Distinct time courses and mechanics of right ventricular hypertrophy and diastolic stiffening in a male rat model of pulmonary arterial hypertension

Abstract

While pulmonary arterial hypertension (PAH) leads to right ventricle (RV) hypertrophy and structural remodeling, the relative contributions of changes in myocardial geometric and mechanical properties to systolic and diastolic chamber dysfunction and their time courses remain unknown. Using measurements of RV hemodynamic and morphological changes over 10 weeks in a male rat model of PAH and a mathematical model of RV mechanics, we discriminated the contributions of RV geometric remodeling and alterations of myocardial material properties to changes in systolic and diastolic chamber function. Significant and rapid RV hypertrophic wall thickening was sufficient to stabilize ejection fraction in response to increased pulmonary arterial pressure by week 4 without significant changes in systolic myofilament activation. After week 4, RV end-diastolic pressure increased significantly with no corresponding changes in end-diastolic volume. Significant RV diastolic chamber stiffening by week 5 was not explained by RV hypertrophy. Instead, model analysis showed that the increases in RV end-diastolic chamber stiffness were entirely attributable to increased resting myocardial material stiffness that was not associated with significant myocardial fibrosis or changes in myocardial collagen content or type. These findings suggest that whereas systolic volume in this model of RV pressure overload is stabilized by early RV hypertrophy, diastolic dilation is prevented by subsequent resting myocardial stiffening.

Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model

“…None of these numerical permutations fundamentally altered our findings. In support of our findings, Baicu et al and Kwan et al suggested that hypertrophic thickening is primarily an early adaptive mechanism that improves systolic function, while myocardial stiffening is a late adaptive mechanism that improves the RV's resistance to excessive dilation 18,33 ; hence, concurring with our observations that myocardial stiffness is the primary mechanism driving RV stiffening.…”

“…The copyright holder for this preprint (which this version posted April 6, 2023. ; https://doi.org/10.1101/2023.04.03.535491 doi: bioRxiv preprint tricuspid valve leaflets underwent the same fibrotic changes in animals with RV failure 30 and are consistent with a general understanding of microstructural remodeling associated with fibrosis 31 . Importantly, our large animal model of PHT confirmed several previous findings that pulmonary hypertension induces myocardial stiffening 10,13,32,33 . Though, the current study is the first to subject maladapted RV myocardium to multi-directional shear loading scenarios.…”

Knowing All the Angles (on Right Ventricular Myocardial Remodeling)

“…Finally, at week 5, an increase in RV wall stiffness assessed by biomechanical testing was noted. 10 Could the differential response to Sugen/ hypoxia between Sprague Dawley and CDF rats Mendiola et al report be due to different temporal response? Supporting a differential time course between Sprague Dawley and CDF rats is the observation that Sprague Dawley rats had a lower RVSP and higher TAPSE/RVSP than CDF rats.…”

Computational models of ventricular mechanics and adaptation in response to right-ventricular pressure overload

“…It is worth noting that Laplace-type models can be used to study RV mechanics during PAH, beyond just the wall stress state. More recently, Vélez-Rendón et al (2018) and Kwan et al (2021) employed such a model to discriminate the contributions of morphological and intrinsic mechanisms (i.e., altered contractility and chamber stiffness) towards compensated RV function during the early stages of PAH. Their model of the RV comprised the RV cavity (assumed to be a fraction of a sphere), the RVFW and septum.…”

“…Myocardial structure and mechanics are altered in response to pressure overload as shown in animal experimental models of PAH ( Bogaard et al, 2009b ; Rain et al, 2013 ; Vélez-Rendón et al, 2019 ; Kwan et al, 2021 ). The alteration in structure is mainly in the form of myocardial fibrosis, which leads to increased RV diastolic stiffness, supplemented by altered RV contractile force ( Rain et al, 2016 ; Wang et al, 2018 ).…”