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

作者：Iyer Vivek; Heller Victoria; Armoundas Antonis A^*

来源：Journal of Applied Physiology, 2012, 112(6): 944-955.

DOI：10.1152/japplphysiol.00609.2011

• electrophysiological
• molecular
• EC coupling
• calcium
• remodeling
• heart failure
• arrhythmias

Iyer V, Heller V, Armoundas AA. Altered spatial calcium regulation enhances electrical heterogeneity in the failing canine left ventricle: implications for electrical instability. J Appl Physiol 112: 944-955, 2012. First published December 22, 2011; doi: 10.1152/japplphysiol.00609.2011.-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 electrophysiology and Ca2+ homeostasis in the failing LV is incompletely understood. We studied action potentials (APs), the L-type calcium (Ca2+) current (I-Ca,I-L), and intracellular Ca2+ transients ([Ca2+](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,I-L density in normal Endo, Mid, and Epi myocytes, whereas in the failing heart, I-Ca,I-L density was downregulated by 45% and 26% (at +10 mV) in Endo and Mid myocytes, respectively. The rates of sarcoplasmic reticulum (SR) Ca2+ release and decay of the [Ca2+](i) were slowed, and the amplitude of the [Ca2+](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+-Ca2+ exchanger to remove cytosolic Ca2+ 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 Ca2+ uptake in modulating the potentially arrhythmogenic repolarization in HF. In conclusion, these results demonstrate that spatially heterogeneous decreases in I-Ca,I-L and defective cytosolic Ca2+ removal contribute to the altered [Ca2+](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.

• 出版日期2012-3