title: T-tubule disruption promotes calcium alternans in failing ventricular myocytes: mechanistic insights from computational modeling.
abstract: In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in "orphaned" RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF.
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Nivala
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: zqu@mednet.ucla.edu.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
mesh_terms: D000200:Action Potentials; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D003198:Computer Simulation; D015536:Down-Regulation / Q000235:genetics; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: T-tubule disruption; alternans; arrhythmias; heart failure; remodeling