Altered spatial calcium regulation enhances electrical heterogeneity in the failing canine left ventricle: implications for electrical instability

摘要

Myocytes across the left ventricular (LV) wall of the mammalian heart are known to exhibit heterogeneity of electrophysiological properties; however, the transmural variation of cellular electrophys-iology and Ca~(2+) homeostasis in the failing LV is incompletely understood. We studied action potentials (APs), the L-type calcium (Ca~(2+)) current (I_(Ca,L)), and intracellular Ca~(2+) transients ([Ca~(2+)]_i) of subendocardial (Endo), midmyocardial (Mid), and subepicardial (Epi) tissue layers in the canine normal and tachycardia pacing-induced failing left ventricles. Heart failure (HF) was associated with significant prolongation of the AP duration in Mid myocytes. There were no differences in I_(Ca,L) density in normal Endo, Mid, and Epi myocytes, whereas in the failing heart, I_(Ca,L) density was downregulated by 45% and 26% (at +10 mV) in Endo and Mid myocytes, respectively. The rates of sarcoplasmic reticulum (SR) Ca~(2+) release and decay of the [Ca~(2+)]_i were slowed, and the amplitude of the [Ca~(2+)]_i was depressed in Endo and Epi myocytes isolated from failing, compared with normal, hearts. Experiments in sodium (Na~+)-free solutions showed that Epi and Mid myocytes of the failing ventricle exhibit a greater reliance on the Na~+-Ca~(2+) exchanger to remove cytosolic Ca~(2+) than myocytes isolated from normal hearts. Simulation studies in Endo, Mid, and Epi canine myocytes demonstrate the importance of L-type current density and SR Ca~(2+) uptake in modulating the potentially arrhythmogenic repolarization in HF. In conclusion, these results demonstrate that spatially heterogeneous decreases in I_(Ca,L) and defective cytosolic Ca~(2+) removal contribute to the altered [Ca~(2+)]_i and AP profiles across the canine failing LV. These distinct electrophysiological features in myocytes from a failing heart contribute to a characteristic electrogram arising from increased dispersion of refractoriness across the LV, which may result in significant arrhythmogenic sequellae.