Multiscale structure-function relationships in right ventricular failure due to pressure overload

Abstract

Right ventricular (RV) failure (RVF) is the major cause of death in pulmonary hypertension. Recent studies have characterized changes in RV structure in RVF, including hypertrophy, fibrosis, and abnormalities in mitochondria. Few, if any, studies have explored the relationships between these multiscale structural changes and functional changes in RVF. Pulmonary artery banding (PAB) was used to induce RVF due to pressure overload in male rats. Eight weeks postsurgery, terminal invasive measurements demonstrated RVF with decreased ejection fraction (70 ± 10 vs. 45 ± 15%, sham vs. PAB, P < 0.005) and cardiac output (126 ± 40 vs. 67 ± 32 ml/min, sham vs. PAB, P < 0.05). At the organ level, RV hypertrophy was directly correlated with increased contractility, which was insufficient to maintain ventricular-vascular coupling. At the tissue level, there was a 90% increase in fibrosis that had a direct correlation with diastolic dysfunction measured by reduced chamber compliance ( r² = 0.43, P = 0.008). At the organelle level, transmission electron microscopy demonstrated an abundance of small-sized mitochondria. Increased mitochondria was associated with increased ventricular oxygen consumption and reduced mechanical efficiency ( P < 0.05). These results demonstrate an association between alterations in mitochondria and RV oxygen consumption and mechanical inefficiency in RVF and a link between fibrosis and in vivo diastolic dysfunction. Overall, this work provides key insights into multiscale RV remodeling in RVF due to pressure overload. NEW & NOTEWORTHY This study explores the functional impact of multiscale ventricular remodeling in right ventricular failure (RVF). It demonstrates correlations between hypertrophy and increased contractility as well as fibrosis and diastolic function. This work quantifies mitochondrial ultrastructural remodeling in RVF and demonstrates increased oxygen consumption and mechanical inefficiency as features of RVF. Direct correlation between mitochondrial changes and ventricular energetics provides insight into the impact of organelle remodeling on organ level function.

Keywords: mitochondria; myocardial energetics; pressure-volume loops; pulmonary artery banding; right ventricular failure.

Fig. 1.

A–C: pulmonary artery banded (PAB) rats exhibited elevated right ventricular (RV) end-systolic pressure (A), diminished ejection fraction (B), and decreased cardiac output (C) compared with sham rats. D: representative RV pressure-volume loops measured in sham and PAB rats. Data are presented as means ± SD. A two-tailed Student’s t-test was used to determine significant differences between groups. n = 7 sham and 8 PAB rats. *P < 0.05 and **P < 0.005, sham vs. PAB.

Fig. 2.

A–C: pulmonary artery banded (PAB) rats displayed increased end-systolic elastance (E_es; A), elevated arterial elastance (E_a; B), and decreased ventricular-vascular coupling (E_es/E_a; C) compared with sham rats. D–F: PAB resulted in an elevated maximal derivative of pressure (dP/dt_max) compared with the sham group (D), which was positively correlated to right ventricular (RV) weight relative to left ventricular and septum weights (LV + S; E) and echocardiography-derived RV wall thickness (F). Pearson’s correlation indicated the statistically significant relationships between RV hypertrophy and contractility. In A–D, data are presented as means ± SD. In E and F, data are presented as measurements taken from each PAB and sham rat; n = 7 sham and 8 PAB rats. A two-tailed Student’s t-test was used to determine significant differences between groups. *P < 0.05 and **P < 0.005, sham vs. PAB.

Fig. 3.

A: representative images of right ventricular (RV) tissue stained with picrosirius red demonstrating collagen accumulation in pulmonary artery banded (PAB) rats. B–D: PAB rats displayed a significant increase in collagen deposition (B), an increase in the isovolumic relaxation time constant (τ Weiss; C), and a decrease in RV chamber compliance (D) compared with sham rats. E: collagen deposition in the RV was positively correlated to RV chamber compliance. Pearson’s correlation indicated the statistically significant relationship between collagen deposition and RV stiffness. In B–D, data are presented as means ± SD. In E, data are presented as measurements taken from each PAB and sham rat; n = 7–8 sham and 8–10 PAB rats. A two-tailed Student’s t-test was used to determine significant differences between groups. *P < 0.05 and **P < 0.005, sham vs. PAB.

Fig. 4.

A and B: representative electron micrographs of mitochondria from the right ventricle (RV) of sham and pulmonary artery banded (PAB) rats taken at ×5,600 (A) and ×25,000 (B) magnifications. C–E: PAB rats exhibited increased number of mitochondria per high-power field (C), decreased cross-sectional area (D), and increased RV mitochondrial mass (E) compared with sham rats. Data are presented as means ± SD; n = 5 for both sham and PAB rats. A two-tailed Student’s t-test was used to determine significant differences between groups. *P < 0.05 and **P < 0.005, sham vs. PAB.

Fig. 5.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is downregulated in the right ventricle of pulmonary artery banded (PAB) rats compared with sham rats. Hypoxanthine phosphoribosyltransferase 1 (Hprt1) was used as the housekeeping gene. Data are presented as means ± SD; n = 8 sham and 10 PAB rats. A two-tailed Student’s t-test was used to determine significant differences between groups. *P < 0.05, sham vs. PAB.

Fig. 6.

Pulmonary artery banded (PAB) rats demonstrated an elevated pressure-volume area (PVA; A), increased external work (EW; B), and reduced mechanical efficiency (EW/PVA; C) compared with sham rats. Data are presented as means ± SD; n = 7 sham and 8 PAB rats. A two-tailed Student’s t-test was used to determine significant differences between groups. *P < 0.05 and **P < 0.005, sham vs. PAB.

Fig. 7.

A–C: pressure-volume area (PVA) was correlated to right ventricular (RV) mitochondrial mass (A), number of mitochondria per high-power field (HPF; B), and mitochondrial cross-sectional area (C) in pulmonary artery banded (PAB) and sham rats. D–F: mechanical efficiency (EW/PVA) showed correlations with mitochondrial mass (D), number of mitochondria (E), and mitochondrial cross-sectional area (F). Pearson’s correlation indicated the statistically significant relationship between mitochondrial changes and RV mechanoenergetics. Data are presented as measurements taken from each PAB and sham rat; n = 5 sham and 4 PAB rats.