Transmural remodeling of right ventricular myocardium in response to pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) imposes substantial pressure overload on the right ventricular free wall (RVFW), leading to myofiber hypertrophy and remodeling of its collagen fiber architecture. The transmural nature of these adaptations and their effects on the macroscopic mechanical behavior of the RVFW remain largely unexplored. In the present work, we extended our constitutive model for RVFW myocardium to investigate the transmural mechanical and structural remodeling post-PAH. Recent murine experimental studies provided us with comprehensive histomorphological and biaxial mechanical data for viable, passive myocardium for normal and post hypertensive cases. Multiple fiber-level remodeling events were found to be localized in the midwall region (40% < depth < 60%): (i) reorientation and alignment of both myo- and collagen fibers towards longitudinal (apex-to-outflow tract) direction, (ii) substantial increase in the rate of the recruitment of collagen fibers with strain, and (iii) a corresponding increase in the mechanical interactions between the collagen and myofibers. These adaptations suggest a denser and more fibrous connective tissue in the midwall region, and led to a substantially stiffer mechanical response along the longitudinal direction in post-PAH tissues. Moreover, using a Laplace-type mechanical equilibrium analysis of the right ventricle to approximate the wall stress state, we estimated that the longitudinal component of stress remained higher in the hypertensive state while the circumferential component approximately maintained homeostasis values. This result was consistent with our observation from the fiber- and tissue-level remodeling that longitudinally oriented collagen fibers, localized in the midwall region, dominated the remodeling process. The findings of this study highlight the need for more integrated cellular-tissue-organ analysis to better understand the remodeling events during PAH and design interventions.

Interactions Between Structural Remodeling and Hypertrophy in the Right Ventricle in Response to Pulmonary Arterial Hypertension

“…The G&R model was able to generate the fiber reorientation across the RVFW thickness as seen in the PAH heart (Fig. 8), and also consistent with previous histological studies [10,12]. The fibers exhibited an average reorientation of $16 deg from horizontal (Fig.…”

“…A gradual increase in RV volume with a modest rate as well as slight changes in the fiber structure were also observed. Stiffening has been attributed to multiple mechanisms, including changes in myocyte biophysical properties, such as titin upregulation, changes in the collagen recruitment rate [12], and collagen fibrosis. Similarly, the changes in the RVFW contractility may stem from intrinsic changes in myocyte properties such as alterations in actin/myosin protein isoforms [2] as well as myofiber hypertrophy through sarcomerogenesis.…”

“…These changes are primarily caused by mechanical stimuli through a direct pressure overload and by activation of the neurohormonal system [7][8][9]. Parallel to these changes, structural remodeling in terms of fiber-level stiffening, as well as fiber reorientation and alignment, takes place [5,[10][11][12] that significantly contributes to the changes in both RV diastolic and contractile functions. At the organ level, a progressive RV dilation, considered to be a maladaptive (or decompensatory) response, is activated at later stages of PAH development to maintain the RV stroke volume once the increase in RVFW contractility is at its limit [5,9].…”

Relative Contributions of Matrix and Myocytes to Biaxial Mechanics of the Right Ventricle in Pulmonary Arterial Hypertension

“…While we found a greater increase in circumferential than AOT stress during hypertrophic remodeling in the SuHx rat, AOT stiffness increased more than circumferential stiffness in the PA-banded rat [7,8]. Based on histology and a microstructural constitutive analysis [6], those authors also concluded that the anisotropic changes seen in the PA-banded rat were due to reorientation of myofibers and matrix during hypertrophy.…”

“…Our recent analysis of right ventricular hemodynamics in the monocrotaline-treated rat model of PAH [5] showed that, while systolic function remained compensated against increased pulmonary artery pressure by increased RV volume and contractility, there was also a significant increase in end-diastolic myocardial stiffness though chamber compliance was unaltered due to the RV dilation. Previous multi-axial testing studies of RV myocardium (MYO) in small animal models of RV hypertrophy have reported increased myocardial stiffness [6][7][8]. Therefore, we sought to determine whether RV myocardial biaxial mechanical properties were also altered in an animal model of PAH.…”