Aphysiomic approach to evaluate the role of mechano-electrical feedback in arrhythmia

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We evaluated the response of membrane potential to the uni-axial stretch in the single cardiomyocytes using the carbon-fiber based stretching device coupled with the simultaneous fluorescence measurement from the voltage sensitive dye. To achieve the quantitative estimation of membrane potential without the motion artifact, we adopted the ratiometry technique. Membrane potential of the myocytes responded to the stretch in an amplitude dependent manner and, with a large stretch exceeding 20% of the cell length, we observed the development of the action potential. The stretch applied during the plateau phase prolonged the action potential Administration of gadolinium, a non-selective blocker of stretch-activated channel, abolished such responses. We also found that the responses of membrane potential were dependent on the speed of stretch indicating that the visco-elastic nature of the link connecting cell surface and channels. Replacement of ions in the experimental solutions changed the membrane potential response and from these results, we considered that the Ca^2+ is the major charge carrier for the stretch of small amplitude, while the Na^+ dominates the response when the larger stretch is applied. In addition, focal indentation applied transversely invoked a local rise in intracellular Ca^2+ concentration. Finally, we incorporated such characteristics into the proposed mathematical model of the stretch-activated ion channel and developed a ventricular wall model of heterogeneous structure. The model could successfully reproduce the stretch-induce arrhythmia. Such findings obtained in this study will contribute to our understanding of the mechanisms of arrhythmia in diseased condition in which heart is subjected to stretch under abnormal loading conditions.