Hypertrophic cardiomyopathy caused by mutations in the thin filament regulatory proteins of the sarcomere

Hypertrophic cardiomyopathy (HCM) is by far the most frequent and life-threatening hereditary cardiac disease. It is generally diagnosed after puberty, sometimes following a dramatic event as syncope or sudden death that occurs in 2-3% of the individuals (4-6% in childish or adolescence). In more than 60% of cases, HCM is caused by a genetically-determined defect in the contractile machinery of the heart (sarcomeres), which is constituted by a regular lattice of thin and thick filaments, interacting to produce force and ultimately pump the blood. The majority of HCM patients have a genetic-based abnormality in the thick filament, but in a distinct subgroup (7-8%) HCM is caused by a genetic defect of a thin filament protein. “Thin filament HCM” has been reported to be associated with a more severe form of the disease. So far, therapeutic approaches to thin filament HCM are based on the expertise of single clinicians and no evidence-based therapy is available. In the present project we will assess the clinical peculiarities of thin (vs. thick) filament HCM in a large multicenter cohort. Further, the alterations of cardiac muscle contraction and electrical activity will be assessed on myocardial samples from both thin filament HCM patients undergoing cardiac surgery and mice carrying analogue thin filament genetic defects. Some pharmacological compounds that we have already positively tested on human samples in vitro (e.g. Ranolazine) will be tested on mice in vivo, in order to verify whether they are able to interfere with disease onset and progression. In parallel to standard methods of experimental cardiology, newly developed techniques will be employed, taking advantage of partners’ expertise in different fields. We believe that this multimodal approach will lead to determine novel disease-specific therapeutic strategies for thin filament HCM, giving the basis for clinical trials.