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Identification and therapeutic targeting of common arrhythmia trigger mechanisms

Final Report Summary - EUTRIGTREAT (Identification and therapeutic targeting of common arrhythmia trigger mechanisms)

Executive Summary:
The EUTrigTreat consortium addressed an apparent lack of rationales to support novel diagnostic and therapeutic options for patients at risk for arrhythmias and sudden cardiac death through a translational, integrative, and collaborative project strategy with the objectives to:
• Overcome the current lack of understanding of complex arrhythmia mechanisms
• Apply an innovative translational strategy including patient and experimental studies
• Characterize genetic and environmental arrhythmia modulators and their interactions
• Develop novel risk biomarkers, diagnostic strategies and therapeutic interventions
Summary of the complex project background vis a vis the EUTrigTreat objectives: significant improvements of arrhythmia prevention and treatment depends critically on better mechanistic understanding of arrhythmia phenotypes, in particular those mechanisms that initiate arrhythmias (intrinsic and extrensic triggers). This novel insight was considered a key prerequisite to identify more meaningful arrhythmia risk biomarkers. However, studies of arrhythmia mechanisms in patients (foreground) have proved to be exceedingly complex, since genetic linkage or gene association studies typically suggest multiple, complex, and/or weak associations between gene defects and environmental modulators of arrhythmia susceptibility. Even under strictly controlled experimental conditions, the specific molecular and cellular mechanisms of arrhythmia initiation (triggers) and their modulation by genetic and/or environmental factors remain incompletely understood. It is therefore not surprising, that existing clinical diagnostic and therapeutic strategies for patients with rare as well as common arrhythmia syndromes are by nature incomplete are limited and lack or incompletely address meaningful risk biomarkers of triggers. Furthermore, currently no molecularly targeted therapies to prevent arrhythmias by a rationally defined mechanism exist. Instead, existing anti-arrhythmic drug and device therapies are typically based on empirical outcome studies. From the patient perspective, significant side effects and risks limit current clinical approaches. To overcome the current dilemma towards novel arrhythmia diagnosis and prevention strategies, consequently EUTrigTreat investigated common and “rare” arrhythmia mechanisms side-by-side to gain mechanistic insight. Mechanistic studies assessed intracellular ion homeostasis and detailed subcellular arrhythmia mechanisms, and multiple levels from the molecule to in vivo. In summary, EUTrigTreat investigators elucidated complex arrhythmia mechanisms, environmental and genetic modulators, and studied potential biomarkers towards development of novel diagnostic strategies. Furthermore, novel device and drug strategies were tested at the preclinical stage.
EUTrigTreat successfully completed a multi-center Clinical Trial via European patient enrolment and in-depth arrhythmia phenotype and genetic analysis, ultimately to improve diagnostic risk prediction and therapeutic decisions for patients with increased but - importantly - not without increased arrhythmia risk, who are typically treated with invasive Internal Cardioverter Defibrillator (ICD) devices based on current clinical guidelines. Due to high individual ICD costs, significant risks and side effects, and a rapidly growing number of sick and aging patients who may depend on ICD therapy, correct diagnostic decision taking is critical yet remains uncertain for individual patients, health care providers, and other stakeholders. To overcome this dilemma, the Clinical Trial developed new diagnostic protocol procedures based on mechanistic hypothesis for clinical and electrophysiological risk assessment and to improve arrhythmia risk prediction and patient treatment through risk scoring and consideration of genetic and environmental modulators such as cellular ion metabolism. Clinical Trial data support data analysis and prediction about the economic impact of through risk scoring to project public health costs.

Project Context and Objectives:
Summary of the complex project background vis a vis the EUTrigTreat objectives: significant improvements of arrhythmia prevention and treatment depends critically on better mechanistic understanding of arrhythmia phenotypes, in particular those mechanisms that initiate arrhythmias (intrinsic and extrensic triggers). This novel insight was considered a key prerequisite to identify more meaningful arrhythmia risk biomarkers. However, studies of arrhythmia mechanisms in patients (foreground) have proved to be exceedingly complex, since genetic linkage or gene association studies typically suggest multiple, complex, and/or weak associations between gene defects and environmental modulators of arrhythmia susceptibility. Even under strictly controlled experimental conditions, the specific molecular and cellular mechanisms of arrhythmia initiation (triggers) and their modulation by genetic and/or environmental factors remain incompletely understood. It is therefore not surprising, that existing clinical diagnostic and therapeutic strategies for patients with rare as well as common arrhythmia syndromes are by nature incomplete are limited and lack or incompletely address meaningful risk biomarkers of triggers. Furthermore, currently no molecularly targeted therapies to prevent arrhythmias by a rationally defined mechanism exist. Instead, existing anti-arrhythmic drug and device therapies are typically based on empirical outcome studies. From the patient perspective, significant side effects and risks limit current clinical approaches. To overcome the current dilemma towards novel arrhythmia diagnosis and prevention strategies, consequently EUTrigTreat investigated common and “rare” arrhythmia mechanisms side-by-side to gain mechanistic insight. Mechanistic studies assessed intracellular ion homeostasis and detailed subcellular arrhythmia mechanisms, and multiple levels from the molecule to in vivo. In summary, EUTrigTreat investigators elucidated complex arrhythmia mechanisms, environmental and genetic modulators, and studied potential biomarkers towards development of novel diagnostic strategies. Furthermore, novel device and drug strategies were tested at the preclinical stage.

Project Results:
The EUTrigTreat project aimed to support the health of people, particularly patients at risk for arrhythmias in the European population by improved diagnosis, prevention and therapy. Arrhythmias are undisputed a leading cause of sudden death requiring immediate public health intervention strategies and better risk analysis. The table-like list (see publishable summary for table version) summarizes the foreseeable intervention levels for arrhythmic forms of heart disease contributed through EUTrigTreat:

Intervention ----- Endpoint ----- Target Population ----- EUTrigTreat

Individual rescue Sudden death Sick/at-risk patients Device therapy, drugs, improved diagnosis
Medical care Sudden death Sick/at-risk patients Drugs, risk prevention
Access to care All cause deaths At-risk patients Recommendations
Public health Risk scoring At-risk and/or sick patients Recommendations for risk identification, modification
Expert Services All cause deaths All individuals Recommendations
Social Networks Sudden death All individuals Economic options

Throughout the 66 month project period, the EUTrigTreat consortium has completed all planned activities through detailed project aims and objectives described individually for each work package in the following section of this final project report.

Potential Impact:
EUTrigTreat investigated several different, clinically highly relevant forms of electrical heart disease (arrhythmias). In particular, life-threatening arrhythmia phenotypes with a high risk for sudden cardiac death (SCD) and thrombembolic stroke were studied. This included rare genetic ion channelopathies, common environmental risk factors, and heart failure as the most prevalent and exponentially growing arrhythmogenic syndrome in aging. Furthermore, shared objectives were addressed through strategically interconnected clinical and experimental studies. In particular, molecular mechanisms of arrhythmia initiation, new experimental and clinical diagnostic readouts, better strategies to determine arrhythmia risk in individual patients, and novel therapeutic rationales were developed. Importantly, based on significantly improved mechanistic knowledge, new therapeutic concepts both for anti-arrhythmic drug compounds and implantable devices were developed (see below). In addition, new diagnostic strategies assessed the risk of arrhythmias both for rare genetic and highly prevalent forms of heart disease. Ultimately, EUTrigTreat investigators addressed a very critical area of health and disease by combining improved understanding of arrhythmia initiating Trigger mechanisms with new Treatment rationales to improve patient diagnosis and treatment through groundbreaking mechanistic insight and novel treatment strategies.

List of Websites:
www.eutrigtreat.eu
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