Sex‐Specific Gene Expression in Isolated Human Cardiomyocytes under Pressure Overload

Abstract

Cardiac hypertrophy manifests differently between men and women and there are pronounced sex differences in disease progression and outcome. To better understand remodeling and elucidate underlying mechanisms, most approaches have been limited to animal models or multicellular tissue samples. However, little is known about the role of biological sex in remodeling of human cardiomyocytes. We aimed at studying gene expression in isolated human cardiomyocytes under pressure overload hypothesizing significant sex differences. Cardiomyocytes were isolated from the left ventricular (LV) septum of aortic stenosis patients (n = 34; 50% men; 67.5 ± 9.6 years old) undergoing surgical aortic valve replacement. Patients underwent 2D‐guided M‐mode transthoracic echocardiography during the week before surgery and 20.06 ± 9.7 days after surgery. We measured with qRT‐PCR structural genes, as they are involved in cardiac hypertrophy and remodeling, thereby influencing cardiac function. The study was conducted in conformance with the Basic Principles of the Declaration of Helsinki. There was no significant difference between men and women in age, body mass index, systolic and diastolic blood pressure, co‐morbidities and medication. Preoperative 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. At similar levels of aortic valve area index between the sexes, preoperative ejection fraction (EF) was significantly lower in men than women (P = 0.01). Postoperative EF levels improved in men reaching those of women. Male cardiomyocytes had significantly higher levels of ACTC1 (P = 0.03), CTGF (P = 0.03), GATA4 (P = 0.03), GJA1 (P = 0.03), MYH6 (P = 0.02), MYL4 (P = 0.03), NFKB1 (P = 0.01), NPPA (P = 0.03) and NPPB (P = 0.05) than female cardiomyocytes. Next, we asked whether there is an association between gene expression and postoperative EF. The expression of 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) was negatively correlated with postoperative EF in men only. In conclusion, gene expression is regulated in a sex‐specific manner in isolated cardiomyocytes of aortic stenosis patients. Compared with women, men had higher levels of maladaptive remodeling factors, which may be part of the molecular mechanisms underlying the observed sex differences in cardiac function, i.e. EF. Given the male‐specific changes in EF postoperatively, cardiomyocyte‐specific gene regulation at the time of surgery might inform disease progression.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.