Normal and pathological excitation–contraction coupling in the heart – an overview

This issue of The Journal of Physiology includes a series of review articles arising from a symposium held at the joint meeting of the UK, German and Scandinavian Physiological Societies. The articles focus on different aspects of the cellular control of contraction. The basic mechanism of cardiac excitation-contraction coupling (‘calcium-induced calcium release’) is now reasonably well-established. Calcium enters the cell from the extracellular fluid via the voltage-dependent L-type Ca²⁺ channel. This results in a ‘trigger’ increase of [Ca²⁺]_i in the space between the sarcolemma and sarcoplasmic reticulum (SR) and this leads to the opening of the SR Ca²⁺ release channel or ‘ryanodine receptor’ (RyR). As exemplified by the papers from the symposium, much current work is focused on how this mechanism is modified in different circumstances. These include autonomic modulation, but also pathological conditions such as cardiac hypertrophy and failure, a recurrent theme in several of these papers.

Cardiac action potentials have a variety of different shapes. The classical long plateau, essential for preventing re-excitation and arrhythmias, can often be preceded by an initial rapid repolarization that results from the transient outward (potassium) current. The amplitude of this current (and therefore the prominence of the rapid repolarization) varies between regions of the ventricle and in heart failure. Cellular cardiac physiologists often belong to two communities: electrophysiologists who are concerned with such byzantine complexities of action potential shape and those interested in excitation-contraction coupling who tend to be less focused on these issues. Peter Backx and coworkers show that an integrated approach is needed as a change in the initial rate of repolarization can have pronounced effects on the Ca²⁺ transient. Decreasing the rate of repolarization can decrease the Ca²⁺ transient, probably because at positive voltages the current through single L-type channels is less than that at negative voltages. Furthermore, the slowed repolarization results in desynchronized Ca²⁺ release analogous to that seen in failure. Since heart failure is often accompanied by a decrease in the transient outward potassium current, these studies provide an interesting perspective to what at first glance seems to concern electrophysiologists only.

The vast majority of papers on cardiac excitation- contraction coupling deal with the ventricle. The paper by Lothar Blatter et al. restores attention to the atrium. The less prominent transverse tubular system in the atrium (compared to the ventricle) means that the sarcolemmal Ca²⁺ channels can only trigger Ca²⁺ release from SR located near the periphery of the cell. This results in Ca²⁺ release from the periphery of the cell that then spreads as a wave into the interior triggering Ca²⁺ release from more centrally located SR. This observation is of interest for at least two reasons. (1) It shows that Ca²⁺ waves, which are often thought to be pathological in the ventricle, underpin normal excitation- contraction coupling in the atrium. (2) The paper also shows that the resulting Ca²⁺ release can alternate in amplitude from beat to beat. ‘Alternans’ is well known to occur in diseased conditions and this work shows a cellular basis for it. Since the newest working hypotheses on the mechanisms of atrial fibrillation are focusing on abnormal automaticity, it will be of interest to examine these particular mechanisms in diseased atrial myocytes, a currently unexplored field.

Perhaps the greatest current challenge to cellular cardiac physiologists is to explain why the heart beats more weakly in failure. At a cellular level there are many hypotheses of which the SR is central to most. However, as summarized by Ole Sejersted and coworkers, it is still controversial as to exactly what the SR defect is. Altered Ca²⁺ release and decreased SR content have both been suggested and, in the latter case, it is uncertain as to whether the change of content results from decreased pumping of Ca²⁺ into the SR or increased leak out. This paper contains another important message that, where possible, heart failure should be investigated using a variety of techniques from the whole heart to the subcellular level. In particular, one must be aware of the potential problems caused by cell dialysis. Cellular changes may indeed be quite diverse in different stages of cardiac remodelling. Information on the in vivo cardiac and haemodynamic status is essential for classification and correct interpretation of the cellular observations.

eNOS and NO production are more immediately associated with the regulation of vascular tone than with regulation of cardiac function. Yet eNOS appears to be prominently expressed in ventricular myocytes as well and is part of the autonomic regulation of heart rate and contraction, as reviewed by Massion & Balligand. Many of these insights have been gained from the use of transgenic mice, lacking eNOS. Different groups have studied the role of eNOS and NO in the signalling cascade of muscarinic receptor stimulation with different results. The authors join the point of view that this mechanism may be redundant for the muscarinic pathway. eNOS and NO are also part of the signalling cascade for the β3 adrenergic receptor, contributing to a negative inotropic effect. In heart failure with an altered balance between β3 and the cAMP-linked β1/β2 receptors, eNOS may thus contribute to a weaker contraction. On the other hand, eNOS by itself may be cardioprotective, as eNOS^−/- mice are more prone to remodelling after myocardial infarction. These latter results offer interesting perspectives for modulation of NO production in heart failure.

A very different approach to improve cardiac function in heart failure is presented by del Monte & Hajjar. These authors were the first to explore the potential of gene transfer to raise the levels of SERCA, the sarco- and endoplasmic reticulum Ca²⁺-ATPase, in ventricular myocytes of failing hearts. In many studies it has been shown that expression and function of this protein is reduced in heart failure. Gene transfer of SERCA in myocytes from failing heart indeed restores contractile function. Using transgenic techniques decreasing the phospholamban inhibition of SERCA function equally enhances cardiac systolic and diastolic function. Is this just a sophisticated proof of principle, or a realistic approach to treat heart failure? The authors review the current available technology and express cautious optimism. Even if gene therapy should not live up to these expectations, it will most certainly have contributed substantially to our insights in physiology and pathophysiology of cardiac excitation-contraction coupling.

This collection of reviews illustrates how studies of excitation- contraction coupling are being integrated into a wider perspective on cardiac function, with particular emphasis on the changes in heart failure. We trust they will stimulate further work in the field.