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Resilience and Trigger Factors in Cardiac Arrhythmia: Risk Stratification and Drug Design

Project description

Beating cardiac arrhythmia

An arrhythmia refers to a condition when the heart beats too fast or too slow. Improving the clinical outcome for individuals with inherited arrhythmias – passed down from generation to generation – is the main objective of the EU-funded MOLEC ANTI-ARRHYT project. It will forge new paths for personalised risk stratification, drug design and clinical management. Characterised by diverse clinical manifestations, the project will investigate an important yet unexplored underlying cause – endogenous resilience and trigger factors that interact with mutated cardiac ion channels to alter arrhythmia severity. It will use front-line experimental and computational approaches, as well as cardiac potassium channels for this study.

Objective

Up to 30% of individuals with inherited cardiac arrhythmias such as Long QT syndrome are not protected from sudden cardiac death despite state-of-the-art treatment. A major hurdle for effective risk stratification and treatment of inherited cardiac arrhythmias is the poor correlation between genetic variant and clinical manifestations. Affected individuals, who harbour the same arrhythmia-causative mutation, paradoxically display a spectrum of clinical phenotypes ranging from a lifelong asymptomatic state to sudden death in infancy. Up to 40% of genotype-positive individuals, depending on type of arrhythmia, do not display clinical manifestation. Based on our unpublished observations, I propose that an important, yet unexplored, underlying cause of the diverse clinical manifestations are endogenous resilience and trigger factors, which interact with mutated cardiac ion channels to alter arrhythmia severity. MOLEC ANTI-ARRHYT utilizes front-line experimental and computational approaches and the cardiac IKs potassium channel, which is strongly linked to lethal arrhythmias and sudden cardiac death, as a prototype. We aim to: (i) identify major classes of endogenous ligands with therapeutic (resilience factors) or pathological (trigger factors) effects on the IKs channel, (ii) provide proof of mechanism for how the effect of resilience and trigger factors is determined by arrhythmia-causative mutations in the IKs channel, (iii) utilize resilience mechanisms to develop a fundamentally novel concept of anti-arrhythmic drug development: Resilience-Mimetic Drug Development. The successful completion of this project will open up new avenues for personalized risk stratification and clinical management, which ultimately will improve the clinical outcome for individuals with inherited arrhythmias.

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Coordinator

LINKOPINGS UNIVERSITET
Net EU contribution
€ 1 499 998,00
Address
Campus valla
581 83 Linkoping
Sweden

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Region
Östra Sverige Östra Mellansverige Östergötlands län
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Beneficiaries (1)