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Review
. 2014 Jul;41(7):524-32.
doi: 10.1111/1440-1681.12231.

Cardiac alternans and intracellular calcium cycling

Joshua N Edwards  1 , Lothar A Blatter
Affiliations
Review

Cardiac alternans and intracellular calcium cycling

Joshua N Edwards et al. Clin Exp Pharmacol Physiol. 2014 Jul.

Abstract

Cardiac alternans refers to a condition in which there is a periodic beat-to-beat oscillation in electrical activity and the strength of cardiac muscle contraction at a constant heart rate. Clinically, cardiac alternans occurs in settings that are typical for cardiac arrhythmias and has been causally linked to these conditions. At the cellular level, alternans is defined as beat-to-beat alternations in contraction amplitude (mechanical alternans), action potential duration (APD; electrical or APD alternans) and Ca(2+) transient amplitude (Ca(2+) alternans). The cause of alternans is multifactorial; however, alternans always originate from disturbances of the bidirectional coupling between membrane voltage (Vm ) and intracellular calcium ([Ca(2+) ]i ). Bidirectional coupling refers to the fact that, in cardiac cells, Vm depolarization and the generation of action potentials cause the elevation of [Ca(2+) ]i that is required for contraction (a process referred to as excitation-contraction coupling); conversely, changes of [Ca(2+) ]i control Vm because important membrane currents are Ca(2+) dependent. Evidence is mounting that alternans is ultimately caused by disturbances of cellular Ca(2+) signalling. Herein we review how two key factors of cardiac cellular Ca(2+) cycling, namely the release of Ca(2+) from internal stores and the capability of clearing the cytosol from Ca(2+) after each beat, determine the conditions under which alternans occurs. The contributions from key Ca(2+) -handling proteins (i.e. surface membrane channels, ion pumps and transporters and internal Ca(2+) release channels) are discussed.

Keywords: Ca2+ regulation; action potential; arrhythmia; cardiac alternans; excitation-contraction coupling; restitution.

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Figures

Figure 1
Figure 1. Ca2+ cycling during cardiac excitation-contraction coupling
A; Schematic of intracellular Ca2+ cycling induced by an action potential in a ventricular myocyte. B; Comparison of mechanism of excitation-contraction coupling and SR Ca2+ release in ventricular and atrial myocytes.
Figure 2
Figure 2. Cellular and subcellular Ca2+ alternans in cardiac myocytes
A–B; Spatiotemporal characteristics of Ca2+ transients during alternans in an atrial (A) and ventricular (B) myocyte. From top: whole cell Ca2+ transients, transverse confocal line scan images and subcellular [Ca2+]i profiles recorded from subsarcolemmal (ss, black) and central (ct, red) regions of the myocyte. Panels A and B modified from Hüser et al. (10) with permission. C; Spatiotemporal characteristics of Ca2+ transients during alternans in an atrial myocyte where subcellular discordant or ‘out-of-phase’ alternans are present. The global [Ca2+]i profile suggests no Ca2+ alternans, however spatially restricted profiles identify subcellular regions with no alternans coexisting with regions alternating out-of-phase.
Figure 3
Figure 3. Electrical, mechanical and Ca2+ alternans in cardiac myocytes
A; Simultaneous recordings of action potentials and cell shortening from a single ventricular myocyte revealing discordant electromechanical alternans. To the right, two action potentials recorded during successive small- (open circle) and large-amplitude (filled circle) shortenings are superimposed to illustrate the differences in duration and kinetics. Modified from Hüser et al. (10) with permission. B; Simultaneous recordings of cytosolic ([Ca2+]i; top) and intra-SR ([Ca2+]SR; bottom) Ca2+ alternans from a single ventricular myocyte. C; Simultaneous recordings of [Ca2+]i (top) and ICa (bottom) in voltage-clamped atrial myocytes. To the right, an overlay of ICa measured during a large-amplitude Ca2+ transient (L; blue trace) and a small-amplitude Ca2+ transient (S; red trace) shows that Ca2+ alternans are not accompanied by alternating peak ICa. Modified from Shrkyl et al. (67) with permission.
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