Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Monday Speaker Abstracts

EXCITATION-CONTRACTION COUPLING ALTERATIONS IN HYPERTROPHIC CARDIOMYOPATHY AND ARRHYTHMIA PROPENSITY Raffaele Coppini 1 ; Cecilia Ferrantini 1 ; Lorenzo Santini 1 ; Chiara Palandri 1 ; Josè M Pioner 1 ; Marianna Langione 1 ; Chiara Tesi 1 ; Elisabetta Cerbai 1 ; Iacopo Olivotto 1 ; Corrado Poggesi 1 ; 1 University of Florence, Firenze, Italy Hypertrophic Cardiomyopathy (HCM) is the most frequent inherited cardiomyopathy, often associated with sarcomeric protein mutations. In our long lasting collaboration with the Florence Cardiomyopathy Referral Center we performed biophysical investigations on a large number of preparations from surgical samples of HCM patients undergoing septal myectomy and compared the results with those of control hearts (either donors or samples from non-failing non hypertrophic hearts). We found that HCM mutations may primarily affect sarcomere function through different mechanisms but all mutations affect cardiomyocyte electrophysiology and Ca 2+ transient due to remodeling. HCM cardiomyocytes always showed prolonged action potentials (APs) and slower Ca 2+ transients. These changes were associated with a higher likelihood of early and delayed after-depolarizations (EADs and DADs). Among HCM samples, those which scored positive for EADs had longer AP duration as compared with those showing no EADs; moreover, samples from DAD-positive patients showed longer Ca 2+ -transient decay with respect to DAD-negative samples. These observations confirm that EADs are associated with AP prolongation and DADs are linked with altered Ca 2+ cycling. Clinical follow-up of the patients who had provided the cardiomyocytes used for experiments allowed us to establish a correlation between the presence of EADs and DADs in cardiomyocytes and the occurrence of clinical arrhythmias in the same patients. Patients who scored positive for EADs or DADs were more likely to experience arrhythmic episodes during follow up. Additional investigations in mouse and iPSC models of HCM allowed us to establish that (i) the severity of the HCM E-C coupling remodeling and its sequelae vary with the mutation and the related myofilament dysfunction; (ii) the HCM E-C coupling remodeling may be a compensation (though pro arrhythmogenic) for the impact of the mutation on myofilament function; (iii) the HCM E-C coupling remodeling occurs early in the disease.

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