P Kohl1, K Day, D Noble. 1. University Laboratory of Physiology, University of Oxford, United Kingdom. peter.kohl@physiol.ox.ac.uk
Abstract
BACKGROUND: Cardiac mechanical and electrical activity are closely interrelated. While excitation-contraction coupling is rather well characterized, less is known about cellular mechanisms that promote mechanically induced changes in cardiac electrical activity--mechano-electric feedback. OBJECTIVE: To integrate experimental findings on stretch activation of ion channels and length-dependent changes in intracellular calcium handling into a mathematical description of cardiac cellular activity. METHODS: Simulations are based on the cellular OXSOFT HEART v4.8 models of electrical activity of single cardiac cells of different populations and species. Sarcolemmal stretch-activated channels, mechanically induced changes in the affinity of troponin C to calcium, and length-dependent modulation of calcium handling by the sarcoplasmic reticulum were introduced into the models and linked to a description of sarcomere length or isometric tension. RESULTS: Transient or sustained stretch of cardiomyocytes was simulated during electrical systole and diastole. The electrophysiological response observed in the model depended on timing and severity of mechanical stimulation and on the main subcellular target of the intervention. Responses ranged from triggering of premature action potentials, over changes in action potential shape and duration, to length-dependent variations in contractile behaviour. Modelling findings could be related to experimental observations and may help to explain some of the contradictory data in the literature. The model is sufficiently complete to reproduce experimental findings and to help identify causally linked events.
BACKGROUND: Cardiac mechanical and electrical activity are closely interrelated. While excitation-contraction coupling is rather well characterized, less is known about cellular mechanisms that promote mechanically induced changes in cardiac electrical activity--mechano-electric feedback. OBJECTIVE: To integrate experimental findings on stretch activation of ion channels and length-dependent changes in intracellular calcium handling into a mathematical description of cardiac cellular activity. METHODS: Simulations are based on the cellular OXSOFT HEART v4.8 models of electrical activity of single cardiac cells of different populations and species. Sarcolemmal stretch-activated channels, mechanically induced changes in the affinity of troponin C to calcium, and length-dependent modulation of calcium handling by the sarcoplasmic reticulum were introduced into the models and linked to a description of sarcomere length or isometric tension. RESULTS: Transient or sustained stretch of cardiomyocytes was simulated during electrical systole and diastole. The electrophysiological response observed in the model depended on timing and severity of mechanical stimulation and on the main subcellular target of the intervention. Responses ranged from triggering of premature action potentials, over changes in action potential shape and duration, to length-dependent variations in contractile behaviour. Modelling findings could be related to experimental observations and may help to explain some of the contradictory data in the literature. The model is sufficiently complete to reproduce experimental findings and to help identify causally linked events.