined as the cycle length (BCL) at which at least 10% of the RV exhibited alternans. We observed that the local onset of CaA alternans always occurred first, followed by APD and then CaD alternans. We constructed APD, CaD, and CaA restitution portraits for 2 regions of the heart defined at B(onset) : the 1:1alt region, which developed alternans, and the 1:1 region, which did not. Our results also show that the slopes S12 Max and SDyn were higher in 1:1alt region (SDyn  = 0.99 ± 0.04 vs 0.73 ± 0.06; S12 Max  = 0.95 ± 0.13 vs 0.65 ± 0.1, P < 0.05) prior to onset of CaD alternans, while S12 and S12 Max were significantly higher in the 1:1alt region (S12  = 0.59 ± 0.19 vs 0.19 ± 0.02; S12 Max  = 1.09 ± 0.1 vs 0.61 ± 0.08, P < 0.05) prior to onset of CaA alternans. CONCLUSION: We successfully applied the restitution portrait technique to the prediction of [Ca(2+) ]i (both CaA and CaD) alternans. The slopes of the APD/CaD/CaA restitution portrait are definitive indicators of APD, CaD, and CaA alternans.