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Interactions between structural remodeling and volumetric growth in right ventricle in response to pulmonary arterial hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) exerts substantial pressure overload on the right ventricle (RV). The associated RV free wall (RVFW) adaptation could consist of 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, RV dilation will prevail as an exit mechanism which usually decompensates the 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 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 recent rodent heart models (RHM) of PAH, we integrated mathematical models that describe time-evolution volumetric growth of the RV and structural remodeling of the RVFW. Results suggest that 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 towards the longitudinal (apex-to-base) direction was a maladaptive mechanism that impaired the contractile pattern of RVFW and advanced along with RV dilation at later stages of PAH development.

SUBMITTER: Avazmohammadi R

PROVIDER: S-EPMC6807999 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Avazmohammadi Reza R Mendiola Emilio A EA Li David S DS Vanderslice Peter P Dixon Richard A F RAF Sacks Michael S MS

Journal of biomechanical engineering 20190901 9

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 ...[more]

PMID: 31260516

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Project description:BackgroundIn pulmonary arterial hypertension (PAH) increased afterload leads to adaptive processes of the right ventricle (RV) that help to maintain arterio-ventricular coupling of RV and preserve cardiac output, but with time the adaptive mechanisms fail. In this study, we propose a multimodal approach which allows to estimate prognostic value of RV coupling parameters in PAH patients.MethodsTwenty-seven stable PAH patients (49.5 ± 15.5 years) and 12 controls underwent cardiovascular magnetic resonance (CMR). CMR feature tracking analysis was performed for RV global longitudinal strain assessment (RV GLS). RV-arterial coupling was evaluated by combination of RV GLS and three proposed surrogates of RV afterload-pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC). 18-FDG positron emission tomography (PET) analysis was used to assess RV glucose uptake presented as SUVRV/LV. Follow-up time of this study was 25 months and the clinical end-point was defined as death or clinical deterioration.ResultsCoupling parameters (RV GLS/PASP, RV GLS/PVR and RV GLS*PAC) significantly correlated with RV function and standardized uptake value (SUVRV/LV). Patients who experienced a clinical end-point (n = 18) had a significantly worse coupling parameters at the baseline visit. RV GLS/PASP had the highest area under curve in predicting a clinical end-point and patients with a value higher than (-)0.29%/mmHg had significantly worse prognosis. It was also a statistically significant predictor of clinical end-point in multivariate analysis (adjusted R2 = 0.68; p < 0.001).ConclusionsCoupling parameters are linked with RV hemodynamics and glucose metabolism in PAH. Combining CMR and hemodynamic measurements offers more comprehensive assessment of RV function required for prognostication of PAH patients.Trial registrationNCT03688698, 09/26/2018, retrospectively registered; Protocol ID: 2017/25/N/NZ5/02689.

Project description: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.

Dataset Information

Interactions between structural remodeling and volumetric growth in right ventricle in response to pulmonary arterial hypertension.

Publications

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

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