Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ET _A ) Receptor Blockade in Chronic Heart Failure

Abstract

Background— The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET A antagonist darusentan in addition to modern standard therapy in patients with CHF. Methods and Results— A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure ≥12 mm Hg, and a cardiac index ≤2.6 L · min −1 · m −2 were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment ( P <0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly ( P =0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. Conclusions— This study demonstrates for the first time in a large patient population that 3 weeks of selective ET A receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET A blockade is beneficial in CHF.

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

“…These findings of ET-1-induced diminished contractile function are parallel with previously reported in vivo effects (26). Also consistent with our findings, several clinical trials [Endothelin Antagonism with Bosentan and Lowering Events (ENABLE), Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH), Randomized Intravenous TeZosentan Study (RITZ-4), and Heart Failure ET A Receptor Blockade Trial (HEAT)] have shown that systolic function and cardiac contractility are maintained by ET-1 receptor blockade, yet unfortunately morbidity and mortality were not improved (25,34,42). These studies evaluated patients with extensive myocardial remodeling (New York Heart Association class II to IV) with the intent of ameliorating progressive deterioration of existing ventricular dysfunction.…”

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

“…These results explain how ET A i improves local NE homeostasis as also shown in DS rats on a high-salt diet. However, why did selective ET A i not result in reduced plasma NE levels in HF patients (11,31)? This discrepancy might be explained by the idea that plasma NE levels are not ideal surrogates for the local cardiac adrenergic drive but rather serve as a marker for a generalized sympathetic activation.…”

Clinical and Hemodynamic Effects of Endothelin Receptor Antagonists in Patients With Heart Failure

“…28) Previous experimental studies have suggested that increased ET-1 and subsequent activation of ET A receptors played a key role in the pathophysiological changes in HF and blockade of the ET system with ERA could effectively ameliorate survival, LV dysfunction, and ventricular remodeling in acute or cardiomyopathy HF models. [29][30][31] Furthermore, several clinical trials confirmed the ability of ERA to improve the hemodynamics of HF [14][15][16] and a recent study 11) found that sitaxsentan was likely to increase exercise tolerance in HFpEF patients. However, the effect of ERA on clinical outcomes of HF patients needs to be further evaluated.…”

“…After title and abstract screening, 2,972 were excluded and 40 potentially relevant articles were retrieved for full text evaluation. In the end, 25 were excluded (Supplementary Table I) and 15 2,9,11,[14][15][16][17][18][20][21][22][23][24][25][26] RCTs that met the predetermined criteria were included in the present study. Major characteristics of the included RCTs are summarized in the Table. In general, the 15 studies, covering a total of 3,624 patients, were published between 1998 and 2013.…”

“…13) Several randomized controlled trials (RCT) have suggested that both non-selective and selective ERAs could alleviate pulmonary and systemic vascular resistance, and increase cardiac index and left ventricular ejection fraction (LVEF) in patients with HF. [14][15][16] In addition, a recent study has demonstrated that sitaxsentan might increase the exercise tolerance in patients of HF with preserved ejection fraction (HFpEF).…”