Contributions of Myocardial Hypertrophy and Stiffening to Right‐Ventricular Remodeling in a Rat Model of Pulmonary Arterial Hypertension

Abstract

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.