Gender differences in hearts subjected to decreased NO-production and elevated blood pressure

Abstract

Hypertension is one of the most important risk factors for heart failure in the general population. Hypertensive heart failure is associated with heart failure with preserved ejection fraction (HFpEF). Women have an increase proportion of HFpEF compared to men. Endothelial dysfunction thereby reduced NO production is proposed to play an important role in the pathophysiology of HFpEF. A suggested aetiology is related to cGMP´s important roles in myocardial cells. Females normally have higher constitutively activity of NOS and thereby NO production, an important stimulator of sGC and thereby cGMP. PKG1 is a cGMP-regulated protein that has cardio protective effects in rodents. In this experimental study we wanted to investigate gender differences when NOS was blocked. Adult rats, males, females and ovariectomized females were treated with L-NAME in drinking water for 4 weeks. Blood pressure was measured, and hearts investigated by echocardiography, histology and gene expression analysis at endpoint. MAP increased in all treatment groups; the increase was significantly larger in Males and Females Ovariectomized (OVX) compared to Females. Histological analysis of collagen showed no increase in interstitial or perivascular collagen. Gene expression analysis showed an increase in fibrosis genes, ANF and BNP, most pronounced in Females OVX and intact Females. There was also an isoform shift of MHC, more pronounced in Females OVX. Echocardiography showed a higher relative increase in LV mass in intact Females than Males. There was an increase in LV mass in all treatment groups, but no changes in diastolic or systolic diameter, suggesting concentric remodeling. There were no clinical signs of heart failure in treatment groups and cardiac output was maintained.This study confirm that with loss of NO production females developed more hypertrophy than males independent of blood pressure. Females also tended to have more extreme changes in expression of genes related to heart failure compared to males.