DEFINING SEX-BASED DIFFERENCES IN CARDIOPULMONARY RESPONSE TO SLOW-PROGRESSIVE PRESSURE OVERLOAD

Abstract

Approximately 50% of patients are classified as having heart failure with preserved ejection fraction (HFpEF). While HFpEF was formerly known as diastolic heart failure, it is now recognized as a complex syndrome characterized by impaired left atrial (LA) function and enlargement, increased left ventricle (LV) wall thickness, and elevated levels of natriuretic peptides sometimes accompanied by systolic dysfunction. Patients have a high prevelance of combordities, including systemic pulmonary hypertension, diabetes mellitus, atherosclerosis, and renal dysfunction. HFpEF is more prevalent in females compared to males. There are well known differences in the cardiac structure and morphology of male and females but how these sex-based differences are exacerbated, and the underlying mechanisms are unknown.Our lab has previously shown that aortic banding induced slow progressive pressure overload (PO) in male felines recapitulates key clinical features human HFpEF. PO in males induced a cardiopulmonary phenotype, including signs and symptoms of HF, elevated NT-proBNP, LA enlargement and dysfunction, LV hypertrophy and diastolic dysfunction, and pulmonary hypertension. Since male felines develop a robust response to PO, it became clear that evaluating the female response to PO was the next step. The goal of this study was to define any critical differences in the cardiopulmonary phenotype between male vs. female felines after slow progressive pressure overload. Female and male kittens underwent aortic banding or sham (normal) surgery following baseline echocardiography (ECHO), pulmonary function testing (PFT), and blood sampling. ECHO, PFT, and blood samples were repeated at 2- and 4-months post-surgery to allow for serial assessment of cardiopulmonary changes. At 4-months post surgery, terminal studies were performed and included invasive hemodynamics, pulmonary mechanics, and blood gas analyses. After all functional data was aquired, tissue was collected for morpholigcal analysis via histology, proteomic analysis via extracellular matrix mass spectrometry (ECM MS), and transcriptional profiling via singlue nucleus RNA sequencing (snRNAseq). Despite females weighing less at 4-months post-banding, both sexes of animals developed a comparable peak systolic pressure gradient across the arotic band, confirming comparable PO. LV EF was preserved throughout the entire study in all groups. Female and male banded animals developed comparable increased LV wall thickness, myocyte cross-sectional area, and heart weight to body weight ratio, all indicative of cardiac hypertrophy. Both sexes of banded animals had decreased LA EF and increased LA end systolic volume. While banded females did not develop elevated LV filling pressures like banded males, they had prolongation of tau, which is another parameter of diastolic dysfunction. Female and male banded animals had similar percentages LV fibrotic area, which developed in a gradient decreasing from the endocardium to epicardium. Both sexes had decreased pulmonary compliance at 4-months post-banding, with trends towards abnormal pulmonary function and structure in several other parameters. These results show that in a model of slow progressive PO, female and male felines develop a similar cardiopulmonary phenotype.