Arrhythmogenesis and cardiogenetics

The central topic of this program is ventricular arrhythmogenesis and sudden cardiac death by primary electrical cardiomyopathies and during conditions of (acquired or congenital) cardiac hypertrophy and failure. The program is fully translational.
Per year, sudden cardiac death accounts for 300,000-400,000 victims in the United States and approximately 14,000 in The Netherlands. In the majority of cases, death is caused by arrhythmias, usually ventricular tachycardia (VT) and/or ventricular fibrillation. While being most often a complication of acute myocardial ischemia, old infarction or heart failure, VTs occur also in patients with structurally normal but electrically-predisposed hearts (primary electrical cardiomyopathies). Pathological hypertrophy is also a risk factor for VT.

Prolongation of the action potential is an electrophysiological hallmark of ventricular myocytes isolated from hypertrophied or failing hearts, regardless of the etiology. However, different forms of ventricular dysfunction are associated with distinct patterns of remodeling of ion-channel functional expression, among which down regulated potassium currents and altered calcium handling. Moreover, altered intracellular signaling during hypertrophy and failure (e.g. beta-adrenergic desensitization accompanied by a reduction in cAMP and phosphodiesterase isoforms) has important impact on cellular functions, including electrical activity. Ion channels and other ion transporters are macromolecular complexes with a key role in many of these signaling cascades. Current studies in our laboratory focus on altered beta-adrenergic signaling and potassium-current down regulation in hypertrophied canine ventricular myocytes.

Other important determinants of arrhythmogenesis are the quantity and pattern of fibrous tissue, the density and distribution of gap junctions, and the availability of sodium current, all of which can be altered in cardiac hypertrophy and failure. Proarrhythmic roles of enhanced sympathetic state, autonomic-nerve remodeling and altered mechanoelectrical feedback have also been demonstrated. Over the last 15 years, Dr. Volders and co-workers have investigated most of the electrophysiological characteristics mentioned above, at the cellular level, in large experimental animals and in human patients. Since our initial reports on acquired polymorphic VT (Circulation. 1998), down regulation of potassium currents IKs and IKr (Circulation. 1999) and enhanced sodium-calcium-exchange current (Circulation. 2000) in dogs with compensated cardiac hypertrophy, various groups have described similar findings in other models.

A strong clinical-experimental infrastructure has been built in Maastricht for the cardiogenetic care of patients with primary cardiomyopathies, including those with inherited arrhythmias. Outpatient clinical care is provided on a weekly basis. Laboratories for DNA Diagnostics, Molecular Biology, Molecular Cardiology, Cellular Electrophysiology/Excitation-Contraction Coupling and In-Vivo Experimental Cardiology are available and managed by members of the Department of Cardiology and the Department of Genetics and Molecular Cell Biology. In the University Hospital there is a strong embedding of Clinical Genetics, Clinical Cardiac Electrophysiology and Implantable Device Technology, and Clinical Cardiac Imaging, including Echocardiographyand MRI. Dr. Volders coordinates the cardiogenetic care of patients on behalf of the Department of Cardiology. Within this clinical-experimental infrastructure there is an active research program to gain novel pathogenetic insights.

Among the primary electrical cardiomyopathies are (1) disorders caused by gene mutations affecting ion-channel function (often leading to inherited cardiac arrhythmias, such as long-QT (LQT) syndrome, short-QT syndrome, Brugada syndrome, familial catecholaminergic polymorphic ventricular tachycardia, cardiac conduction system disease, idiopathic ventricular fibrillation, familial atrial fibrillation); and (2) arrhythmogenic right ventricular cardiomyopathy (ARVC) caused mainly by mutations in desmosomal-junction proteins. Previous publications of the Volders’ team focused on genetic and/or arrhythmogenic mechanisms of LQTsyndrome (notably LQT type 1; Cardiovascular Research.2007), familial atrial fibrillation (Heart Rhythm. 2007), Brugada syndrome (Am J Physiol. 2008; Europace. 2009) and ARVC (Circ Arrhythm Electrophysiol. 2010). Concurrent with the work on native hypertrophied myocytes, actual studies in our laboratory focus on altered beta-adrenergic responsiveness of mutant LQT1 potassium-channel subunits co-transfected with A-kinase anchoring protein in mammalian cell cultures. Finally, numerous studies have indicated trigger roles for increased sympathetic nerve activity and/or elevatedcatecholamines in VT. However, studies demonstrating directly the proarrhythmic influence of sympathetic nerve stimulation are scarce, mainly because the techniques to do so are complex and invasive. Because of this, the mechanisms of sympathetic-related ventricular arrhythmias, at the molecular level and in the intact heart, remain often obscure in individual patients (Volders. Heart Rhythm. 2010).Therapy consisting of beta-adrenergic-receptor blockade and/or implantable cardiac defibrillators is not mechanismspecific and can have important side-effects or may be contra-indicated. One of the aims of this research program is to provide a novel systems-biology approach of the sympathetic neural and neurohumoral effects on cardiac ventricular repolarization and arrhythmogenesis, ultimately to improve the prediction and prevention of sudden cardiac death in patients (ZonMw-NWO Vidi project by Volders). We focus primarily on the normal heart, the congenital LQT syndrome type 1 and conditions with acquired global cardiac overload leading to electrical (and sympathetic?) remodeling. Pilot data indicate important new insights into (1) the molecular-genetic control of repolarization during adrenergic-receptor stimulation, (2) the cellular mechanisms of adrenergic-dependent ventricular proarrhythmia and their detailed computational modeling, (3) the sympathetic triggering of VTs in the beating heart and the modulating influence of neurotrophic factors on myocardial sympathetic innervation and electrical (in)stability, and (4) the utility of these new bench results to improve diagnostic modalities in patients with sympathetic-related VT.

Staff