Spontaneous sarcoplasmic reticulum Ca²⁺ release leads to heterogeneity of contractile and electrical properties of the heart

The cytosolic Ca²⁺ (Ca(i)) oscillation generated by the sarcoplasmic reticulum (SR) in response to an action potential (AP) occurs relatively synchronously within and among cells. The SR can also generate spontaneous Ca(i) oscillations (S-CaOs), i.e., not triggered by sarcolemmal depolarization. The local increase in Ca(i) due to S-CaOs is equivalent to that induced by an AP. Heterogeneity of diastolic Ca(i) caused by asynchronous S-CaOs among cells within myocardial tissue leads to heterogeneous myofilament activation, the summation of which produces a Ca²⁺ -dependent component to diastolic tone. The local increases in Ca(i) due to S-CaOs also cause oscillatory sarcolemmal depolarizations due to Ca²⁺ modulation of the Na/Ca exchanger and of non-specific cation channels. Thus, inhomogeneous levels of diastolic Ca(i) may lead to heterogeneity in cell coupling and thus may also affect the impulse conduction. The magnitude of the S-CaOs induced diastolic tonus and membrane depolarization varies with the extent to which S-CaOs are synchronized; partially synchronized S-CaOs following an AP induced SR Ca²⁺ release produce an after contraction and after depolarization. When local S-CaOs is sufficiently synchronized within the cell the resultant depolarization summates and can be sufficient to trigger spontaneous AP. Inhomogeneity of diastolic SR Ca²⁺ loading and sarcomere lengths within individual cardiac cells due to S-CaOs leads to inhomogeneous systolic Ca(i) levels and sarcomere length inhomogeneities in response a subsequent AP; this heterogeneity compromises the systolic contraction amplitude. Heterogeneity of systolic Ca(i) among cells due to diastolic S-CaOs also leads to heterogeneity of AP repolarization times, due, to heterogeneous Ca(i) modulation of the Na/Ca exchanger, the non-specific cation channel and of the L type sarcolemmal Ca²⁺ channel. S-CaOs occurrence during a long AP plateau may also modulate the removal of voltage inactivation of L type Ca²⁺ channels and affect the likelihood of the occurrence of 'early after depolarizations.' Thus, as a single entity, S-CaOs may be implicated in diverse manifestations of heart failure - impaired systolic performance, increased diastolic tonus and an increased probability for the occurrence of arrhythmias.