A Tale of Two Leaks
Over the last two decades, understanding of the mechanisms that underlie heart failure has grown enormously. One of the key concepts is that heart failure is associated with profound alterations in myocardial calcium handling and excitation-contraction coupling.
Myocardial Ca handling
Most of the calcium that activates contraction comes from the sarcoplasmic reticulum (SR). It leaves the SR through a specialized release channel known as the ryanodine receptor (RyR). The probability that a RyR is open and can therefore allow Ca to leave the SR into the cytoplasm is increased by an increase in the concentration of either cytosolic or SR (luminal) Ca concentration. During the normal heartbeat sarcolemmal Ca channels open and some of the entering Ca binds to the RyRs making them open thereby triggering the release of a much greater amount of Ca from the SR into the cytosol. This Ca release causes a rapid rise of cytosolic Ca to levels that activate the myofilaments and initiate contraction. After termination of release of Ca from the SR (because of closure of RyRs), cytosolic Ca levels decline rapidly and relaxation occurs. Ca is rapidly removed from the cytosol by two major Ca removal systems: the sarcoendoplasmic reticulum Ca ATPase (SERCA) and the sarcolemmal sodium /calcium exchanger (NCX). SERCA pumps Ca back into the SR while NCX pumps 1 Ca2+ ion out in exchange for the influx of 3 Na+ ions into the cell. This rapid cycle of Ca release and reuptake is known as the systolic Ca transient and it is one of the main factors that control force of contraction in the heart. It is worth emphasizing that the normal Ca transient depends on the RyRs being virtually closed in diastole, opening very briefly to produce the systolic increase of Ca and then closing to allow Ca to fall to resting levels.
- Received July 16, 2013.
- Accepted July 16, 2013.