{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:50:28Z","timestamp":1792727428435,"version":"4.5.0"},"reference-count":69,"publisher":"American Physiological Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2012,6,1]]},"abstract":"<jats:p> Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden cardiac death. At the cellular level, Ca<jats:sup>2+<\/jats:sup> alternans appears as cytosolic Ca<jats:sup>2+<\/jats:sup> transients of alternating amplitude at regular beating frequency. Cardiac alternans is a multifactorial process but has been linked to disturbances in intracellular Ca<jats:sup>2+<\/jats:sup> regulation. In atrial myocytes, we tested the role of voltage-gated Ca<jats:sup>2+<\/jats:sup> current, sarcoplasmic reticulum (SR) Ca<jats:sup>2+<\/jats:sup> load, and restitution properties of SR Ca<jats:sup>2+<\/jats:sup> release for the occurrence of pacing-induced Ca<jats:sup>2+<\/jats:sup> alternans. Voltage-clamp experiments revealed that peak Ca<jats:sup>2+<\/jats:sup> current was not affected during alternans, and alternans of end-diastolic SR Ca<jats:sup>2+<\/jats:sup> load, evaluated by application of caffeine or measured directly with an intra-SR fluorescent Ca<jats:sup>2+<\/jats:sup> indicator (fluo-5N), were not a requirement for cytosolic Ca<jats:sup>2+<\/jats:sup> alternans. Restitution properties and kinetics of refractoriness of Ca<jats:sup>2+<\/jats:sup> release after activation during alternans were evaluated by four different approaches: measurements of 1) the delay (latency) of occurrence of spontaneous global Ca<jats:sup>2+<\/jats:sup> releases and 2) Ca<jats:sup>2+<\/jats:sup> spark frequency, both during rest after a large and small alternans Ca<jats:sup>2+<\/jats:sup> transient; 3) the magnitude of premature action potential-induced Ca<jats:sup>2+<\/jats:sup> transients after a large and small beat; and 4) the efficacy of a photolytically induced Ca<jats:sup>2+<\/jats:sup> signal (Ca<jats:sup>2+<\/jats:sup> uncaging from DM-nitrophen) to trigger additional Ca<jats:sup>2+<\/jats:sup> release during alternans. The results showed that the latency of global spontaneous Ca<jats:sup>2+<\/jats:sup> release was prolonged and Ca<jats:sup>2+<\/jats:sup> spark frequency was decreased after the large Ca<jats:sup>2+<\/jats:sup> transient during alternans. Furthermore, the restitution curve of the Ca<jats:sup>2+<\/jats:sup> transient elicited by premature action potentials or by photolysis-induced Ca<jats:sup>2+<\/jats:sup> release from the SR lagged behind after a large-amplitude transient during alternans compared with the small-amplitude transient. The data demonstrate that beat-to-beat alternation of the time-dependent restitution properties and refractory kinetics of the SR Ca<jats:sup>2+<\/jats:sup> release mechanism represents a key mechanism underlying cardiac alternans. <\/jats:p>","DOI":"10.1152\/ajpheart.00079.2012","type":"journal-article","created":{"date-parts":[[2012,3,31]],"date-time":"2012-03-31T05:38:54Z","timestamp":1333172334000},"page":"H2310-H2320","source":"Crossref","is-referenced-by-count":82,"title":["Refractoriness of sarcoplasmic reticulum Ca<sup>2+<\/sup> release determines Ca<sup>2+<\/sup> alternans in atrial myocytes"],"prefix":"10.1152","volume":"302","author":[{"given":"Vyacheslav M.","family":"Shkryl","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua T.","family":"Maxwell","sequence":"additional","affiliation":[{"name":"Department of 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