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Sudden Cardiac Death and Electrical Dyssynchrony Mediated by Purkinje-His Dysfunctional Activity

Final Report Summary - SYMPHONY (Sudden Cardiac Death and Electrical Dyssynchrony Mediated by Purkinje-His Dysfunctional Activity)

Cardiovascular disease is the first cause of mortality in the whole world, responsible for 700000 deaths each year in Europe. Half of this mortality is due to heart failure, a progressive deterioration of cardiac contraction, which can be caused or further aggravated by electrical conduction disturbance. The other half of cardiac mortality occurs suddenly, mainly due to ventricular fibrillation (VF) during which abnormal and random electrical wave propagation seriously compromises cardiac function.

The main objectives of the SYMPHONY project were to advance our understanding in the trigger and substrate mechanisms of Sudden Cardiac Death (SCD) with a special focus on the Purkinje network, and to elucidate the causes and impact of conduction disorders in heart failure. A multi-disciplinary and multi-level approach has been utilized to achieve these objectives. An important methodological achievement of the project has been the launch of a human heart donor program, allowing for unique ex vivo functional investigations with a direct relevance to patients.

At a cellular level, we have characterized the expression of key proteins involved in calcium regulation in healthy and infarcted ovine hearts. Our results indicate that a significant intracellular reorganization of these proteins occurs during ischemia both in ovine and human hearts that could explain arrhythmogenicity from Purkinje fibers surviving within the myocardial infarct. We have also elucidated how Transient Receptor Potential M4 (TRPM4) channel over-expression in the Purkinje system can lead to conduction block using a detailed computer model of the TRPM4 channel. We showed that inhomogeneous expression of TRPM4 can produce the types of conduction disturbances observed in patients with TRPM4 gain-of-function mutations.

At a tissue level, we have shown that the Purkinje network can have a significant impact on the ventricular repolarization heterogeneity and that alterations of this heterogeneity disease may provide an arrhythmogenic substrate and predispose to SCD. We have also shown a novel role for the moderator band in sustaining macro-reentrant arrhythmias, first in large animal hearts and then confirmed in the human heart. We have further advanced our understanding on the role of pathological conduction and repolarization gradients in arrhythmogenesis and how non-invasive body surface mapping approaches can be used to detect these heterogeneities and predict the arrhythmogenic risk.

In the context of heart failure and dyssynchrony, experimental work has looked into tissue remodelling and the use of non-invasive body surface mapping approaches to evaluate the degree of conduction block. We have shown significant remodelling of conduction and repolarization in the right ventricle in the context of right heart failure, but interestingly also modifications in the electrophysiological properties of the left ventricle prior to any functional changes. This may have significant implication in the treatment options, including resynchronization therapy, available to these patients. We have also validated the use of non-invasive mapping in evaluating electrical dyssynchrony in a novel large animal model of left bundle branch block and ischemic cardiomyopathy.

Several new experimental approaches have been developed throughout the SYMPHONY project including high resolution magnetic resonance imaging approaches, three-dimensional optical imaging and non-invasive mapping of ventricular substrates and ventricular fibrillation. The latter approach has been successfully applied in the clinic and has led to a major breakthrough in our understanding of ventricular fibrillation mechanisms in patients with structurally normal hearts. We have, for the first time, shown that micro-structural alterations, invisible to current imaging techniques, underlie a vast majority of unexplained SCD. Current work is looking at expanding this approach to SCD patients from diverse aetiologies. These findings and novel methodologies open important perspectives for risk stratification, prevention and targeted treatments in a wide variety of cardiac diseases.