Bosentan does not improve pulmonary hypertension and lung remodeling in heart failure

Abstract

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction associated with heart failure (HF) carry a poor prognosis. Although endothelin receptor antagonists (ERAs) demonstrated benefits in pulmonary arterial hypertension, their efficacy in PH associated with HF was not specifically evaluated.2 weeks after myocardial infarction (MI) rats received bosentan (100 or 200 mg?kg -1 ?day -1 ) or no treatment for 3 weeks. PH, RV hypertrophy and function as well as lung remodeling and function were evaluated. LV echocardiographic wall motion abnormality and function measured before treatment (2 weeks after MI) and after treatment (5 weeks after MI) were similar in MI control and MI treatment groups. HF induced PH and RV hypertrophy compared with sham: RV systolic pressure 39¡5 versus 23¡0.8 mmHg and RV/left ventricular+septum weight 52¡7 versus 24¡0.5% (all p,0.01). Bosentan did not significantly modify these parameters. In addition, bosentan did not improve depressed RV function measured by echocardiograph from the RV myocardial performance index and tricuspid annular plane systolic excursion. The respiratory pressurevolume relationship revealed that HF caused a restrictive lung syndrome with histological lung remodeling and fibrosis, also not improved by bosentan.Dual ERA therapy with bosentan does not reduce PH, RV hypertrophy and lung remodeling and dysfunction associated with ischaemic HF.

Unlooked-for Significance of Cardiac Versus Vascular Effects of Endothelin-1 in the Pathophysiology of Pulmonary Arterial Hypertension

“…28 Recent work using rats with secondary PAH induced by ischemic heart failure has also shown that RV dysfunction is not improved by bosentan treatment. 29 The study by Nagendran et al 26 may partly explain why treatment with bosentan provides no significant improvement of RV dysfunction in PAH observed in those studies.…”

Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models

“…In the complex post-MI state, MCP-1 alone is unlikely to be solely responsible for lung remodelling; we have also identified elevated IL-6 levels (figure 4). Similarly, work by others has addressed other mediators, such as endothelin-1, although outcomes in both clinical trials of endothelin antagonists in HF and animal models have been negative 43 44. In addition, our modelling of the mechanical effects of PVH on the microvascular endothelium using CMS via the Flexercell system is reductionalist, but has the benefit of using HLMVECs, potential upstream targets of elevated LAP.…”

Pulmonary Vasodilation in Acute and Chronic Heart Failure: Empiricism and Evidence

“…Plasma endothelin levels correlate with the severity of HF and with pulmonary arterial pressure and PVR, and there is direct evidence that endothelin contributes to secondary PH in the presence of left ventricular systolic dysfunction [6][7][8]. The benefits of endothelin antagonist in experimental HF have been mixed [9,10]. In some studies, they facilitated favorable hemodynamic and structural changes [9].…”