In cardiac muscle from HCM patients primary changes in myofilament function, related to the presence of disease-causing mutations in sarcomeric proteins, are always associated with secondary abnormalities due to adverse remodeling of cardiomyocyte EC-coupling(Coppini et al,Circulation 2013). The latter are likely major contributors of the mechanical dysfunction and arrhythmogeneity of HCM human hearts. Here we characterize the changes in sarcomere function and EC-coupling that occur in two HCM mouse models carrying different mutations in cTnT (R92Q and E163R). Echocardiography showed LV hypertrophy, enhanced contractility, diastolic dysfunction and enlarged left atria in both HCM models; the phenotype was more pronounced in the R92Q mice. In E163R ventricular myofibrils, in spite of a significant increase in the rate of the initial isometric slow phase of relaxation, overall relaxation from maximal activation was impaired and prolonged vs WT and R92Q myofibrils that exhibited similar relaxation kinetics. Resting tension was higher in the E163Q compared to WT and R92Q myofibrils. Isometric ATPase both at rest and at maximal Ca2+-activation and the energy cost of tension generation were increased in E163R vs WT and R92Q skinned trabeculae. Myofilament Ca2+-sensitivity was increased in both mutant lines compared to WT; the change was larger in the R92Q preparations. R92Q intact cardiomyocytes and trabeculae compared to WT and E163R preparations showed blunted response to inotropic interventions, reduced amplitude and slower decay of Ca2+-transients with reduced SERCA function. Twitch kinetics were prolonged in both HCM mouse models, despite Ca2+-transient kinetics was faster and SERCA function unchanged in the E163R mice. Intact preparations of both HCM mouse models showed increased probability of arrhythmogenic behavior that increased in response to isoproterenol. The results suggest that similar HCM phenotypes can be generated through different pathogenic pathways. Grant Telethon-GGP13162.
|Titolo:||Myocardial Dysfunction in Hypertrophic Cardiomyopathy: Primary Effects of Sarcomeric Mutations Versus Secondary EC-Coupling Remodelling|
|Anno di registrazione:||2015|
|Autori di Ateneo:|
|Autori:||Coppini, Raffaele; Ferrantini, Cecilia; Gentile, Francesca; Mazzoni, Luca; Tosi, Benedetta; Pioner, José Manuel; Scellini, Beatrice; Piroddi, Nicoletta; Tardiff, Jil C; Tesi, Chiara; Cerbai, Elisabetta; Poggesi, Corrado|
|Appare nelle tipologie:||1c - Abstract su rivista|