Abstract
Electro-mechanical and Ca alternans is a beat-to-beat alternation of action potential duration, contraction strength and Ca transient amplitude observed in cardiac myocytes at regular stimulation frequency. Ca alternans is a multifactorial process that is causally linked to cardiac arrhythmias. At the cellular level, conditions that increase fractional release from the sarcoplasmic reticulum or reduce diastolic Ca sequestration favor the occurrence of alternans. Mitochondria play a significant role in cardiac excitation–contraction coupling and Ca signaling by providing the energy for contraction and ATP-dependent processes and possibly by serving as Ca buffering organelles. Here we tested the hypothesis that impairment of mitochondrial function generates conditions that favor the occurrence of Ca alternans. Alternans were elicited by electrical pacing (>1 Hz) in single cat atrial myocytes and intracellular Ca ([Ca]i) was measured with the fluorescent Ca indicator Indo-1. The degree of alternans was quantified as the alternans ratio (AR = 1 − S/L, where S/L is the ratio of the small to the large amplitude of a pair of alternating Ca transients). Dissipation of mitochondrial membrane potential (with FCCP) as well as inhibition of mitochondrial F1/F0-ATP synthase (oligomycin), electron transport chain (rotenone, antimycin, CN−), Ca-dependent dehydrogenases and mitochondrial Ca uptake or extrusion, all enhanced AR and lowered the threshold for the occurrence of Ca alternans. The data indicate that impairment of mitochondrial function adversely affects cardiac Ca cycling leading to proarrhythmic Ca alternans.
Highlights
IntroductionCardiac alternans: A brief review Cardiac alternans describes the cyclic, beat-to-beat variations in contraction amplitude (mechanical alternans), action potential duration (electrical or APD alternans), and Ca transient amplitude (Ca alternans) at constant stimulation frequency (e.g., Wohlfart, 1982)
Cardiac alternans: A brief review Cardiac alternans describes the cyclic, beat-to-beat variations in contraction amplitude, action potential duration, and Ca transient amplitude (Ca alternans) at constant stimulation frequency (e.g., Wohlfart, 1982)
Effect of dissipation of ∆Ψm and inhibition of ATP synthesis on Ca alternans The electrochemical potential (∆Ψm) across the inner mitochondrial membrane (IMM) is sustained by the mitochondrial respiratory chain and drives mitochondrial ATP synthesis and provides www.frontiersin.org increased metabolic demands by accelerating mitochondrial ATP production
Summary
Cardiac alternans: A brief review Cardiac alternans describes the cyclic, beat-to-beat variations in contraction amplitude (mechanical alternans), action potential duration (electrical or APD alternans), and Ca transient amplitude (Ca alternans) at constant stimulation frequency (e.g., Wohlfart, 1982). Alternans occurs in cardiac failure (e.g., Dumitrescu et al, 2002), during myocardial ischemia, and is believed to be an important factor in the pathogenesis of arrhythmias (Dilly and Lab, 1988; Konta et al, 1990) and the development of re-entry phenomena (Rubenstein and Lipsius, 1995; Berger, 2000; Pastore and Rosenbaum, 2000). T-wave alternans has been linked to ventricular fibrillation and sudden cardiac death under various conditions including acute myocardial ischemia (Smith et al, 1988; Verrier and Nearing, 1994) and long-QT syndrome (Shimizu and Antzelevitch, 1999). Atrial fibrillation is the most common cardiac arrhythmia that affects a significant segment of the elderly population and is linked to high risk of embolytic complications and stroke (for review see Nattel, 2002). Alternans is a well established risk factor for ventricular dysrhythmias, and for atrial arrhythmia
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