ROLE OF ENDOGENOUS ENDOTHELIN IN CHRONIC HEART-FAILURE - EFFECT OF LONG-TERM TREATMENT WITH AN ENDOTHELIN ANTAGONIST ON SURVIVAL, HEMODYNAMICS, AND CARDIAC REMODELING

Background Plasma levels of the vasoconstrictor peptide endothelin (ET ) are increased in chronic heart failure (CHF), and ET levels are a ma jor predictor of mortality in this disease. Thus, ET may play a delete rious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a ra t model of CHF. Methods and Results Rats were subjected to coronary ar tery ligation and were treated for 2 or 9 months with placebo or bosen tan (30 or 100 mg.kg(-1).d(-1)). Bosentan 100 mg.kg(-1) markedly incre ased survival (after 9 months: untreated, 47%; bosentan, 65%; P < .01) . Throughout the 9-month treatment period, bosentan significantly redu ced arterial pressure and heart rate. After 2 or 9 months of treatment , the ET antagonist reduced central venous pressure and left ventricul ar (LV) end-diastolic pressure as well as plasma catecholamines, urina ry cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume r elationship ex vivo). Echocardiographic studies performed after 2 mont hs showed that the ET antagonist reduced hypertrophy and increased con tractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg.kg(-1)), which had no major hemodynamic or structural effects, als o had no effect on survival. Conclusions Long-term treatment with an E T antagonist markedly increases survival in this rat model of CHF. Thi s increase in survival is associated with decreases in both preload an d afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatm ent with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.