Investigating the effects of Progressive Right Ventricular Remodeling on Systolic and Diastolic RV Function in a Longitudinal Animal Model Study of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive vasculopathy which increases pulmonary vascular resistance and induces a pressure overload on the right ventricle, however the mechanisms by which the RV adapts to pressure overload is not well understood 1. The purpose of this study was to characterize the mechanistic progression of earlier-stage right ventricular compensated remodeling in an animal model of PAH. In a longitudinal study of the Sugen-Hypoxia animal model of PAH, invasive RV catherization measurements were used to assess right heart function, including RV pressure and volume relations, hemodynamic parameters, and systolic and diastolic elastance measures. Because RV ejection fraction has been found to be transiently maintained in early stage remodeling, this study also sought to distinguish the contributions of systolic and diastolic volume preservation or increases in stroke volume to this maintenance 2. To elucidate the mechanistic contributions to changes in organ-level cardiac function over the course of PAH progression, a computational model was developed to differentiate between contributions due to RV geometric remodeling such as chamber dilatation and wall thickening from contributions due to intrinsic sarcomere changes such as myocardial contractility. Over the course of PAH progression, pulmonary vascular resistance and end systolic and end diastolic pressures continuously increased, while end systolic and diastolic volumes seemed to maintain. Ejection fraction and stroke volume also seemed to maintain over this period of compensated RV remodeling. Computational model analysis of RV myocardial wall mechanics and RV geometry seemed to indicate that changes in sarcomere mechanical properties were required to predict both end-systolic and end-diastolic PV relations throughout the study time points. Passive material parameters increased between early weeks 3–4 to mid weeks 5–6 to late weeks 8–10. Active material parameters indicated that large increases in myocardial inotropy, in part due to increases in intracellular calcium concentration and sarcomere length, occurred in order to maintain RV compensation after four weeks, and remained high through ten weeks. Ongoing biochemical analysis and tissue mechanical testing of the extracellular matrix indicate that significant contribution of fibrotic collagen deposition and stiffening of the ECM in the later weeks may explain increase in diastolic stiffness. Distinguishing between the specific mechanistic contributors to RV compensated remodeling can help identify the mediators of the transition between early stage compensated RV remodeling and later stage decompensated RV remodeling. Support or Funding Information National Institutes of Health NHLBI 1T32HL 105373