Altered Calcium Handling and Ventricular Arrhythmias in Acute Ischemia

Abstract

Acute ischemia results in deadly cardiac arrhythmias that are a major contributor to sudden cardiac death (SCD). The electrophysiological changes involved have been extensively studied, yet the mechanisms of ventricular arrhythmias during acute ischemia remain unclear. What is known is that during acute ischemia both focal (ectopic excitation) and nonfocal (reentry) arrhythmias occur, due to an interaction of altered electrical, mechanical, and biochemical properties of the myocardium. There is particular interest in the role that alterations in intracellular calcium handling, which cause changes in intracellular calcium concentration and to the calcium transient, play in ischemia-induced arrhythmias. In this review, we briefly summarize the known contributors to ventricular arrhythmias during acute ischemia, followed by an in-depth examination of the potential contribution of altered intracellular calcium handling, which may include novel targets for antiarrhythmic therapy.

Keywords: calcium transient; ectopy; intracellular calcium concentration; reentry; sudden cardiac death.

Figure 1

Evidence for the importance of a difference in calcium transient duration (Ca_iTD₈₀) and action potential duration (APD₈₀) for early afterdepolarizations in acute ischemia. (A, B) Membrane potential (V_m) and intracellular calcium concentration (Ca_i) recordings at baseline (Stage 1), after 30 minutes of perfusion without (A) or with (B) BAPTA (Stage 2), and after 5 minutes (Stage 3) and 10 minutes (Stage 4) of global ischemia in the isolated rabbit heart (blue and black numbers indicate Ca_iTD₈₀ and APD₈₀, respectively; red asterisks indicate a greater difference between the two when perfusion with and without BAPTA are compared). (C, D) Average values of Ca_iTD₈₀ and APD₈₀ over the four experimental stages (^†P < 0.01 and ^#P < 0.001 compared to baseline; ^*P < 0.05 and ^**P < 0.001 when Ca_iTD₈₀ is compared to APD₈₀). Reproduced from Wu et al., with permission from John Wiley and Sons. © 2011 Wiley Periodicals, Inc.

Figure 2

Effects of localized catecholamine (norepinephrine, NE) application in the isolated rabbit heart. (A) Transmembrane potential (V_m) activation time, (B) calcium (Ca²⁺) transient duration at 50% amplitude (CaTD₅₀), and (C) V_m-Ca²⁺delay measured during a premature ventricular excitation induced by local injection (at the site indicated by the white asterisk) of normal Tyrode’s solution (i; NT – CON) or NE (ii; NE – CON) under control conditions, or after local NE injection with moderate cellular uncoupling by pre-application of carbenoxolone (iii; NE – CBX). (D) CaTD₅₀ and (E) V_m–Ca²⁺ delay for each type of injection as a function of distance from the injection site. (F) Number of premature ventricular complexes (PVCs) per injection and (G) the proportion of injections resulting in ≥1 PVC (right) for low-dose (gray) and high-dose (black) NE under control conditions (solid bars) and with application of CBX (hatched bars; ^*P < 0.05 and ^**P < 0.01 when compared to control). Reproduced from Myles et al., with permission from Wolters Kluwer Health, Inc. Promotional and commercial use of the material is prohibited without permission from the publishers, Wolters Kluwer. Please contact helathpermissions@wolterskluwer.com.