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

ended

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 Based on our unpublished observations, I propose that an important, yet unexplored, underlying cause of the diverse clinical manifestations are endogenous resilience and trigger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.