title: Spontaneous sarcoplasmic reticulum Ca2+ release leads to heterogeneity of contractile and electrical properties of the heart.
abstract: The cytosolic Ca2+ (Cai) 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 Cai oscillations (S-CaOs), i.e., not triggered by sarcolemmal depolarization. The local increase in Cai due to S-CaOs is equivalent to that induced by an AP. Heterogeneity of diastolic Cai caused by asynchronous S-CaOs among cells within myocardial tissue leads to heterogeneous myofilament activation, the summation of which produces a Ca(2+)-dependent component to diastolic tone. The local increases in Cai 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 Cai 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 aftercontraction 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 Cai levels and sarcomere length inhomogeneities in response a subsequent AP; this heterogeneity compromises the systolic contraction amplitude. Heterogeneity of systolic Cai among cells due to diastolic S-CaOs also leads to heterogeneity of AP repolarization times, due, to heterogeneous Cai 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.
authors.affiliation: Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: E G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: A
authors.initials: A
authors.lastname: Talo
authors.forename: M C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: H A
authors.initials: HA
authors.lastname: Spurgeon
authors.forename: M D
authors.initials: MD
authors.lastname: Stern
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004594:Electrophysiology; D006321:Heart / Q000502:physiology*; D006801:Humans; D009200:Myocardial Contraction; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D002118:Calcium