Abstract
Tetralogy of Fallot (TOF) is associated with increasingly recognized late morbidity due to arrhythmias and right heart failure. Better understanding of the underlying mechanisms of these issues is needed to facilitate new therapeutic approaches. We aim to identify mechanisms generating arrhythmias in a swine model of repaired TOF with progressive right ventricular (RV) dysfunction. Surgery to mimic repaired TOF was done in 24 piglets (using a previously validated model); 24 animals served as control. Two, 4 and 6 months after surgery respectively, animals were sacrified for subsequent analysis. Haemodynamic parameters and ventricular remodeling were analyzed by cardiac magnetic resonance (CMR) and echocardiography before sacrifice. In isolated perfused hearts, electrical activity was measured by optical mapping. Sarcoplasmic reticular calcium handling and proteins involved in calcium management were studied in single myocytes. Compared with control animals, a right bundle branch block was present and the action potential (AP) duration was increased in the RV with a mechanical delay observed at 2 and 4 months post-operative in operated groups (p<0.05). Discordant AP alternans occured in isolated failing hearts and calcium transient alternans in failing myocytes. These results were correlated with fibrosis revealed by CMR. Six months post-operative data are in progress. Electromechanical and calcium management dysfunctions are progressive in the RV and may partly explain arrhythmias in repaired TOF. These mechanisms are potential therapeutic targets for the correction of arrhythmias in failing right ventricles.
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