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Control of Intracellular Calcium in Arrhythmias

Final Report Summary - CONTICA (Control of Intracellular Calcium in Arrhythmias)

Sudden cardiac death is a major cause of death worldwide. Only a few years ago, it became clear that mutations in the cardiac sarcoplasmic reticulum (SR) Ca2+ release channel, or ryanodine receptor (RyR2), can cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a stress-induced cardiac arrhythmia, which can lead to syncope and sudden cardiac death. At about the same time, it was also found that dysfunction of RyR2 in cardiac disease, such as heart failure, can likewise result in fatal arrhythmias, pointing to RyR2 as a key player in inherited as well as acquired fatal human arrhythmias. The major scientific objectives of the CONTICA project, therefore, were to determine the mechanisms underlying fatal inherited arrhythmias related to RyR2 mutations as well as the mechanisms underlying fatal acquired arrhythmias related to RyR2 dysfunction in cardiac disease.

The CONTICA partners are among the world-leading laboratories in CPVT genetics and genotype-phenotype correlations, mouse models of CPVT, construction of RyR2 plasmids and expression in heterologous systems, lipid bilayer studies of single RyR2 channels, mathematical modelling, animal models of arrhythmias, assessment of arrhythmogenic mechanisms in human myocardium, heart failure research, and studies with patients. Thus, they combine the expertise from bench to bedside providing a true and unique translational approach to the topic of arrhythmias and sudden cardiac death.

CONTICA has been exerting a strong and lasting impact on its research field. With the world's largest database with CPVT patients, CONTICA partner FSM is the leading cardiology laboratory in its field. The CONTICA partners have generated the first mouse model of CPVT and have elucidated the molecular and cellular mechanisms underlying CPVT in unprecedented detail. Furthermore, by combining the CPVT mouse model with physiological and pathological stimuli, CONTICA has been gaining novel insights also into the development of hypertrophy and heart failure and arrhythmogenesis in these cardiac diseases. Finally, the CPVT mouse model of CONTICA has been serving as a unique in vivo and in vitro model for testing of anti-arrhythmic compounds targeted against CPVT.

The impact of CONTICA can also be appreciated from its publications. CONTICA has already generated several publications in leading journals of cardiology, physiology, biophysics, and biochemistry. Many more manuscripts by the CONTICA partners have been submitted for publication or are in preparation. It is expected, therefore, that the scientific impact of CONTICA will further increase. CONTICA has also exerted an enormous impact on the general population by increasing the awareness for sudden cardiac death and its causes through press conferences, newspaper, internet, and TV reports reaching several million people in the EU.

The EC-funded project CONTICA has investigated the calcium-dependent mechanisms underlying inherited and acquired forms of heart rhythm disturbances (i.e. arrhythmias) linked to stress-induced sudden cardiac death, one of the major health burdens in Europe and worldwide. In vivo, in vitro, and in silico studies were performed on patients with inherited and acquired arrhythmias, on isolated human heart tissue, on novel and unique animal models, on cell models, on isolated proteins, and by means of novel computer models using state-of-the-art research techniques. The results have revealed, with unprecedented detail, important and exciting new insights into the molecular, cellular, and in vivo mechanisms underlying calcium-mediated fatal arrhythmias. Novel genetic abnormalities, i.e. mutations and polymorphisms, causing life threatening arrhythmias were discovered and characterised, novel methods for diagnosis of arrhythmias were developed and verified, and existing and novel anti-arrhythmic drugs were evaluated for their potential to prevent and treat these fatal arrhythmias. The CONTICA investigators have presented their findings and achievements on numerous national and international scientific meetings and have published the major results of the project in leading basic science and cardiology journals thereby disseminating the scientific knowledge gained from the project to the scientific and medical community worldwide. Furthermore, press conferences, coverage in newspapers and on the internet, and TV reports on the CONTICA project with an estimated overall audience of > 5 million people have fostered the awareness on the topic of sudden cardiac death and its major causes also in the general population within the EU. A useful, informative, and vivid video introduction to the project and its major aims, entitled 'The secret of sudden death', can be found on the internet at

In summary, the project CONTICA has improved the awareness on sudden cardiac death and its underlying causes in the general population and in the scientific and medical community within the EU and worldwide. It has yielded unprecedented novel insights into the molecular mechanisms causing fatal arrhythmias and provided a major contribution to improved diagnosis and therapy of stress-induced cardiac arrhythmias that may cause sudden cardiac death.

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