Karin P Hammer1, Senka Ljubojevic2, Crystal M Ripplinger3, Burkert M Pieske4, Donald M Bers5. 1. Department of Pharmacology, University of California, Davis, GBSF, Davis, CA 95616-8636, USA. Electronic address: karin.hammer@ukr.de. 2. Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8010 Graz, Austria. Electronic address: lj.senka@gmail.com. 3. Department of Pharmacology, University of California, Davis, GBSF, Davis, CA 95616-8636, USA. Electronic address: cripplinger@ucdavis.edu. 4. Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8010 Graz, Austria; Department of Cardiology, Charité - Medical University Berlin, Augustenburgerplatz 1, 13353 Berlin, Germany. Electronic address: burkert.pieske@medunigraz.at. 5. Department of Pharmacology, University of California, Davis, GBSF, Davis, CA 95616-8636, USA. Electronic address: dmbers@ucdavis.edu.
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.
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.
Authors: Diana Shy; Ludovic Gillet; Jakob Ogrodnik; Maxime Albesa; Arie O Verkerk; Rianne Wolswinkel; Jean-Sébastien Rougier; Julien Barc; Maria C Essers; Ninda Syam; Roos F Marsman; Anneke M van Mil; Samuel Rotman; Richard Redon; Connie R Bezzina; Carol Ann Remme; Hugues Abriel Journal: Circulation Date: 2014-06-03 Impact factor: 29.690
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