Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle.

Abstract

Drug-induced triggered arrhythmias in heart muscle involve oscillations of membrane potential known as delayed or early afterdepolarizations (DADs or EADs). We examined the mechanism of DADs and EADs in ferret ventricular muscle. Membrane potential, tension and aequorin luminescence were measured during exposure to elevated ICa2i0, strophanthidin and/or isoproterenol (to induce DADs), or cesium chloride (to induce EADs). Ryanodine (10-'-10' M), an inhibitor of Ca2" release from the sarcoplasmic reticulum, rapidly suppressed DADs and triggered arrhythmias. When cytoplasmic Ca2`-buffering capacity was enhanced by loading cells with the Ca"2 chelators BAPTA or quin2, DADs were similarly inhibited, as were contractile force and aequorin luminescence. In contrast to DADs, EADs induced by Cs were not suppressed by ryanodine or by loading with intracellular Ca2" chelators. The possibility that transsarcolemmal C entry might produce EADs was evaluated with highly specific dihydropyridine Ca channel agonists and antagonists. Bay K8644 (100-300 nM) potentiated EADs, whereas nitrendipine (3-20 MM) abolished EADs. We conclude that DADs and DAD-related triggered arrhythmias are activated by an increase in intracellular free Ca2" concentration, whereas EADs do not require elevated [Ca2+i but rather arise as a direct consequence of Ca2' entry through sarcolemmal slow Ca channels.

A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity

“…A DAD is a voltage depolarization caused by spontaneous calcium (Ca 2þ ) release (SCR) during the diastolic phase after a previous AP (9)(10)(11)(12)(13). If the depolarization is large enough to reach the I Na threshold, the DAD can trigger an AP causing TA.…”

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na + /Ca 2+ Exchanger in a Murine Model

“…Some studies have suggested an NCX-independent mechanism: Thus, reactivation of Ca 2+ influx via L-type Ca 2+ channels (I Ca ) during the repolarization phase may re-depolarize the membrane potential resulting in an EAD. 2,3 However, others have suggested that DADs and EADs share a common mechanism that may be NCX dependent. 4 To date, the role of chronically altered NCX expression in the generation of arrhythmia has been limited to models with increased NCX expression 5 and to animal models of heart failure or hypertrophy 1,[6][7][8][9][10] in which NCX is known to be overexpressed.…”

Remodeling of cardiac passive electrical properties and susceptibility to ventricular and atrial arrhythmias

“…These waves reflect spontaneous calcium release from the sarcoplasmic reticulum (Kimura et al, 1984;Marban et al, 1986). The sodium-calcium exchanger then operates in the forward mode generating a depolarizing current.…”