Calcium and cardiac rhythms: physiological and pathophysiological.

Calcium plays two pivotal roles in cardiac excitationcontraction (E-C) coupling.1 Ca drives myofilament activation and carries or regulates ionic currents that are responsible for normal electrical rhythms2 as well as life-threatening arrhythmias.3 In this editorial, I will focus on Ca and pacemaker activity and arrhythmogenesis. Ca entry via Ca current (ICa) triggers sarcoplasmic reticulum (SR) Ca release via ryanodine receptors (RyRs), and relaxation is driven by Ca transport by the SR Ca ATPase and Na -Ca exchange. Two ICa types occur in cardiac myocytes: L-type (ICa,L) activated at Em 40 mV and T-type (ICa,T) activated at Em 60 mV (near the pacemaker range). Inward ICa,T and ICa,L can contribute importantly to both normal and abnormal cardiac depolarization. ICa,L is crucial in E-C coupling in all cardiac myocytes. ICa,T is absent in most ventricular myocytes but is present in neonatal ventricular myocytes, some atrial myocytes, and in conducting and pacemaker cells. -Adrenergic receptors ( -ARs) and cAMP-dependent protein kinase (PKA) increase ICa,L amplitude and shift activation to more negative Em (closer to the pacemaker range). Parasympathetic stimulation of the heart (via muscarinic receptors) can offset the -AR effect. Withdrawal of muscarinic activation can also cause a rebound overshoot in ICa,L and may contribute directly to postvagal tachycardia.4,5 ICa,L is rapidly inactivated by local [Ca ] at the inner channel mouth (mediated by calmodulin associated with the channel).6,7 As [Ca ]i declines, ICa,L can recover partially from inactivation, even at depolarized Em. This can allow ICa,L reactivation before the action potential (AP) fully repolarizes, inducing early afterdepolarizations (EADs). Resting myocytes exhibit spontaneous, localized SR Ca release events (Ca sparks),9 attributed to clusters of 6 to 20 RyRs localized at a single sarcolemmal-SR junction.1 During normal E-C coupling, Ca entry via ICa,L triggers SR Ca release (as sparks), but the temporal synchronization by the AP obscures individual Ca sparks. Diastolic Ca spark probability is increased by elevation of either local [Ca ]i or intra-SR Ca content. When cellular Ca load is high, Ca spark frequency and amplitude are high. At sufficiently high SR Ca load, waves of Ca -induced Ca release propagate in myocytes. SR Ca release can activate ionic currents that contribute to normal pacemaker activity, delayed afterdepolarizations (DADs), and triggered arrhythmias. Na -Ca exchange produces inward or outward current (INa/Ca) depending on Em, [Ca ], and [Na ]. Depolarization favors Ca influx (outward INa/Ca), but as [Ca ]i rises and Em repolarizes, Ca efflux (inward INa/Ca) is more strongly favored. Moreover, high submembrane [Ca ]i during ICa and SR Ca release drives Ca extrusion via INa/Ca at an earlier time during the AP than would be expected from the global Ca transient.10 Inward INa/Ca, activated by high [Ca ]i, can contribute to both normal pacemaker activity and arrhythmogenesis.