Review articleDyssynchrony of Ca2+ release from the sarcoplasmic reticulum as subcellular mechanism of cardiac contractile dysfunction
Research Highlights
► Synchronized sarcoplasmic reticulum Ca release is essential for efficient contraction. ► Synchrony of RyR is achieved within couplons, organized in t-tubules. ► Remodeling of couplons and t-tubules reduces synchrony in disease.
Introduction
Although dyssynchrony may not be in the Oxford English Dictionary (asynchrony being more correct), it is a term that has entered common use. Indeed, a search for the term in the PubMed database yields over 800 articles that, with a few exceptions, all relate to cardiac disease where the normal contraction pattern of the heart is disturbed. Synchronizing contraction of the ventricles within each heart beat is a key requirement for efficient ejection and re-filling and relies on a correct sequence of electrical activation. This is orchestrated by the specialized electrical conduction system of the heart with its different branches and by cell-to-cell propagation. In cardiac remodeling and heart failure, disturbed electrical conduction with abnormal sequence of activation of the ventricle, as reflected by a broad QRS complex in the ECG, not only reduces cardiac pump function, it also causes abnormal regional myocardial stress and can further exacerbate remodeling [1] Recent clinical studies have shown that symptomatic mechanical dyssynchrony can occur despite apparently normal electrical activation (e.g. [2]) implying dyssynchrony at the cellular level.
A more limited number of recent studies have been concerned with synchrony at the level of a single cell. These studies examined synchrony of Ca2+ release within cardiac myocytes as a factor which dictates the efficiency of cell contraction during systole.
Spontaneous Ca2+ release events that are not linked to depolarization, often referred to as “diastolic” Ca2+ release events, were the first to be described in relation to loss of synchrony [3], [4]. These spontaneous Ca2+ release events can affect contractile function as well as electrical stability of the cell. Spontaneous Ca2+ release during or after repolarization has been linked to activation of membrane currents, predominantly Na+/Ca2+ exchanger current, promoting afterdepolarizations. Understanding of its role in arrhythmia initiation, however, is complicated by the fact that the accumulation of a large number of spontaneous Ca2+ release events is necessary to induce sufficient depolarization to trigger an action potential [5] Furthermore, in the myocardium intercellular electrotonic coupling suppresses irregular electrical activity from single cardiac myocytes [6], [7] Thus, paradoxically, the impact of spontaneous, stochastic subcellular Ca2+ release on arrhythmogenesis may depend on a certain level of synchronization of these events within and between cells [8], [9] .
In this review we will focus on mechanisms that reduce the synchrony of Ca2+ release events within a single cardiac myocyte during depolarization, in the context of contractile dysfunction in cardiac remodeling and heart failure. Where dyssynchrony is mentioned, it will refer to the degree of temporal dispersion of subcellular SR Ca2+ release events during the systolic Ca2+ transient.
Section snippets
Structural and functional regulation of synchronous Ca2+ release
A cardiac myocyte can be considered a miniature ‘pump’ consisting of contractile units, sarcomeres, in series and parallel that must exhibit synchronized shortening for an optimal contraction. The subcellular organization of structures reflects the need for a rapid and efficient, yet graded contractile response following electrical activation. The functional components of this process are shown in Fig. 1. The sarcolemmal membrane of ventricular myocytes comprises a network of invaginations
Dyssynchrony in cardiac hypertrophy and failure
In heart failure cytosolic Ca2+ transients following depolarization are reduced in amplitude and characterized by a slowed upstroke and prolonged decay. A reduction in SR Ca2+ content is one of the major observations in studies of end-stage heart failure in humans, though this is not necessarily the case in earlier stages of cardiac remodeling studied in animal models. Reduced Ca2+ uptake due to decreased SERCA activity, an increased extrusion of Ca2+ by the sarcolemmal NCX, and an increased
Whole cell measurement of gain
The relation between Ca2+ release and triggering Ca2+ influx is the gain of ECC. Variation in SR Ca2+ load alters the amount of Ca2+ released for a given triggering Ca2+ influx [64]. In the strictest sense gain describes the coupling of RyR Ca2+ flux to LTCC Ca2+ flux under conditions where the Ca2+ availability or load in the SR is constant. Measurement of gain thus implies a measurement of a flux:flux ratio.
L-type Ca2+ current is a direct sarcolemmal flux measurement, and the peak current is
Conclusion
The physiological coupling of electrical excitation and transmembrane Ca2+ influx to activation of RyRs leads to an efficient, synchronized Ca2+ release and contraction. For each couplon Ca2+ influx and release determine local gain. Gain at the cellular level is not simply a summation of each individual gain function but is modulated by the synchrony of SR Ca2+ release between couplons and the presence of uncoupled RyR clusters. During the progression of heart failure, different factors can
Funding
This work was supported by the FWO, the Fund for Scientific Research Flanders (G.0384.07), the European Union (LSHM-CT-2005–018833, EUGeneHeart) and the Belgian Science Program IAP6/31.
Disclosures
None.
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