Ventricular arrhythmias often occur in a setting of abnormal repolarization, and an increase in adrenergic drive is a common triggering event. In diseased hearts that are prone to arrhythmias, repolarization is intrinsically less stable, showing larger variability in the duration of the QT interval or action potential (AP) on a beat-to-beat basis, which then further destabilizes upon an arrhythmogenic challenge. This beat-to-beat variability of repolarization (BVR) is thought to reflect a reduced repolarization reserve due to a loss of repolarizing, or a gain of inward currents. In the predisposed heart, also β-adrenergic stimulation causes beat-to-beat instability1. One mechanism is a blunted response of IKS to β-agonists which prevents accumulation of repolarizing current and compromises repolarization reserve2. One other possible mechanism is increased SR Ca2+ release as a consequence of β-adrenergic stimulation. In single cardiomyocytes, beat-to-beat variability increases with AP duration, and at long durations there is also variability in the duration of the global Ca2+ transient. This is because changes in voltage and Ca2+ are interrelated through Ca2+-dependent membrane currents. At shorter AP durations, there is no variability in global Ca2+ duration and amplitude, but AP variability remains. However, inhibition of SR Ca2+ release (caffeine, thapsigargin) reduces BVR while increasing SR Ca2+ release (BayK) promotes BVR. There might be variability in SR Ca2+ release at the subcellular level which is not reflected in the global Ca2+ transient. Variability in local Ca2+ release must then be translated in AP variability through Ca2+-dependent currents in close proximity of release sites. The most likely candidates are the L-Type Ca2+ channel (LTCC) and Na/Ca exchanger (NCX). LTTC is located near RyR release sites and senses local Ca2+ release through feedback by Ca2+-dependent inactivation. When Ca2+ declines, a fraction of channels recovers from release-dependent inactivation. When SR Ca2+ release is large, there is more inactivation, but also more recovery of Ca2+ channels, producing a larger Ca2+ window current facilitating the development of early afterdepolarizations (EADs)3. A fraction of NCX also senses local Ca2+ near release sites4. SR Ca2+ release activates inward NCX current which superimposes on the inactivating Ca2+ current and precedes reactivation of the Ca2+ window current. Blocking NCX reduces the recovery of Ca2+ window current, probably by slower removal of Ca2+ from the LTTC microdomain. In a well-established canine model of repolarization-dependent arrhythmias, the dog with chronic atrioventricular block, partial block of NCX with SEA-0400 stabilized dofetilide-induced BVR and suppressed TdP arrhythmias, at the cellular level and during in vivo experiments. Selective LTCC block was also effective, but unlike SEA-0400, caused negative inotropic effects. In conclusion, under β-adrenergic stimulation, NCX may reduce repolarization reserve by producing inward current during the AP plateau, and possibly indirectly, by modulating the Ca2+ microdomain near LTCC. Partial NCX block stabilizes repolarization and is an effective antiarrhythmic strategy against repolarization-dependent arrhythmias.