Compensated right ventricular function of the onset of pulmonary hypertension in a rat model depends on chamber remodeling and contractile augmentation

Abstract

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.

Keywords: effective arterial elastance (Ea); end-diastolic elastance (Eed); end-systolic elastance (Ees); monocrotaline (MCT); sarcomere length-stress.

Fig. 1.

Schematic of the RV computational model modeled as a fraction of a sphere of outer radius R and mid-wall radius r. In a cross-section of the sphere, the RV cavity V_RV, RV free wall V_w, and septum V_sw volumes illustrate the different compartments of the RV model.

Fig. 2.

Summary statistics of cardiac performance during systole (a) and diastole (b). *P < 0.05.

Fig. 3.

Summary statistics of RV hypertrophy evidenced with Fulton Index, RV thickness, and RV weight. (a) No changes in animal weights are shown. (b) mPAP and total PVR. *P < 0.05.

Fig. 4.

(a) Representative occlusion PV loops of control and after 4 weeks of MCT administration (chronic PAH). Ees: slope of dashed black line (ESPVR); E_a: slope with dashed dark gray line; E_ed: slope with light gray line. (b) Summary statistics of E_es, E_a, E_ed, and η are also depicted. *P < 0.05.

Fig. 5.

(a) Comparison of measured raw (open circles) and averaged (blue dots and bars) right-ventricular end-diastolic and end-systolic pressure-volume relations with computational model predictions. Control: Model-predicted end-diastolic and end-systolic PV relations (squares and gray lines) using control-group geometry and control-matched material properties. PAH1-4: Model-predicted end-diastolic and end-systolic PV relations (squares and gray lines) using control-group geometry and control material properties. Model-predicted end-diastolic and end-systolic PV relations (solid lines) using PAH geometry and control material properties. Model-predicted end-diastolic and end-systolic PV relations (dashed lines) using PAH geometry and PAH-matched material properties. (b) Model-predicted isometric end-systolic and end-diastolic sarcomere length-tension relations for all 5 animal groups determined by optimizing material parameters to match measured RV pressure-volume relations. Note the increase in predicted systolic sarcomere elastance 2–4 weeks after MCT. End-diastolic sarcomere stiffness tension decreases at week 1 of PAH and increases by.

Fig. 6.

(a) Model-predicted changes in RV SVs from weeks 1–4 due to: (SV₁) changes in preload and afterload only; (SV₂–SV₁) the additional contribution of geometric remodeling on the EDPVR; (SV₃–SV₂) the further contribution of altered diastolic compliance on the EDPVR; (SV₄–SV₃) the further contribution of geometric remodeling on the ESPVR; (SV₅–SV₄) the further contribution of altered contractility on the ESPVR. (b) Graphical definitions of model-predicted SVs SV₁–SV₅ obtained from model-predicted EDPVR and ESPVR computed using: control-group geometry and control-group material properties (dotted lines); PAH geometries and control material properties (solid lines); PAH geometries and PAH material properties (dashed lines).