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. 2016 Nov;9(11):e003381.
doi: 10.1161/CIRCHEARTFAILURE.116.003381.

Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction

Maria Valero-Munoz  1 , Shanpeng Li  1 , Richard M Wilson  1 , Batbold Boldbaatar  1 , Marc Iglarz  1 , Flora Sam  2
Affiliations

Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction

Maria Valero-Munoz et al. Circ Heart Fail. 2016 Nov.

Abstract

Background: Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension.

Methods and results: In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF.

Conclusions: These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF.

Keywords: endothelin receptor antagonists; endothelin-1; heart failure, diastolic; hypertrophy, left ventricular; myocytes, cardiac.

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Figures

Figure 1
Figure 1
Serum endothelin (ET)-1 levels in patients with heart failure with preserved ejection fraction (HFpEF). A, ET-1 levels are increased in patients with chronic, stable HFpEF (n=30) vs controls (n=10), and (B) in a subcohort (n=26) of only those patients with hypertension-associated HFpEF (HTN-HFpEF).
Figure 2
Figure 2
Pharmacological inhibition of endothelin (ET)-1 reduced cardiac hypertrophy in heart failure with preserved ejection fraction (HFpEF) mice. A, Representative macroscopic and microscopic (hematoxylin-eosin staining, ×20) images of the heart from sham and HFpEF mice fed a normal chow or treated with macitentan (30 mg/kg per day) for 2 weeks; scale bar is 25 mm and 25 μm, respectively. B, Heart weight:body weight ratio. C, Cardiomyocyte size and atrial natriuretic peptide (anp). D, Brain natriuretic peptide (bnp). E, Relative mRNA expression in the left ventricle of Sham and HFpEF mice fed a normal chow (NC) or chow mixed with macitentan (MC; 30 mg/kg per day) for 2 weeks. n=5 to 10 mice per group. Data shown as mean±SEM.
Figure 3
Figure 3
Pretreatment with macitentan (MACI 10 μmol/L) prevented hypertrophy in cardiac myocytes via myocyte enhancer factor 2 (MEF2). A, Adult rat ventricular cardiac myocyte (ARVM) relative size and representative microscopic images (×10). B, Relative mRNA expression of hypertrophic signaling pathway markers: gata4, mef2a, mef2c, myocardin, and nfat. Histogram bars represent the mean±SEM of n=4 to 6 experiments. C, Simplified diagram of the proposed mechanism of action of MACI on the regulation of cardiomyocyte hypertrophy. ALDO indicates aldosterone (1 μmol/L); and CT, control.
Figure 4
Figure 4
Pharmacological inhibition of endothelin (ET)-1 reduces cardiac fibrosis and stiffness in heart failure with preserved ejection fraction (HFpEF) mice. Fibrosis quantification of pricosirius red staining and representative microscopic images (×20; A), and relative mRNA expression of tgfβ (B), collagen 1 (C) and collagen 3 (D), and collagen 1:collagen 3 ratio (E) in left ventricular tissue of Sham and HFpEF mice fed a normal chow (NC) or treated with macitentan (MC; 30 mg/kg per day) for 2 weeks. n=5 to 10 mice per group. Data shown as mean±SEM. MACI indicates macitentan; n.s., not significant; and ROI, regions of interest.
Figure 5
Figure 5
Effect of pharmacological inhibition of endothelin (ET)-1 in heart failure with preserved ejection fraction (HFpEF) mice. Relative mRNA expression of titin transcription variant n2ba (A) and n2b (B) in the left ventricle of Sham and HFpEF mice fed a normal chow (NC) or treated with macitentan (MC; 30 mg/kg per day) for 2 weeks. n=5 to 10 mice per group. Data shown as mean±SEM. n.s. indicates not significant.
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