Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis; however, how the right ventricle (RV) adapts to the pressure overload is not well understood. Here, we aimed at characterizing the time course of RV early remodeling and discriminate the contribution of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in a monocrotaline (MCT) animal model. In a longitudinal study of PAH, ventricular morphology and function were assessed weekly during the first four weeks after MCT exposure. Using invasive measurements of RV pressure and volume, heart performance was evaluated at end of systole and diastole to quantify contractility (end-systolic elastance) and chamber stiffness (end-diastolic elastance). To distinguish between morphological and intrinsic mechanisms, a computational model of the RV was developed and used to determine the level of prediction when accounting for wall masses and unloaded volume measurements changes. By four weeks, mean pulmonary arterial pressure and elastance rose significantly. RV pressures rose significantly after the second week accompanied by significant RV hypertrophy, but RV stroke volume and cardiac output were maintained. The model analysis suggested that, after two weeks, this compensation was only possible due to a significant increase in the intrinsic inotropy of RV myocardium. We conclude that this MCT-PAH rat is a model of RV compensation during the first month after treatment, where geometric remodeling on EDPVR and increased myocardial contractility on ESPVR are the major mechanisms by which stroke volume is preserved in the setting of elevated pulmonary arterial pressure. The mediators of this compensation might themselves promote longer-term adverse remodeling and decompensation in this animal model.

In a monocrotaline (MCT) induced-pulmonary arterial hypertension (PAH) rat animal model, the dynamic stress-strain relation was investigated in the circumferential and axial directions using a linear elastic response model within the quasi-linear viscoelasticity theory framework. Right and left pulmonary arterial segments (RPA and LPA) were mechanically tested in a tubular biaxial device at the early stage (1 week post-MCT treatment) and at the advanced stage of the disease (4 weeks post-MCT treatment). The vessels were tested circumferentially at the in vivo axial length with matching in vivo measured pressure ranges. Subsequently, the vessels were tested axially at the mean pulmonary arterial pressure by stretching them from in vivo plus 5% of their length. Parameter estimation showed that the LPA and RPA remodel at different rates: axially, both vessels decreased in Young's modulus at the early stage of the disease, and increased at the advanced disease stage. Circumferentially, the Young's modulus increased in advanced PAH, but it was only significant in the RPA. The damping properties also changed in PAH; in the LPA relaxation times decreased continuously as the disease progressed, while in the RPA they initially increased and then decreased. Our modeling efforts were corroborated by the restructuring organization of the fibers imaged under multiphoton microscopy, where the collagen fibers become strongly aligned to the 45 deg angle in the RPA from an uncrimped and randomly organized state. Additionally, collagen content increased almost 10% in the RPA from the placebo to advanced PAH.

A longitudinal study of monocrotaline‐induced pulmonary arterial hypertension (PAH) was carried out in Sprague‐Dawley rats to investigate the changes in impedance (comprising resistance and compliance) produced by elevated blood pressure. Using invasively measured blood flow as an input, blood pressure was predicted using 3‐ and 4‐element Windkessel (3WK, 4WK) type lumped‐parameter models. Resistance, compliance, and inductance model parameters were obtained for the five different treatment groups via least‐squares errors. The treated animals reached levels of hypertension, where blood pressure increased two folds from control to chronic stage of PAH (mean pressure went from 24 ± 5 to 44 ± 6 mmHg, P < 0.0001) but blood flow remained overall unaffected. Like blood pressure, the wave‐reflection coefficient significantly increased at the advanced stage of PAH (0.26 ± 0.09 to 0.52 ± 0.09, P < 0.0002). Our modeling efforts revealed that resistances and compliance changed during the disease progression, where changes in compliance occur before the changes in resistance. However, resistance and compliance are not directly inversely related. As PAH develops, resistances increase nonlinearly (R d exponentially and R at a slower rate) while compliance linearly decreases. And while 3WK and 4WK models capture the pressure‐flow relation in the pulmonary vasculature during PAH, results from Akaike Information Criterion and sensitivity analysis allow us to conclude that the 3WK is the most robust and accurate model for this system. Ninety‐five percent confidence intervals of the predicted model parameters are included for the population studied. This work establishes insight into the complex remodeling process occurring in PAH.

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.

Pulmonary arterial hypertension (PAH) commonly leads to right ventricular (RV) hypertrophy and fibrosis that affect the mechanical properties of the RV myocardium (MYO). To investigate the effects of PAH on the mechanics of the RV MYO and extracellular matrix (ECM), we compared RV wall samples, isolated from rats in which PAH was induced using the SuHx protocol, with samples from control animals before and after the tissues were decellularized. Planar biaxial mechanical testing, a technique first adapted to living soft biological tissues by Fung, was performed on intact and decellularized samples. Fung's anisotropic exponential strain energy function fitted the full range of biaxial test results with high fidelity in control and PAH samples both before and after they were decellularized. Mean RV myocardial apex-to-outflow tract and circumferential stresses during equibiaxial strain were significantly greater in PAH than control samples. Mean RV ECM circumferential but not apex-to-outflow tract stresses during equibiaxial strain were significantly greater in the PAH than control group. The ratio of ECM to myocardial stresses at matched strains did not change significantly between groups. Circumferential stresses were significantly higher than apex-to-outflow tract stresses for all groups. These findings confirm the predictions of a mathematical model based on changes in RV hemodynamics and morphology in rat PAH, and may provide a foundation for a new constitutive analysis of the contributions of ECM remodeling to changes in RV filling properties during PAH.

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Pulmonary Arterial Hypertension (PAH) is a progressive vasculopathy which increases pulmonary vascular stiffness and induces a pressure overload on the right ventricle (RV). In patients with PAH, the RV remodels in response to increased pulmonary pressure, including myocardial hypertrophy and RV geometric remodeling, but can result in intractable right heart failure. Given that the underlying mechanisms of RV remodeling are not well understood,1 we carried out invasive RV catherization in the sugen‐hypoxia (SuHx) rat model to assess systolic and diastolic chamber function during the progression of PAH. To distinguish the relative contributions of RV geometric remodeling from myocardial material remodeling to changes in RV function, a biomechanics model was fitted to measured RV pressure‐volume relations and morphology after three, five, and eight weeks of sugen injections. After an initial decrease in RV ejection fraction (66±10% to 44±6%, p<0.01), systolic function stabilized (subsequent 2% change in EF through the end of the study, p>0.05), despite progressive increases to RV end‐systolic pressure. The model attributed these changes to RV myocardial hypertrophic wall‐thickening, with only minor increases in myocyte force generating capacity at week 5 (Figure 1). After RV systolic function stabilized, end‐diastolic pressure increased significantly (p<0.05), with maintained RV diastolic volumes. Unlike end systole, RV end‐diastolic volume was maintained due to stiffening of myocardium resting properties (Figure 1, panel 2‐3). These passive stiffness findings are in agreement with previously identified increases in diastolic chamber and myocardial stiffening in both PAH animals and patients occurring before the onset of severe systolic dysfunction2,3. While significant myocardial passive stiffness was found in this study, there was no evidence of changes in total collagen content (p>0.05) or collagen type I to III ratio (p>0.05). This points towards possible collagen matrix remodeling such as collagen fiber structure, tortuosity, or cross‐linking, or changes in titin isoforms or phosphorylation. This progressive increase in RV myocardial passive stiffness that occurs after RV hypertrophy has stabilized systolic function may be a compensatory mechanism to delay or prevent RV dilation but may also eventually contribute to diastolic dysfunction. [1] Van de Veerdonk MC et al. Heart Fail Rev. 2016. [2] Vélez‐Rendón D et al. J Biomech Eng. 2019. [3] Rain S et al. Circ Heart Fail. 2016.

Introduction: Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis. By relating ventricular hemodynamics to wall mechanics, we aimed to discriminate the contributions of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in two commonly used PAH animal models at end-systole (ES) and end-diastole (ED) to the maintenance of cardiac output during the early compensated phase. Methods: PAH was induced in 13 male Sprague-Dawley rats. The MCT group (N=4) was injected with a single dose of 60mg/kg of monoctroaline and kept in normoxia for 4 weeks. The SuHx group (N=9) was injected with a single dose of 20mg/kg of sugen, a VEGF inhibitor, and was placed on a hypoxia chamber for 3 weeks followed by 3 weeks of normoxia. 7 animals were used as a control group. In-vivo measurements of RV pressure and volume with preload changes were acquired. To relate ventricular pressure-volume relations to sarcomere mechanics, a computational model of the RV was developed. Using ventricular morphology and volume measurements from PAH groups, sarcomere material mechanics were adjusted to evaluate ES and ED functions in the treated animals. Results: ED pressures rose significantly in the treated groups (31.7 vs. 70.5 and 71.1 mmHg). ED and ES volumes remained the same in SuHx and CTL group, but increased significantly in the MCT group. RV hypertrophy increased in both PAH animal models, but it was significantly higher in the SuHx group. Even though differences in pressure, volume and morphology exist between the PAH groups, SV and CO were preserved in all treated animals. Model material parameters of increased in PAH, significantly in MCT maximal isometric tension. Conclusions: The model analysis suggests compensation to ESP rises was only possible due to a significant increase in the contractility of RV myocardium in the MCT and SuHx animals. No changes in diastolic function were found in the MCT animals, but there was an increase stiffness in the SuHx animals.