Multiscale Consequences of Spontaneous Calcium Release on Cardiac Delayed Afterdepolarizations

Abstract

Spontaneous calcium (Ca) release in cardiac myocytes can produce delayed afterdepolarizations (DADs) that promote arrhythmias. In these studies, we combined experimental and computational approaches to investigate quantitatively how Ca release features at subcellular, cellular, and tissue scales influence DADs. Spontaneous Ca release events and corresponding DADs were measured experimentally from isolated rabbit ventricular myocytes exposed to elevated extracellular Ca (2.7 mM) and isoproterenol (0.25 μM), and were compared between lower and higher total intracellular Ca levels following 1 or 5 paced beats at 400 ms intervals, respectively. At the subcellular scale, Ca waves emerged simultaneously from an average of 1.36 (low) and 2.5 (high) sites per Ca release event. Consistent with the criticality-based theory of Ca wave emergence, Ca wave numbers were proportional to sarcoplasmic reticulum (SR) Ca levels that produced INCX with −71.1 pA/pF×ms (low) and −106.0 pA/pF×ms (high) integrated current densities upon rapid exposure to caffeine (10 mM). At the cellular scale, whole-cell calcium transients had peak amplitudes of 0.462 F/Fo (low) and 0.717 F/Fo (high) and full widths at half maximum (FWHMs) of 309.0 ms (low) and 180.0 ms (high). Resultant DADs had peak amplitudes of 1.41 mV (low) and 6.03 mV (high) and FWHMs of 302.3 ms (low) and 140.3 ms (high). Ca wave latencies in single myocytes, which determine Ca release synchrony in cardiac tissue, were 0.996 s (low) and 0.416 s (high). Computer simulation analyses implementing various combinations of the experimentally measured factors suggest that greater numbers of Ca waves, increased SR Ca release, and greater synchrony are associated with larger DAD amplitudes in cardiac tissue. Simulations also suggest that the subcellular number of Ca waves has the largest impact on DAD amplitude in tissue.