Editorial Focus The chicken or the egg? Voltage and calcium dynamics in the heart

the ventricles, has been shown to predict the risk of cardiac arrhythmias and sudden cardiac death (13, 25). Theoretical studies have shown that arrhythmogenic repolarization alter-nans can originate from either the dynamics of membrane voltage (12, 14, 33) or intracellular calcium (Cai) cycling (21, 28, 34). In reality, however, both of these factors always coexist, since voltage and Cai are bidirectionally coupled through calcium-dependent ionic currents (1). This makes it a challenging problem to identify experimentally the sources of instabilities. For example, alternans in Cai cycling also causes alternans in action potential duration and vice versa, raising a classic “chicken or egg ” conundrum (30). Experiments in isolated myocytes using action potential-clamp (4, 32) or voltage-clamp (8, 10) techniques, in which Cai alternans was observed to occur without alternans of th