Ventricular arrhythmias are a major cause of mortality. Currently there is no causal treatment available, largely because our understanding of their molecular basis is poor. Altered intracellular Ca²⁺ handling may be a final common pathway predisposing to ventricular tachycardias and sudden death in acquired or congenital heart diseases. In particular, dysfunction of the sarcoplasmic reticulum (SR) Ca²⁺ release channel (ryanodine receptor, RyR2) has been implicated in arrhythmogenesis and sudden death in heart failure and in catecholaminergic polymorphic ventricular tachycardia (CPVT), a fatal inherited disease caused by mutations in RyR2. CPVT is a form of ventricular tachycardia triggered by exercise (Fig.1) or emotional stress. Eventually, ventricular tachycardia (VT) may degenerate into ventricular fibrillation and sudden death.

Fig.1. ECG recording of a CPVT patient affected with a RyR2 mutation. Following exercise, the patient developed polymorphic VT that was reversible after termination of exercise. (Source: S.Priori and C. Napolitano, IRCCS Fondazione Salvatore Maugeri, Pavia)

RyR2 dysfunction may be acquired (as in heart failure) or inherited (as in CPVT). But how can dysfunction of this intracellular Ca²⁺ release channel cause arrhythmias? Current evidence suggests that uncontrolled Ca²⁺ release from the SR through dysfunctional ("leaky") RyR2 leads to activation of the Na⁺/Ca²⁺ exchanger (NCX) in the surface membrane of a cardiac myocyte, which, in turn, may generate delayed afterdepolarisations (DADs) and arrhythmias (Fig.2). Understanding the complex function of the RyR2 Ca²⁺ channel and its regulatory mechanisms, therefore, holds the promise to develop new diagnostic and therapeutic strategies for effective treatment of these lethal arrhythmias. One major approach pursued within CONTICA, therefore, is to develop novel treatments against RyR2-mediated arrhythmias, for example by pharmacologically sealing leaky RyR2 (Fig.3).

Fig.2. Proposed cellular mechanism causing RyR2-mediated arrhythmias.

The CONTICA Investigators are a multidisciplinary team composed of cardiologists, geneticists, molecular biologists, biophysicists and physiologists with established and complementary interests and expertise in the study of intracellular Ca²⁺ handling and arrhythmias. The goal pursued by the CONTICA Consortium is the elucidation of the molecular mechanisms linking defective RyR2 function to the generation of arrhythmias. Employing a wide range of state-of-the-art techniques, the group will perform in depth studies on RyR2 dysfunction in animal and human arrhythmias on the molecular, cellular and whole organism level. Of particular importance, data gathered from the world's largest collective of individuals affected by mutations in RyR2 will reveal novel insights into the genetics of CPVT and enable genotype-phenotype correlations and expression studies of mutated RyR2 in cell lines and animals. The combined knowledge gained from these studies will be used to develop and test novel diagnostic approaches and anti-arrhythmic drugs to help alleviate one of the largest health burdens to the European society, i.e. malignant ventricular arrhythmias.

Fig.3. Envisaged pharmacological approach to treat RyR2-mediated arrhythmias.

Top: RyR2 may become leaky and cause arrhythmias either in heart failure (due to defective regulation) or in CPVT (due to mutations). Bottom: Sealing the RyR2 leak by pharmacological means, therefore, may causally treat these arrhythmias. (Modified from Kockskämper & Pieske. Circ Res. 2006;99:333-5.)