Prevention of diastolic heart failure by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart

Abstract

Objectives  

Despite the clinical frequency of diastolic heart failure, its therapeutic strategy has not been established. Our recent study demonstrated activation of the endothelin (ET) system in a diastolic heart failure model with hypertension. Several studies have reported that ET type A (ET_A) receptor antagonist improves systolic function and prevents systolic heart failure; however, its effects on diastolic heart failure are unknown. We investigated the effects of chronic administration of ET_A receptor antagonist in diastolic heart failure.

Design and methods  

Dahl-Iwai salt-sensitive rats fed on a high-salt diet from 7 weeks of age, in which congestive heart failure develops following hypertension without cardiac chamber dilatation or systolic dysfunction, were divided into groups with and without administration of a subdepressor dose of ET_A receptor antagonist.

Results  

Hypertension induced compensatory left ventricular (LV) hypertrophy at 13 weeks in six untreated rats. Persistent pressure overload developed progressive LV hypertrophy and fibrosis from 13 to 19 weeks, resulting in elevated LV filling pressure and increased lung weight. Chronic ET_A receptor blockade did not restrain compensatory LV hypertrophy at 13 weeks; however, it attenuated LV hypertrophy and fibrosis thereafter (n = 6). These beneficial effects resulted in the maintenance of normal LV filling pressure without changes in LV end-diastolic diameter, indicating prevention of LV stiffening.

Conclusions  

Chronic ET_A receptor blockade is likely to exert beneficial effects in diastolic failure through attenuation of the progression of LV hypertrophy and fibrosis.