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.

Using dominant eigenvalue analysis to predict formation of alternans in the heart.

Ventricular fibrillation at the whole heart level is often preceded by the alternation of action potential duration (APD), i.e., alternans, at the cellular level. As proven in many experiments, traditional approaches based on the slope of the restitution curve have not been successful in predicting alternans formation. Recently, a technique has been theoretically developed based on dominant eigenvalue analysis to predict alternans formation in isolated cardiac myocytes. Here, we aimed to demonstrate that this technique can be applied to predict alternans formation at the whole heart level. Optical mapping was performed in Langendorff-perfused hearts from New Zealand white rabbits (n = 4), which were paced at decreasing basic cycle lengths to introduce APD alternans. In each heart, the basic cycle length corresponding to the local onset of alternans, B(onset), was determined and two regions of the heart were identified at B(onset): one region which exhibited alternans (1:1(alt)) and one which did not (1:1). Corresponding two-dimensional eigenvalue (λ) maps were generated using principal component analysis by analyzing action potentials after short perturbations from the steady state, and mean eigenvalues (λ[over ¯]) were calculated separately for the 1:1 and 1:1(alt) regions. We demonstrated that λ[over ¯] calculated at B(onset) was significantly different (p<0.05) between the two regions. Our results suggest that this dominant eigenvalue technique can be used to successfully predict the local alternans formation in the heart.