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How do mechano-electrical interactions and their modifications impact on arrhythmia formation in 'electrical' long-QT and short-QT syndrome?

English title How do mechano-electrical interactions and their modifications impact on arrhythmia formation in 'electrical' long-QT and short-QT syndrome?
Applicant Odening Katja
Number 197595
Funding scheme Project funding
Research institution Translational Cardiology University Clinic for Cardiology Bern University Hospital / University of Ber
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.02.2021 - 31.01.2025
Approved amount 690'018.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Pathophysiology

Keywords (5)

LQTS; Sudden Cardiac Death; SQTS; electro-mechanical function; mechaism-based therapies

Lay Summary (German)

Lead
Bei 'elektrischen' Herzerkrankungen wie dem Long-QT (LQTS) und dem Short-QT Syndrom (SQTS) bestehen durch elektro-mechanische Interaktionen auch regionale Alterationen der Herzmechanik. Diese mechanischen Alterationen korrelieren mit dem individuellen Risiko für potenziell tödliche Herzrhythmusstörungen. Ziel des Projektes ist ein besseres Verständnis der kausalen Bedeutung von mechano-elektrischen Interaktionen für das Entstehen von Rhythmusstörungen.
Lay summary

Inhalt und Ziele des Forschungsprojekts: Bei den 'elektrischen' Herzerkrankungen LQTS und SQTS dachte man lange Zeit, dass Rhythmusstörungen nur durch elektrische Funktionsstörungen verursacht werden. Ziel des Projektes ist es, in den 'elektrisch' erkrankten Herzen zu untersuchen, inwieweit mechanische Veränderungen und mechano-elektrische Wechselwirkungen ebenfalls Rhythmusstörungen auslösen können. Hierzu werden gezielt mechanische Eigenschaften des Herzens verändert und die resultierenden elektrischen Änderungen untersucht. In einem zweiten Schritt werden Mediatoren der mechano-elektrische Interaktionen blockiert und untersucht, inwieweit dies mechanisch induzierte Rhythmusstörungen verhindert.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts: Das Projekt befasst sich mit Grundlagenforschung in experimentellen LQTS und SQTS Modellen. Diese genetischen Herzerkrankungen sind häufige Ursachen des plötzlichen Herztodes. Die bisherige Risikostratifizierung kann das Risiko jedoch nur bedingt vorhersagen. Ein detaillierteres Wissen zur mechano-elektrischen Interaktion kann zukünftig eine präzisere Risikostratifizierung und neue mechanismus-basierte Therapien ermöglichen, um LQTS- und SQTS-Patienten besser vor potenziell tödlichen Rhythmusstörungen zu schützen.

Direct link to Lay Summary Last update: 11.01.2021

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Abstract

Background and Rationale. In the heart, electrical and mechanical functions interact with each other via electro-mechanical (E-M) and mechano-electrical (M-E) interactions. Therefore, changes in either process will affect the other. Recent experimental and clinical data suggest that long-QT and short-QT syndromes (LQTS, SQTS) are not purely ‘electrical’ cardiac diseases, but also exhibit (subtle) mechanical dysfunction and heterogeneity, which appears to correlate with the individual’s risk for arrhythmia. Understanding the mechanisms of E-M and M-E cross-talk and their causative link to arrhythmia formation may thus help to improve risk stratification in LQTS and SQTS and may form the basis for novel mechanism-based therapies.Objective. The overall goal is to gain important basic science insights uncovering novel mechanistic and causal links between adverse E-M and M-E interactions and arrhythmia formation in inherited 'electrical' arrhythmia disorders LQTS and SQTS. Specific Aims. We aim to achieve this goal with the following Specific Aims:-Aim 1: Pathophysiological Mechanisms: Understanding M-E interactions and their role in arrhythmogenesis in 'electrical diseases' LQTS and SQTS using targeted interventions that change mechanical function. -Aim 2: Novel Mechanism-based Therapeutic Interventions: Identification and validation of important drivers for M-E feedback and arrhythmia initiation and their potential as therapeutic target in LQTS and SQTS. Approach and Methods. To identify mechanistic links between M-E interaction and arrhythmias, we will use interventions that change mechanical function in transgenic rabbit models for LQTS/SQTS (that closely mimic human E-M and M-E function and can be subjected to defined interventions to modify risk) and will investigate resulting electrical changes on multiple levels: in vivo, whole heart and isolated cardiomyocytes (Aim 1). For this, we will utilize in vivo multi-channel ECG, MRI, strain-echo, ex vivo voltage-calcium optical mapping combined with strain echo in beating hearts and cellular patch clamping, calcium imaging and contraction / relaxation assessment. E-M-E features indicative of low or high arrhythmic risk will be identified. To search for potential novel M-E based therapies, we will identify important drivers for M-E feedback / arrhythmia initiation (Aim 2). To this end, we will investigate whether the blockade of M-E drivers (stretch-activated channels / stretch-induced ROS-mediated RyR activation) affects electrical function and has anti-arrhythmic effects in LQTS/SQTS in whole hearts ex vivo. Expected results. We expect to identify pronounced changes in E-M-E heterogeneities and interactions in 'electrical' diseases LQTS and SQTS compared to healthy hearts. Using targeted interventions changing mechanical function, we further expect to discover causative M-E interactions, providing a better mechanistic understanding of the link between M-E dysfunction and arrhythmias. We expect to identify pronounced differences in E-M-E features in different risk groups, providing a basis for future risk assessment. The identification of potential beneficial effects of a blockade of M-E drivers may provide novel means of mechanism-based anti-arrhythmic therapies in LQTS/SQTS.Impact. We expect that the insights obtained with this project have the potential to lead to a paradigm shift in the scientific field of cardiac electrophysiology, recognizing the mechanistic importance of adverse E-M and M-E interactions in diseases considered 'purely electrical'. This will have a general impact for mechanistic research in all 'arrhythmogenic' cardiac diseases. In addition, this mechanistic understanding has the potential to provide the basis for novel E-M-E-based personalized risk assessment and innovative therapies in LQTS/SQTS.
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