LSHM-CT-2005-018802

Coordinator: Burkert Pieske, University of Gottingen / University of Graz
Team Leader: Alexandra Zahradníková

Duration: February 2006 – July 2009
Coordinating Organization: University of Gottingen, Germany / Medical University of Graz, Austria

Annotation: (see http://www.contica.eu/110.htm)

Ventricular arrhythmias are a frequent cause of death. Currently there is no effective therapy available, since their molecular basis is not sufficiently understood. The project is aimed to study the molecular mechanisms of CPVT (catecholaminergic polymorphic ventricular tachycardia) arrhythmias caused by mutations in the RyR2 protein that controls calcium release from the intracellular stores of cardiac myocytes. The basic hypothesis of the project is that CPVT arrhythmias arise due to premature calcium release caused by the changed properties of RyR2 due to mutations. The consortium of cardiologists, molecular biologists, biophysicists and physiologists aims to gain understanding of the molecular concept mechanisms that result in the incorrect function of mutant RyR channels and to develop and test new diagnostics and new antiarrhythmic drugs.

Keywords:

ryanodine receptor, catecholaminergic polymorphic ventricular tachycardia, calcium release

Objectives: (see http://www.contica.eu/129.htm)

The major scientific objective of the CONTICA project is to determine the subcellular mechanisms underlying fatal inherited arrhythmias related to mutations in the SR Ca2+ release channel (ryanodine receptor, RyR2). Based on initial evidence that arrhythmias observed in patients with heart failure (acquired arrhythmias) are also caused by defective intracellular Ca2+ handling and RyR2 dysfunction, we will compare the basic mechanisms of inherited arrhythmias in transgenic animals harbouring RyR2 mutations to those of acquired arrhythmias in animal models of hypertrophy and heart failure, as well as in native human myocardium. In addition, mathematical modelling will aid in understanding mechanisms of arrhythmias as well as in predicting susceptibility to triggered arrhythmias. The ultimate goal of the CONTICA investigators is to develop novel diagnostic and therapeutic concepts and test new pharmacological compounds that may be effective in preventing inherited and acquired arrhythmias related to abnormalities in intracellular Ca2+ handling.

The team at the Department of Muscle Cell Research IMPG SAS contributes to the project at three fronts: first, characterization of the properties of mutant RyR2 protein and in collaboration with other partners to determine, which changes of RyR2 properties are responsible for arrhythmogenicity; second, to test the interpretation of experimental results with the use of mathematical models; and third, to characterize the mechanism of the tested antiarrhythmic drugs on RyR2 activity.

Publications: