Right Ventricular Architectural Remodeling and Functional Adaptation in Pulmonary Hypertension.

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.

Two dimensional computational model coupling myoarchitecture-based lingual tissue mechanics with liquid bolus flow during oropharyngeal swallowing.

Biomechanical relationships involving lingual myoanatomy, contractility, and bolus movement are fundamental properties of human swallowing. To portray the relationship between lingual deformation and bolus flow during swallowing, a weakly one-way solid-fluid finite element model (FEM) was derived employing an elemental mesh aligned to magnetic resonance diffusional tractography (Q-space MRI, QSI) of the human tongue, an arbitrary Lagrangian-Eulerian (ALE) formulation with remeshing to account for the effects of lingual surface (boundary) deformation, an implementation of patterned fiber shortening, and a computational visualization of liquid bolus flow. Representing lingual tissue deformation in terms of its 2D principal Lagrangian strain in the mid-sagittal plane, we demonstrated that the swallow sequence was characterized by initial superior-anterior expansion directed towards the hard palate, followed by sequential, radially directed, contractions of the genioglossus and verticalis to promote lingual rotation (lateral perspective) and propulsive displacement. We specifically assessed local bolus velocity as a function of viscosity (perfect slip conditions) and observed that a low viscosity bolus (5 cP) exhibited maximal displacement, surface spreading and local velocity compared to medium (110 cP, 300 cP) and high (525 cP) viscosity boluses. Analysis of local nodal velocity revealed that all bolus viscosities exhibited a bi-phasic progression, with the low viscosity bolus being the most heterogeneous and fragmented and the high viscosity bolus being the most homogenous and cohesive. Intraoral bolus cohesion was depicted in terms of the distributed velocity gradient, with higher gradients being associated with increased shear rate and bolus fragmentation. Lastly, we made a sensitivity analysis on tongue stiffness and contractility by varying the degree of extracellular matrix (ECM) stiffness through effects on the Mooney-Rivlin derived passive matrix and by varying maximum tetanized isometric stress, and observed that a graded increase of ECM stiffness was associated with reduced bolus spreading, posterior displacement, and surface velocity gradients, whereas a reduction of global contractility resulted in a graded reduction of obtainable accommodation volume, absent bolus spreading, and loss of posterior displacement. We portray a unidirectionally coupled solid-liquid FEM which associates myoarchitecture-based lingual deformation with intra-oral bolus flow, and deduce that local elevation of the velocity gradient correlates with bolus fragmentation, a precondition believed to be associated with aspiration vulnerability during oropharyngeal swallowing.

Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility.

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, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.