Intracellular Ca2 is the central regulator of cardiac contrac-tility. Moreover, it is becoming increasingly apparent that alterations in myocyte Ca2 regulation may be critically important in both the mechanical dysfunction and arrhythmogenesis associated with congestive heart failure. 1, 2 Thus, it is imperative to have a clear and relatively quantitative understanding of how cellular Ca2 levels are regulated during the normal contraction-relaxation cycle. The scope and relevant references in this field are far too large for this format, so my focus here is narrower and more personal than elsewhere. 3–5 Figure 1A shows the key pathways involved in myocyte Ca2 transport. During the cardiac action potential (AP) L-type Ca2 channels are activated and Ca2 enters the cell via Ca2 current (ICa) and also a much smaller amount enters via Na-Ca2 exchange (NCX). Ca2 influx triggers Ca2 release from the sarcoplasmic reticulum (SR) and, to some extent, can also contribute to activation of the myofilaments directly. The Ca2 entry plus the amount released from the SR via Ca2-induced Ca2 release (CICR) raises cytosolic free [Ca2]([Ca2] i), causing Ca2 binding to multiple cytosolic Ca2 buffers. One of the most functionally important cytosolic Ca2 buffers is the thin-filament protein troponin C (TnC). When Ca2 binds to TnC, it switches on the myofilaments in a cooperative manner activating contraction. For relaxation and diastolic filling to occur,[Ca2] i must decline such that Ca2 dissociates from TnC, thereby turning off the contractile machinery. Four Ca2 transporters remove Ca2 from the cytosol:(1) SR Ca2-ATPase,(2) sarcolemmal NCX,(3) sarcolemmal Ca2-ATPase, and (4) mitochondrial Ca2 uniporter. The SR Ca2-ATPase and NCX are most important quantitatively.

Data on Ca2 binding, functional effects, and transport from multiple laboratories and with different experimental approaches allow consideration of Ca2 cycling in relatively quantitative terms. Although these numbers will continue to be refined, they are useful to consider. For consistency, cellular Ca2 will be discussed below in units of mol/L cytosol (where cytosol is 65% of cell volume and excludes mitochondrial volume that is 30% of cell volume). 3