The experimental activity of CONTICA is devoted to the following lines of research:

Objective 1: Identification of new disease related genes by large-scale candidate genes screening. The CONTICA partners can count on the world’s largest population of patients affected by CPVT and, therefore, they are in an excellent position for performing genetic screening on several candidate genes.

Objective 2: In vitro expression of mutant proteins to study their functional consequences. Although site-directed mutagenesis of the RyR2 gene is a very difficult technique, the CONTICA partners have mastered this technique and can now routinely perform these delicate experiments with RyR2. The in vitro studies performed so far have gathered valuable new information on the structure-function relationship of RyR2 and have generated novel hypotheses that will be further tested in this project.

Objective 3: Generation and phenotypic characterisation of transgenic animals harbouring mutant RyR2. After the identification of RyR2 mutations in CPVT patients transgenic animal models for this disease will be generated in order to study in detail the phenotype induced by abnormal intracellular Ca²⁺ handling and to gather new information for the development of novel therapeutic strategies.

Objective 4: In vivo and in vitro characterisation of animal models of acquired vs. inherited arrhythmias involving the SR Ca²⁺ release channel.

Objective 5: Characterisation of the mechanisms underlying Ca²⁺-mediated arrhythmias in human myocardium. The CONTICA group has long-standing and large-scale access to myocardium from human heart. Thus, using native human myocardium, we will be able to assess whether the arrhythmogenic mechanisms identified and characterised in animal models of VT are also operating in the human heart.

Objective 6: Characterisation of a new mathematical model of cardiac excitation-contraction coupling and the development of DADs that takes into account defective RyR2 channel gating in inherited and acquired cardiac disease. This model will be applied to patients with inherited and acquired arrhythmias as well as to the animal models included in our project in order to optimise this method for non-invasive diagnosis of abnormal intracellular Ca²⁺ handling and for the assessment of the efficacy of targeted therapy.

Objective 7: Test novel diagnostic techniques for better risk assessment. In this part, electrophysiological methods will be tested as indicators of (inherent) triggered arrhythmic activity. Ultimately, we will validate and use these methods for assessing the antiarrhythmic effects of novel compounds targeted at the RyR2.

Objective 8: Test novel therapeutic compounds directed at stabilising the RyR2 channel to prevent triggered arrhythmias. This part of the project includes a strong interaction with pharmacological companies that have expressed a vivid interest in pursuing novel approaches for the correction of intracellular Ca²⁺ handling abnormalities. The companies will supply various newly developed agents with antiarrhythmic properties and will be committed to develop new drugs based on the input of the CONTICA investigators.

Objective 9: Improve clinically relevant awareness and risk stratification: Based on our continuous genotyping of patients affected by inherited arrhythmias, the identification of novel mutations, and an extension of the world´s largest clinical data base on CPVT patients, we will be able to improve risk stratification based on genotype-phenotype correlations.