Abstract 490: Sex-Specific Inflammatory Gene Expression in the Hypertrophied and Failing Human Heart

Abstract

Heart failure (HF) is a devastating syndrome with poor prognosis that is most often preceded by a left ventricular (LV) pressure overload (PO) disorder, such as aortic stenosis (AS). As pressure inside the LV increases, LV hypertrophy (LVH) develops. Persistent inflammation is known to be detrimental to the heart, which might promote HF. LVH manifests differently between men and women and there are pronounced sex differences in disease progression and outcome. However, the mechanisms that cause these differences are poorly understood. Hypothesizing significant sex differences, we aimed at studying the expression of inflammatory and remodeling genes in cardiomyocytes (CMs) isolated from the LV septum of AS patients ( n = 34; 50% men; 67.5 ± 9.6 years old) undergoing aortic valve replacement. Echocardiography was performed 1 week before surgery and 20.06 ± 9.7 days after surgery. Ethics committee approval and patient consent were obtained. There was no significant difference between men and women in age, body mass index, systolic and diastolic blood pressure, co-morbidities and medication. Posterior wall thickness ( P = 0.02), LV end diastolic diameter ( P = 0.007) and mass index ( P = 0.03) were higher in men than women. Preoperative ejection fraction (EF) was significantly lower in men than women ( P = 0.01). Postoperative EF levels improved in men reaching those of women. Compared to female CMs, male CMs had significantly higher levels of CTGF ( P = 0.03) and NFKB1 ( P = 0.01), as well as ACTC1 ( P = 0.03), GATA4 ( P = 0.03), GJA1 ( P = 0.03), MYH6 ( P = 0.02), MYL4 ( P = 0.03), NPPA ( P = 0.03) and NPPB ( P = 0.05). We found a negative association between gene expression and postoperative EF in men only for GATA4 ( r = -0.77, P = 0.01), GJA1 ( r = -0.69, P = 0.03), MYH6 ( r = -0.69, P = 0.04), MYH7 ( r = -0.82, P = 0.008), MYL4 ( r = -0.71, P = 0.03), NPPA ( r = -0.9, P = 0.001) and NPPB ( r = -0.79, P = 0.01). In end-stage HF, the levels of the chemokine receptor CXCR4 were higher ( P = 0.04) in LV samples of female ( n = 5) vs. male ( n = 4) patients. Collectively, in PO and HF, the expression of inflammatory and remodeling genes is regulated in a sex-specific manner, which may contribute to the mechanisms underlying sex differences in disease progression and outcome.