Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N ′ )-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C ∆C0-C1f ), displayed dilated cardiomyopathy, underscoring the importance of the N ′ -region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, Abbreviations: cMyBP-C FL , full-length cardiac myosin binding protein C; cMyBP-C ∆C0-C1f , cMyBP-C lacking the C0-C1f region; TG, transgenic; WT, wild type; S2, subfragment 2; RLC, regulatory light chain; non-transgenic, NTG; C0-C1f, the first 271 residues of N ′ -region of cMyBP-C; I-R, ischemia-reperfusion; N ′ , amino terminal; t/t, cMyBP-C null homozygous mice; HF, heart failure; C0-C2, the first 448 residues of N ′ -region of cMyBP-C.
BACKGROUND: Global indices of right ventricle (RV) function provide limited insights into mechanisms underlying RV remodeling in pulmonary hypertension (PH). While RV myocardial architectural remodeling has been observed in PH, its effect on RV adaptation is poorly understood. METHODS: Hemodynamic assessments were performed in 2 rodent models of PH. RV free wall myoarchitecture was quantified using generalized Q-space imaging and tractography analyses. Computational models were developed to predict RV wall strains. Data from animal studies were analyzed to determine the correlations between hemodynamic measurements, RV strains, and structural measures. RESULTS: In contrast to the PH rats with severe RV maladaptation, PH rats with mild RV maladaptation showed a decrease in helical range of fiber orientation in the RV free wall (139º versus 97º; P =0.029), preserved global circumferential strain, and exhibited less reduction in right ventricular-pulmonary arterial coupling (0.029 versus 0.017 mm/mm Hg; P =0.037). Helical range correlated positively with coupling ( P =0.036) and stroke volume index ( P <0.01). Coupling correlated with global circumferential strain ( P <0.01) and global radial strain ( P <0.01) but not global longitudinal strain. CONCLUSIONS: Data analysis suggests that adaptive RV architectural remodeling could improve RV function in PH. Our findings suggest the need to assess RV architecture within routine screenings of PH patients to improve our understanding of its prognostic and therapeutic significance in PH.
Introduction: Right Ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH) is the major cause of mortality. Myocardial architecture determines the basis of heart function and can be assessed by generalized Q-space imaging by MRI (GQI), yet remains understudied in the RV. Therefore, we assessed myocardial fiber architecture patterns and correlated them with disease severity in two models of PAH. Methods: PAH was induced in Sprague-Dawley (SD) and Fischer (CDF) male rats by SU5416 (20 mg/kg; s.c.) followed by 3 wks of hypoxia (10% FiO2). Controls received vehicle and were kept at normoxia. After 4 wks, echocardiography and hemodynamics were performed. Whole hearts were resected in some animals (SD n=9, CDF n=8) and imaged via high-angular resolution GQI using a 7T magnet (512 directions, b=750 s/mm2). Patterns of inter-voxel coherence (tractography) were reconstructed, and transmural helix angle distribution (HAD) were assessed at 3 points across the LV and RV (Panel A) and normalized to a common vector. Finite-element models were developed via registering myofiber direction to anatomical mesh. Results: Both animal strains developed PAH, however CDF rats had lower pulmonary artery acceleration time (14±0.6 vs. 19±1.3 ms, p<0.05) and TAPSE (1.5±0.06 vs. 1.9±0.09 mm, p<0.05) and higher RV afterload (1023±167 vs. 285±17, mmHg/mL p<0.05) compared to SD. PAH was associated with steeper slope of the RV transmural HAD in both SD and CDF vs. controls and slightly higher in CDF-PAH compared to SD-PAH (Panel B). No significant changes were noted in the LV (Panel C). Moreover, the RV HAD slope significantly correlated to RV functional parameters (TAPSE r= 0.58, RV global longitudinal strain r= -0.49) and RA area (r= -0.58). Transmural and regional variation in fiber direction was also observed (Panel D). Conclusion: Myoarchitectural analysis of the RV in the setting of PAH reveals that myocardial HAD relates to functional parameters and may be a marker of maladaptation.
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