Establishment of a HFpEF model using female Dahl salt-sensitive rats: a valuable tool for elucidating the pathophysiology of HFpEF in women

Abstract

The pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unclear, and effective treatments are limited. HFpEF is more prevalent in females, indicating potential gender differences in its pathogenesis. However, no female HFpEF model animals have been established. Hypertension is a major contributor to HFpEF, and sympathetic activation is thought to play a role in both conditions. This study aimed to establish a female HFpEF model using hypertensive Dahl salt-sensitive rats and to assess the presence of sympathetic activation. Seven-week-old female Dahl salt-sensitive rats were fed an 8% high-salt diet (HS group, n = 6), while a low-salt diet group (LS group, n = 9) served as controls. The HS group exhibited increased systolic blood pressure and heart rate. Echocardiography revealed an increased left ventricular (LV) wall thickness, a decreased E/A ratio, and an increased E/e' ratio, all indicative of diastolic dysfunction without reduced LV ejection fraction. Additionally, the HS group showed elevated LV end-diastolic pressure, LV weight, and lung weight, along with histological cardiomyocyte hypertrophy and interstitial fibrosis. Gene expression markers for cardiac hypertrophy and fibrosis were also increased. Renal function was significantly impaired, and plasma norepinephrine levels were elevated, consistent with heightened pre-sympathetic neuronal activity in the brain. In conclusion, high salt loading from 7 weeks of age in female Dahl salt-sensitive rats induced hypertensive HFpEF phenotypes with LV hypertrophy and fibrosis, and sympathetic activation by 16 to 19 weeks of age. This model provides a valuable tool for studying HFpEF pathophysiology in women.

Keywords: Female; HFpEF; Hypertension; Sympathetic nervous system.