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Identification and therapeutic targeting of common arrhythmia trigger mechanisms

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Cardiac arrhythmias

Arrhythmias are abnormal cardiac electrical rhythms that are difficult to predict and potentially life threatening. Current therapies include antiarrhythmic drugs and implantable cardioverter-defibrillator (ICD) devices that have limited efficacy.


The EU-funded project EUTRIGTREAT (Identification and therapeutic targeting of common arrhythmia trigger mechanisms) investigated mechanisms involved in arrhythmia initiation and progression to develop better risk prediction, diagnosis and treatment strategies. Four European study sites recruited around 680 patients for identification and analysis of arrhythmogenic gene variants using clinical, electrophysiological and genetic data. In parallel, project members developed and optimised imaging instruments for functional imaging of intact heart tissue. Devices developed include a random access multi-photon microscopy prototype and a new electronic control interface. Studies revealed differences in tissue behaviour and complex action potential. The researchers identified arrhythmia triggers as well as select novel candidate electrocardiographic biomarkers. Computer simulations of arrhythmia-initiating and -terminating mechanisms complemented these experiments. Ultimately, this led to validation of experimental methods for different arrhythmia cases. Researchers further optimised an innovative antiarrhythmic device called low-energy anti-fibrillation pacing through testing of parameters such as frequency ratio and number of pulses. This led to the development of in vivo experimental protocols for eventual application in preclinical design studies. Using transgenic mice and optogenetic techniques, the scientists successfully visualised ultra-rapid electrical excitation of intact hearts. They also developed more transgenic models with patient mutations to study drug or treatment efficacy as well as cardiotoxicity. Novel drugs were tested at the preclinical stage for calcium ion leak inhibition through cell-based assays. A cardiac sodium-calcium exchanger inhibitor to modulate plasma membrane ion transport and key pathophysiological mechanisms was also developed. A multicentre clinical trial with European patients using invasive ICD devices was completed on diagnostic risk prediction. Based on the results, the team developed new diagnostic protocol procedures taking into account genetic and environment modulators such as cell ion metabolism. As individual ICD costs are high, the results of the trial were able to predict the economic impact of risk scoring. EUTRIGTREAT disseminated project outcomes via seminars, lectures, workshops, interviews and exhibitions such as the Science Tunnel. Overall, the project has successfully investigated life-threatening arrhythmia phenotypes with a high risk for sudden cardiac death and thrombembolic stroke. In tandem, better strategies to determine arrhythmia risk in individual patients and novel therapies have been developed.


Cardiac, arrhythmias, ICD device, EUTRIGTREAT, heart, biomarkers

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