title: Cardiac cellular coupling and the spread of early instabilities in intracellular Ca2+.
abstract: Recent experimental and modeling studies demonstrate the fine spatial scale, complex nature, and independent contribution of Ca(2+) dynamics as a proarrhythmic factor in the heart. The mechanism of progression of cell-level Ca(2+) instabilities, known as alternans, to tissue-level arrhythmias is not well understood. Because gap junction coupling dictates cardiac syncytial properties, we set out to elucidate its role in the spatiotemporal evolution of Ca(2+) instabilities. We experimentally perturbed cellular coupling in cardiac syncytium in vitro. Coupling was quantified by fluorescence recovery after photobleaching, and related to function, including subtle fine-scale Ca(2+) alternans, captured by optical mapping. Conduction velocity and threshold for alternans monotonically increased with coupling. Lower coupling enhanced Ca(2+) alternans amplitude, but the spatial spread of early (<2 Hz) alternation was the greatest under intermediate (not low) coupling. This nonmonotonic relationship was closely matched by the percent of samples exhibiting large-scale alternans at higher pacing rates. Computer modeling corroborated these experimental findings for strong but not weak electromechanical (voltage-Ca(2+)) coupling, and offered mechanistic insight. In conclusion, using experimental and modeling approaches, we reveal a general mechanism for the spatial spread of subtle cellular Ca(2+) alternans that relies on a combination of gap-junctional and voltage-Ca(2+) coupling.
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Jia
authors.forename: Harold
authors.initials: H
authors.lastname: Bien
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Shiferaw
authors.forename: Emilia
authors.initials: E
authors.lastname: Entcheva
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004058:Diffusion; D036681:Fluorescence Recovery After Photobleaching; D015726:Giant Cells / Q000166:cytology / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism*; D007700:Kinetics; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002118:Calcium