Right ventricular plasticity in a porcine model of chronic pulmonary hypertension

Abstract

Purpose: Ventricular-arterial coupling is a measure of the relationship between ventricular contractility and afterload. In this study, we sought to determine the relationship between ventricular-arterial coupling and right ventricular (RV) adaptation to chronic pressure overload in a novel porcine model of progressive pulmonary hypertension (PH). Methods: Chronic PH was induced in pigs by ligation of the left pulmonary artery (PA) followed by five weekly injections of cyanoacrylate to progressively obstruct the right lower lobe arteries (PH group, n=10). At 6 weeks, 5 PH animals underwent a reperfusion of the left lung to durably decrease RV afterload, while other animals did not receive any treatment. Five sham-operated piglets were used as controls. RV function was assessed using echocardiography and pressure-volume loops analysis. RV gene expression of β-myosin heavy chain (β-MHC) and B-type natriuretic peptide (BNP) were quantified by reverse transcription polymerase chain reaction. Experimental design was approved by our Institutional Committee on Animal Welfare and the study followed the Principles of laboratory animal care. Results: At 6 weeks, compared to controls, the PH group had higher PA pressure (32±6 vs. 14±2 mmHg, p<0.01), RV end-diastolic area index (RVEDAI, 11.1±2.9 cm2 vs. 4.8±0.3 cm2, p<0.01), PA elastance (Ea, 0.90±0.45 vs. 0.29±0.06 ml/mmHg, p=0.01) and RV elastance (Ees, 0.53±0.14 vs. 0.34±0.06 ml/mmHg, p=0.01), and lower RV fractional area change (27±9% vs. 52±10%, p<0.01) (Table 1). The relationship between Ea and RV-PA coupling could be estimated through a curvilinear relationship (R2=0.90, p<0.01). RV-PA coupling was an important determinant of RVEDAI (R2=0.48, p<0.01), RVFAC (R2=0.84, p<0.01) and stroke volume index response to dobutamine (R2=0.56, p<0.01). Changes in RV-PA coupling were also strongly related to changes in stroke volume index response to dobutamine (R2=0.80, p<0.01). Ventricular-arterial coupling and RV mass index 6 weeks after PH surgical treatment were associated with down-regulation of β-MHC (R2=0.75, p<0.01 and R2=0.71, p<0.01 respectively) and BNP expression (R2=0.91, p<0.01 and R2=0.80, p<0.01) (Figure 1). Conclusions: A curvilinear relationship between pulmonary arterial elastance and RV-PA coupling suggests a faster transition towards uncoupling at the early stage of PH. Contractile protein expression and BNP expression are associated with ventricular mass and ventricular-arterial coupling in a porcine model of RV pressure overload.