Control of Ca Release by Action Potential Configuration in Normal and Failing Murine Cardiomyocytes |
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Authors: | William E Louch Johan Hake Guro Five Jølle Halvor K Mørk Ivar Sjaastad Glenn T Lines |
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Institution: | † Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, Oslo, Norway ‡ Department of Cardiology, Oslo University Hospital Ullevaal, Oslo, Norway § Centre for Heart Failure Research, Faculty of Medicine, University of Oslo, Oslo, Norway ¶ Department of Bioengineering, University of California at San Diego, La Jolla, California ‖ Simula Research Laboratory, Lysaker, Norway |
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Abstract: | Cardiomyocytes from failing hearts exhibit spatially nonuniform or dyssynchronous sarcoplasmic reticulum (SR) Ca2+ release. We investigated the contribution of action potential (AP) prolongation in mice with congestive heart failure (CHF) after myocardial infarction. AP recordings from CHF and control myocytes were included in a computational model of the dyad, which predicted more dyssynchronous ryanodine receptor opening during stimulation with the CHF AP. This prediction was confirmed in cardiomyocyte experiments, when cells were alternately stimulated by control and CHF AP voltage-clamp waveforms. However, when a train of like APs was used as the voltage stimulus, the control and CHF AP produced a similar Ca2+ release pattern. In this steady-state condition, greater integrated Ca2+ entry during the CHF AP lead to increased SR Ca2+ content. A resulting increase in ryanodine receptor sensitivity synchronized SR Ca2+ release in the mathematical model, thus offsetting the desynchronizing effects of reduced driving force for Ca2+ entry. A modest nondyssynchronous prolongation of Ca2+ release was nevertheless observed during the steady-state CHF AP, which contributed to increased time-to-peak measurements for Ca2+ transients in failing cells. Thus, dyssynchronous Ca2+ release in failing mouse myocytes does not result from electrical remodeling, but rather other alterations such as T-tubule reorganization. |
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