ABSTRACT
It is well-known that Ca²âº overload in cardiomyocytes may underlie arrhythmias. However, the possible contribution of mechanical factors to rhythm disturbances in Ca²âº overloaded myocytes has not been sufficiently investigated. We used a mathematical model of the electrical and mechanical activity of cardiomyocytes to reveal an essential role of the mechanisms of cardiac mechano-electric feedback in arrhythmogenesis in Ca²âº overloaded myocardium. In the model, the following mechanical factors increased Ca²âº overload in contracting cardiomyocytes and promoted rhythm disturbances: i) a decrease in the mechanical load for afterloaded contractions; and ii) a decrease in the initial length of sarcomeres for isometric twitches. In exact accordance with the model predictions, in experiments on papillary muscles from the right ventricle of guinea pigs with Ca²âº overloaded cardiomyocytes (using 0.5-1 µM of ouabain), we found that emergence of rhythm disturbances and extrasystoles depends on the mechanical conditions of muscle contraction.
Subject(s)
Arrhythmias, Cardiac/metabolism , Calcium/metabolism , Mechanical Phenomena , Models, Biological , Myocytes, Cardiac/metabolism , Animals , Arrhythmias, Cardiac/physiopathology , Biomechanical Phenomena , Dose-Response Relationship, Drug , Electrophysiological Phenomena/drug effects , Guinea Pigs , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Myocytes, Cardiac/drug effects , Ouabain/pharmacology , Papillary Muscles/drug effects , Papillary Muscles/metabolism , Papillary Muscles/physiopathology , Rats , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitorsABSTRACT
Cardiomyocyte Ca(2+) overload is closely linked to cardiac arrhythmias. We have earlier shown in a mathematical model that myocardium mechanical activity may contribute to rhythm disturbances induced by Ca(2+) overload in cardiomyocytes with reduced Na(+)-K(+) pump work (Sulman et al., 2008). The same model is used here to address possible contribution of the passive mechanical properties of cardiac muscle (i.e. myocardial viscous and elastic properties) to the arrhythmogenesis. In a series of contractions at regular pacing rate of 75 beats/min a model with higher viscosity demonstrated essentially earlier appearance of extrasystoles due to a faster cardiomyocyte Ca(2+) loading up to a level triggering spontaneous Ca(2+) releases from the sarcoplasmic reticulum. The model predicts that myocardial elasticity also may affect arrhythmogenesis in cardiomyocytes overloaded with Ca(2+). Contribution of the mechanical properties of the myocardial tissue to the arrhythmia has been analyzed for wide ranges of both viscosity and elasticity coefficients. The results suggest that myocardial viscoelastic properties may be a factor affecting Ca(2+) handling in cardiomyocytes and contributing to cardiac mechano-electric feedback in arrhythmogenesis.
Subject(s)
Calcium/metabolism , Elasticity , Electricity , Models, Biological , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Biomechanical Phenomena , Feedback, Physiological , Rheology , Sarcomeres/metabolism , Sarcoplasmic Reticulum/metabolism , ViscosityABSTRACT
A mathematical model of the cardiomyocyte electromechanical function is used to study contribution of mechanical factors to rhythm disturbances in the case of the cardiomyocyte calcium overload. Particular attention is paid to the overload caused by diminished activity of the sodium-potassium pump. It is shown in the framework of the model, where mechano-calcium feedback is accounted for that myocardium mechanics may significantly enhance arrhythmogenicity of the calcium overload. Specifically, a role of cross-bridge attachment/detachment processes, a role of mechanical conditions of myocardium contractions (length, load), and a role of myocardium viscosity in the case of simulated calcium overload have been revealed. Underlying mechanisms are analyzed. Several approaches are designed in the model and compared to each other for recovery of the valid myocardium electrical and mechanical performance in the case of the partially suppressed sodium-potassium pump.