Title: A Tale of Two Sexes: Exploring Differences in Right-Sided Heart Failure in a Porcine Model

Introduction: Right-sided heart failure (RHF) exhibits notable sex-based differences, with females generally demonstrating better right ventricular (RV) function compared to males. These disparities have significant prognostic implications, especially in RV-centric diseases like pulmonary hypertension (PH), where RV dysfunction is linked to poor patient outcomes. Despite these observations, there are no therapies that specifically target the failing RV, and potential sex-based differences are understudied. Therefore, we evaluated the cellular and molecular responses to RHF in male and female pigs to identify potential sex-based differences.

Methods: 4-week-old male and female piglets underwent pulmonary artery banding (PAB) for six weeks to induce right ventricular dysfunction. Cardiac MRI changes in RV structure, function, volume, and mass. Wheat Germ Agglutinin evaluated cardiomyocyte hypertrophy. Super resolution confocal micrographs were analyzed using FIJI. Proteomics and metabolomics quantified RV metabolites and proteins. Results: Despite having the same right ventricular ejection fraction, PAB-females had greater relative RV hypertrophy and dilation as assessed by cardiac MRI. Histologically, PAB-females had a nearly two-fold increase in RV cardiomyocyte cross sectional area compared to PAB-males. All four experimental groups clustered separately on hierarchical cluster analysis, suggesting significant groupwise differences in metabolomic profiles. Levels of triacylglycerols and diacylglycerols were reduced in PAB-males and PAB-females compared to their controls. However, PAB-males had increased abundances of acylcarnitines, the mitochondrial form of fatty acids, compared to their controls, suggesting reduced fatty acid metabolism in PAB-males. Proteomics revealed reduced protein abundances in metabolic pathways in PAB-males, but not PAB-females. In addition, proteomics identified proteins in the cardiac muscle contraction pathway are upregulated in PAB-males, compared to control males, but these proteins are mostly unchanged in PAB-females compared to control females.

Conclusion: Male and female piglets exhibit different cellular and molecular responses to PAB, despite similar levels of RV dysfunction. Females have a greater hypertrophic response, less metabolic/energetic derangements, and less relative sarcomeric protein upregulation compared to male pigs.