Cardiac myocyte alternans in intact heart: Influence of cell–cell coupling and β-adrenergic stimulation. (July 2015)

• Record Type: Journal Article
• Authors: Hammer, Karin P.; Ljubojevic, Senka; Ripplinger, Crystal M.; Pieske, Burkert M.; Bers, Donald M.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 84(2015:Jul.)
• Page Start: 1
• Page End: 9
• Publication Date: 2015-07
• Subjects: Calcium -- Whole heart -- Alternans -- β-Adrenergic receptor activation; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.03.012
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca 2 + transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca 2 + alternans and sarcoplasmic reticulum (SR) Ca 2 + release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in the intact heart remains unknown. Objective: We assessed the effects of cell-to-cell coupling on local alternans in intact Langendorff-perfused mouse hearts, measuring single myocyte [Ca 2 + ] alternans synchronization among neighboring cells, and effects of β-adrenergic receptor (β-AR) activation and reduced GJ coupling. Methods and results: Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo8-AM to record cardiac myocyte [Ca 2 + ] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25 μM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. β-AR stimulation only reduced Ca 2 + alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. Conclusions: Ca 2 + alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca 2 + alternans, and made them more sensitive to reversal by β-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established. Highlights: Confocal imaging of Ca 2 + alternans was performed in the intact mouse heart Local alternans was virtually always concordant among neighboring myocytes Partial gap junction (GJ) uncoupling increased propensity for alternans Partial GJ uncoupling increased susceptibility to β-adrenergic alternans suppression Electrical coupling appeared to be crucial in synchronizing alternans phase