Atrial Remodeling in Hypertrophic Cardiomyopathy

Changes in myofilament function related to HCM-associated mutations contribute to the diastolic dysfunction observed in the in vivo patient heart and in intact ventricular preparations from patient samples. HCM mutations that are ubiquitously expressed in the heart (e.g. cMyBP-C or cTnT) could also affect atrial function. Here we investigate whether HCM-associated atrial myopathy is a consequence of mutation-driven sarcomere dysfunction or results from atrial remodeling due to the diastolic dysfunction and increased LV filling pressures. In one HCM patient carrying the Lys814del cMyB-C mutation, changes in sarcomere function (increased myofilament Ca2+ sensitivity and increased cross bridges detachment rate under isometric conditions) were similar in atrial and ventricular myofibrils compared to donor preparations. However, isometric twitch mechanics and kinetics of intact trabeculae from the right atrium of 4 cMyB-C-mutant patients were unaffected as compared to trabeculae from non-HCM patients (N=8), or mutation negative HCM patients (N=3), or HCM patients carrying mutations in beta-myosin (N=2). We extended the study to HCM mouse models carrying mutations in cTnT. In the E163R mouse, atrial and ventricular sarcomere kinetics and energetics were similarly altered compared to WT mice. Isometric ATPase, both at rest and at maximal Ca2+-activation and the energy cost of tension generation were increased in both atrial and ventricular preparations of E163R vs WT. However, isometric twitch kinetics were prolonged in intact ventricular trabeculae of E163R mice vs WT while they were unaffected in atrial trabeculae. In the R92Q mouse model, that is associated with a much more severe degree of LV diastolic dysfunction and left atrial dilatation compared to the E163R, left atrial trabeculae showed prolonged twitch contractions, increased spontaneous activity and a number of E-C coupling alterations that resemble those observed in ventricular preparations. HCM-mutations in cMyBP-C and cTnT induce similar alterations in both atrial and ventricular sarcomeres. However, likely due to the different working conditions of the two chambers, sarcomere dysfunction can significantly alter the mechanics and kinetics of the intact myocardium only in the ventricles. Atrial muscle dysfunction in HCM is induced by remodeling processes that depend on the increased filling pressures.