Details

Autor(en) / Beteiligte

• Cacheux, Marine
• Ilkan, Zeki
• Hulot, Jean-Sebastien
• Akar, Fadi G

Titel

Abstract 14678: Cardiomyocyte-Specific STIM1 Depletion in the Adult Heart Promotes Arrhythmogenic Discordant Alternans

Ist Teil von

• Circulation (New York, N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A14678-A14678

Ort / Verlag

by the American College of Cardiology Foundation and the American Heart Association, Inc

Erscheinungsjahr

2019

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• IntroductionStromal interaction molecule 1 (STIM1) is a calcium (Ca) sensor that regulates cardiac hypertrophy by triggering store-operated Ca entry (SOCE). Recent studies have suggested SOCE independent roles of STIM1 when overexpressed in myocytes, in vitro, namely increased SR Ca load. The homeostatic role of cardiomyocyte (CM) STIM1 in the adult heart remains largely unknown.HypothesisWe hypothesized that CM restricted STIM1 depletion in vivo alters arrhythmia propensity in the adult heart.MethodsInducible CM-restricted STIM1 knockdown was achieved in adult mice using an αMHC MerCreMer system. Mechanical and electrophysiological (EP) properties were examined using echocardiography in vivo and optical action potential (AP) mapping ex vivo in tamoxifen (tx) induced STIM1-Cre (STIM1-KD, N=23), STIM1-Cre (STIM1-Ctl, N=22) and Cre only (Cre-Ctl, N=11).ResultsMarked downregulation in STIM1 protein expression in CM but not whole tissue lysates was observed in STIM1-KD but not STIM1-Ctl myocytes. Although cardiac function of STIM1-KD and Cre-Ctl mice were similarly impaired by tx injection, only STIM1-KD mice exhibited poor survival with >50% mortality after 8 days of CM-restricted STIM1 depletion (A). STIM1-KD hearts exhibited a proclivity for arrhythmic behavior, ranging from frequent ectopy to pacing induced VF (B). Examination of the EP substrate revealed a marked increase in the magnitude of APD alternans during rapid pacing and the emergence of a spatially-discordant alternans profile only in STIM1-KD hearts (C-D). Of note, the magnitude of APD alternans was greater (by 80%) in VF+ vs VF- STIM1-KD hearts. Detailed phase mapping during the initial beats of VF identified rotors that formed along the nodal line separating out of phase alternans regions.ConclusionsEarly mortality caused by CM-restricted STIM1 depletion is likely caused by enhanced susceptibility to VF secondary to discordant APD alternans.