Hypertrophic cardiomyopathy occurs with a frequency of about 1 in 500 people. Approximately 30% of those affected carry mutations within the gene encoding cMyBP-C (cardiac myosin binding protein C). C Show more
Hypertrophic cardiomyopathy occurs with a frequency of about 1 in 500 people. Approximately 30% of those affected carry mutations within the gene encoding cMyBP-C (cardiac myosin binding protein C). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C (Mybpc3 TGFβ (transforming growth factor-β) signaling is implicated in a variety of fibrotic processes, and the goal of this study was to define the role of myofibroblast TGFβ signaling during chronic Mybpc3 To specifically block TGFβ signaling only in the activated myofibroblasts in Mybpc3 Fibrosis and cardiac dysfunction induced by cardiomyocyte-specific expression of Mybpc3 Show less
Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarco Show more
Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. We evaluated autophagy in patients with HCM carrying Altogether, we found that (1) autophagy is altered in patients with HCM carrying Show less
The geometric organization of myocytes in the ventricular wall comprises the structural underpinnings of cardiac mechanical function. Cardiac myosin binding protein-C (MYBPC3) is a sarcomeric protein, Show more
The geometric organization of myocytes in the ventricular wall comprises the structural underpinnings of cardiac mechanical function. Cardiac myosin binding protein-C (MYBPC3) is a sarcomeric protein, for which phosphorylation modulates myofilament binding, sarcomere morphology, and myocyte alignment in the ventricular wall. To elucidate the mechanisms by which MYBPC3 phospho-regulation affects cardiac tissue organization, we studied ventricular myoarchitecture using generalized Q-space imaging (GQI). GQI assessed geometric phenotype in excised hearts that had undergone transgenic (TG) modification of phospho-regulatory serine sites to nonphosphorylatable alanines (MYBPC3(AllP-/(t/t))) or phospho-mimetic aspartic acids (MYBPC3(AllP+/(t/t))). Myoarchitecture in the wild-type (MYBPC3(WT)) left-ventricle (LV) varied with transmural position, with helix angles ranging from -90/+90 degrees and contiguous circular orientation from the LV mid-myocardium to the right ventricle (RV). Whereas MYBPC3(AllP+/(t/t)) hearts were not architecturally distinct from MYBPC3(WT), MYBPC3(AllP-/(t/t)) hearts demonstrated a significant reduction in LV transmural helicity. Null MYBPC3((t/t)) hearts, as constituted by a truncated MYBPC3 protein, demonstrated global architectural disarray and loss in helicity. Electron microscopy was performed to correlate the observed macroscopic architectural changes with sarcomere ultrastructure and demonstrated that impaired phosphorylation of MYBPC3 resulted in modifications of the sarcomere aspect ratio and shear angle. The mechanical effect of helicity loss was assessed through a geometric model relating cardiac work to ejection fraction, confirming the mechanical impairments observed with echocardiography. We conclude that phosphorylation of MYBPC3 contributes to the genesis of ventricular wall geometry, linking myofilament biology with multiscale cardiac mechanics and myoarchitecture. Show less