📋 Tender Overview
Arrhythmogenesis In Dilated Cardiomyopathy: Role Of Mechano-Electric Coupling
Heart Failure Is A Major Cause Of Death In The Western World, With An Estimated Prevalence Of 2-3% Of The Population. A Subgroup Of Heart Failure Patients Is Characterised By Dilated Cardiomyopathy (Dcm) Which Results In Substantial Morbidity And Mortality Due To Progressive Mechanical Pump Failure (70%) Or Sudden Cardiac Death From Ill-Predictable Electrical Disturbances (30%). Dcm Is Commonly Linked To Mutations Encoding Cytoskeletal Proteins, But Our Understanding Of Why A Loss Of Cardiac Myocyte Cytoskeletal Integrity In Inherited Dcm Phenotypes Results In Detrimental Changes To Calcium Handling, And How This Causes Arrhythmias And Sudden Cardiac Death, Remains Limited. Human Studies Have Associated Genetic Mutations And Loss In The Cytoskeletal Protein Filamin C (Flnc) With Arrhythmogenic Dcm And Sudden Death. To Explore The Biomechanical And Mechano-Electric Mechanisms By Which Flnc Deficiency Leads To Mechanical And Electrical Dysfunction, I Will Use Experimental And Mathematical Models That Span Multiple Spatial And Temporal Scales From The Protein Level Up To The Whole Heart. I Hypothesise That Flnc Regulates Myofilament Lattice Spacing And That Loss Of This Structure Leads To Impaired Contractile Force Development By The Sarcomere. I Postulate That These Perturbations In Mechanics May Contribute To The Generation Of Substrate For The Induction And Maintenance Of Lethal Ventricular Arrhythmias Via A Variety Of Mechano-Electric Coupling Mechanisms. Particularly, Stretch-Induced Alterations May Affect Cardiomyocyte Electrophysiology, Which May Contribute To Both The Trigger And The Substrate For Arrhythmias. Thus, Altered Myocardial Mechanics In The Flnc-Null Mouse Model Of Dcm May Contribute To The Triggering Or Maintenance Of Life-Threatening Reentrant Ventricular Arrhythmias Via A Variety Of Mechano-Electric Coupling Mechanisms.
Funded Under
Marie Sklodowska-Curie Actions (Msca)
Total Cost
€ 0,00
Eu Contribution
€ 265 647,84
Coordinated By
Albert-Ludwigs-Universitaet Freiburg
Germany
Start Date
1 September 2024
End Date
31 August 2027
