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

Abstract

Pulmonary arterial hypertension (PAH) exerts substantial pressure overload on the right ventricle (RV), inducing RV remodeling and myocardial tissue adaptation often leading to right heart failure. The associated RV free wall (RVFW) adaptation involves myocardial hypertrophy, augmented intrinsic contractility, collagen fibrosis, and structural remodeling in an attempt to cope with pressure overload. If RVFW adaptation cannot maintain the RV stroke volume (SV), RV dilation will prevail as an exit mechanism, which usually decompensates RV function, leading to RV failure. Our knowledge of the factors determining the transition from the upper limit of RVFW adaptation to RV decompensation and the role of fiber remodeling events such as extracellular fibrosis and fiber reorientation in this transition remains very limited. Computational heart models that connect the growth and remodeling (G&R) events at the fiber and tissue levels with alterations in the organ-level function are essential to predict the temporal order and the compensatory level of the underlying mechanisms. In this work, building upon our recently developed rodent heart models (RHM) of PAH, we integrated mathematical models that describe volumetric growth of the RV and structural remodeling of the RVFW. The time-evolution of RV remodeling from control and post-PAH time points was simulated. The results suggest that the augmentation of the intrinsic contractility of myofibers, accompanied by an increase in passive stiffness of RVFW, is among the first remodeling events through which the RV strives to maintain the cardiac output. Interestingly, we found that the observed reorientation of the myofibers toward the longitudinal (apex-to-base) direction was a maladaptive mechanism that impaired the RVFW contractile pattern and advanced along with RV dilation at later stages of PAH. In fact, although individual fibers were more contractile post-PAH, the disruption in the optimal transmural fiber architecture compromised the effective contractile function of the RVFW, contributing to the depressed ejection fraction (EF) of the RV. Our findings clearly demonstrate the critical need for developing multiscale approaches that can model and delineate relationships between pathological alterations in cardiac function and underlying remodeling events across fiber, cellular, and molecular levels.

Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities?

“…Initially, and as an adaptive response to maintain the pulmonary circulation, the RV endures hypertrophic remodeling, characterized by an increase in cardiomyocyte (CM) size, increased intrinsic contractility and capillary angiogenesis as a way to provide sufficient oxygen and nutrients to the enlarged myocardium [ 57 ]. If pressure overload remains, as in PAH, the adaptive response gradually shifts to maladaptive remodeling towards RV failure [ 58 ] as depicted in Figure 1 . The molecular and cellular responses that drive RV hypertrophy are distinct of what has been described for left ventricular (LV) hypertrophy [ 59 ].…”

Current Understanding of the Right Ventricle Structure and Function in Pulmonary Arterial Hypertension

“…The schematic in Figure 4 demonstrates the different tissue, fiber, and myocyte-level remodeling events during PAH progression. Also worth noting that, similar to Figure 2, the upper/lower bounds of changes in the biomechanical parameters presented in Figure 4 are based on previous reports in the literature (Supplementary Table 2), while the time-course of changes during the progression of PAH are illustrated based on a limited number of available longitudinal studies (Vonk Noordegraaf et al, 2017;Vélez-Rendón et al, 2018;Wang et al, 2018;Avazmohammadi et al, 2019a) and the authors' speculation. This further reveals the need for multi-scale longitudinal studies to evaluate RV biomechanics during the progression of PAH.…”

“…However, RV dilation results in increased wall stress and RV oxygen consumption (Vonk Noordegraaf et al, 2017) and, together with other multi-scale remodeling events at the tissue and myocyte level, eventually leads to depressed organ-level contractility, reduced cardiac output and ejection fraction, and eventually RV dysfunction. It is also worth noting that while the upper/lower bounds of changes in the organ-level functional parameters presented in Figure 2 are based on previous extensive reports in the literature (Supplementary Table 1), the time-course of changes during the progression of PAH are illustrated based on a limited number of available longitudinal studies (Vonk Noordegraaf et al, 2017;Vélez-Rendón et al, 2018;Wang et al, 2018;Avazmohammadi et al, 2019a) and the authors' speculation. Further long-term longitudinal biomechanical studies looking at the time-course of progression of PAH are warranted and would be highly beneficial to establish a better understanding of the effects of remodeling on functional mechanics of the RV.…”

“…Mechanical stimuli play a key role in RV remodeling in response to pressure overload and biomechanical analysis of RV pathophysiology has drawn significant attention over the past years. Multi-scale biomechanical analysis frameworks have been employed to investigate the underlying mechanisms of RV remodeling in PAH (Wang et al, 2018;Avazmohammadi et al, 2019a) and have linked RV biomechanics to physiological function (Jang et al, 2017). Functional measures of RV systolic and diastolic mechanics have been found to be strong predictors of outcomes in PH (Trip et al, 2015;Vanderpool et al, 2015), indicating a potential for translation of biomechanical measures to clinical relevance (Jang et al, 2017).…”

Effects of Healthy Aging on Right Ventricular Structure and Biomechanical Properties

“…In recent years, biomechanical analysis techniques have been employed to better understand the underlying mechanisms of RV remodeling (Avazmohammadi et al, 2017b, 2019; Hill et al, 2014; Sharifi Kia et al, 2020) and have closely linked RV biomechanics to function (Jang et al, 2017). Despite the evidence suggesting an association between aging and alterations in RV structure/function and higher prevalence of PH in the elderly (Hoeper and Gibbs, 2014), a large body of the literature has employed younger animal models and limited data exist on age-associated differences in RV biomechanics.…”