Calcium in the heart: from physiology to disease

Contraction of the heart results from an increase of cytoplasmic Ca2+ concentration ([Ca2+](i)), the so-called systolic Ca2+ transient. Most of this results from the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR). In turn, the amplitude of this Ca2+ transient determines the contractility of the heart. In this lecture, I consider the factors which govern the size and stability of this Ca2+ release. The amplitude of the Ca2+ transient is a steep function of SR Ca, resulting in a requirement for very precise beat-to-beat regulation of SR Ca content. This is achieved by a simple negative feedback mechanism, in which an increase of SR Ca content increases the size of the Ca2+ transient, resulting in a decrease of Ca2+ influx on the L-type Ca2+ current and an increase of efflux through Na+-Ca2+ exchange. Changing the activity of any of the Ca2+-cycling proteins will change the steady-state SR Ca content. This feedback mechanism has many consequences, including the fact that a change of RyR open probability has a only a temporary effect on the amplitude of the Ca2+ transient due to a compensating change of SR Ca content. The remainder of the article considers the link between intracellular Ca2+ waves and arrhythmias. This is done in the context of catecholaminergic polymorphic ventricular tachycardia, which is an inherited arrhythmia syndrome, in many cases due to a RyR mutation, where arrhythmias occur during exercise as a result of beta-adrenergic stimulation. Calcium waves occur only when the SR Ca content exceeds a threshold level. Our data show that the threshold is reduced by the RyR mutation and that the adrenergic stimulation increases SR Ca content.