Sex differences in right ventricular adaptation to pressure overload in a rat model.

With severe right ventricular (RV) pressure overload, women demonstrate better clinical outcomes compared with men. The mechanoenergetic mechanisms underlying this protective effect, and their dependence on female endogenous sex hormones, remain unknown. To investigate these mechanisms and their impact on RV systolic and diastolic functional adaptation, we created comparable pressure overload via pulmonary artery banding (PAB) in intact male and female Wistar rats and ovariectomized (OVX) female rats. At 8 wk after surgery, right heart catheterization demonstrated increased RV energy input [indexed pressure-volume area (iPVA)] in all PAB groups, with the greatest increase in intact females. PAB also increased RV energy output [indexed stroke or external work (iEW)] in all groups, again with the greatest increase in intact females. In contrast, PAB only increased RV contractility-indexed end-systolic elastance (iEes)] in females. Despite these sex-dependent differences, no statistically significant effects were observed in the ratio of RV energy output to input (mechanical efficiency) or in mechanoenergetic cost to pump blood with pressure overload. These metrics were similarly unaffected by loss of endogenous sex hormones in females. Also, despite sex-dependent differences in collagen content and organization with pressure overload, decreases in RV compliance and relaxation time constant (tau Weiss) were not determined to be sex dependent. Overall, despite sex-dependent differences in RV contractile and fibrotic responses, RV mechanoenergetics for this degree and duration of pressure overload are comparable between sexes and suggest a homeostatic target.NEW & NOTEWORTHY Sex differences in right ventricular mechanical efficiency and energetic adaptation to increased right ventricular afterload were measured. Despite sex-dependent differences in contractile and fibrotic responses, right ventricular mechanoenergetic adaptation was comparable between the sexes, suggesting a homeostatic target.

Estrogen receptor-α prevents right ventricular diastolic dysfunction and fibrosis in female rats.

Although women are more susceptible to pulmonary arterial hypertension (PAH) than men, their right ventricular (RV) function is better preserved. Estrogen receptor-α (ERα) has been identified as a likely mediator for estrogen protection in the RV. However, the role of ERα in preserving RV function and remodeling during pressure overload remains poorly understood. We hypothesized that loss of functional ERα removes female protection from adverse remodeling and is permissive for the development of a maladapted RV phenotype. Male and female rats with a loss-of-function mutation in ERα (ERαMut) and wild-type (WT) littermates underwent RV pressure overload by pulmonary artery banding (PAB). At 10 wk post-PAB, WT and ERαMut demonstrated RV hypertrophy. Analysis of RV pressure waveforms demonstrated RV-pulmonary vascular uncoupling and diastolic dysfunction in female, but not male, ERαMut PAB rats. Similarly, female, but not male, ERαMut exhibited increased RV fibrosis, comprised primarily of thick collagen fibers. There was an increased protein expression ratio of TIMP metallopeptidase inhibitor 1 (Timp1) to matrix metalloproteinase 9 (Mmp9) in female ERαMut compared with WT PAB rats, suggesting less collagen degradation. RNA-sequencing in female WT and ERαMut RV revealed kallikrein-related peptidase 10 (Klk10) and Jun Proto-Oncogene (Jun) as possible mediators of female RV protection during PAB. In summary, ERα in females is protective against RV-pulmonary vascular uncoupling, diastolic dysfunction, and fibrosis in response to pressure overload. ERα appears to be dispensable for RV adaptation in males. ERα may be a mediator of superior RV adaptation in female patients with PAH.NEW & NOTEWORTHY Using a novel loss-of-function mutation in estrogen receptor-α (ERα), we demonstrate that female, but not male, ERα mutant rats display right ventricular (RV)-vascular uncoupling, diastolic dysfunction, and fibrosis following pressure overload, indicating a sex-dependent role of ERα in protecting against adverse RV remodeling. TIMP metallopeptidase inhibitor 1 (Timp1), matrix metalloproteinase 9 (Mmp9), kallikrein-related peptidase 10 (Klk10), and Jun Proto-Oncogene (Jun) were identified as potential mediators in ERα-regulated pathways in RV pressure overload.

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

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.