Endothelin 1 Is Associated with Heart Failure Hospitalization and Long-Term Mortality in Patients with Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension

Abstract

Background: The prevalence of pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is increasing. We aim to study the role of big endothelin 1 (Big ET1), endothelin 1 (ET1), and neprilysin (NE) in HFpEF with PH. Method: This was a single center prospective cohort study including 90 HFpEF patients; 30 with no PH, 30 with postcapillary PH, and 30 with combined post- and precapillary PH. After enrollment, pulmonary venous and pulmonary arterial samples of Big ET1, ET1, and NE were collected during right heart catheterization. Subjects were then followed long term for adverse outcomes which included echocardiographic evidence of right ventricular dysfunction, heart failure hospitalization, and all-cause mortality. Results: Patients with HFpEF-PH were found to have increased ET1 in pulmonary veins (endothelin from the wedge; ET1W) compared to controls (2.3 ± 1.4 and 1.6 ± 0.9 pg/mL, respectively). ET1W levels were associated with both PH (OR 2.7, 95% CI 1.5–4.7, p = 0.01) and pulmonary vascular resistance (OR 1.6, 95% CI 1.04–2.3, p = 0.03). No evidence of right ventricular dysfunction was observed after 1 year of follow-up. ET1W (OR 1.8, 95% CI 1.2–2.6, p = 0.01) and ET1 gradient (ET1G; OR 1.4, 95% CI 1.04–2, p = 0.03) were predictive of 1-year hospitalization. ET1G ≥0.2 pg/mL was associated with long-term mortality (log-rank 4.8, p = 0.03). Conclusion: In HFpEF patients, ET1W and ET1G are predictive of 1-year heart failure hospitalization, while elevated ET1G levels were found to be associated with long-term mortality in HFpEF. This study highlights the role of ET1 in developing PH in HFpEF patients and also explores the potential of ET1 as a prognostic biomarker.

Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities

“…Consistent with the increased ET-dependent vasoconstrictor influence on the pulmonary vasculature, circulating ET-1 levels were higher in swine with DM + HC + CKD as compared to Healthy controls suggesting either increased production or impaired clearance. The elevated ET-levels in our swine model are in accordance with human studies, showing elevated plasma ET-levels in HFpEF-PH patients correlating with PA pressures [7,36,41,53], as well as with studies from our laboratory showing that plasma ET-levels are elevated in type II PH in swine, secondary to myocardial infarction [25] or due to pulmonary vein stenosis [58]. Furthermore, wedge ET-1 levels were shown to be higher than pulmonary arterial ET-levels and correlated with PVR in patients with combined pre-and post-capillary but not isolated post-capillary HFpEF-PH [7,36], suggesting that the higher ET-1 levels in patients ET A and ET B receptors are expressed in the pulmonary circulation under both physiological and pathophysiological circumstances [15].…”

“…The elevated ET-levels in our swine model are in accordance with human studies, showing elevated plasma ET-levels in HFpEF-PH patients correlating with PA pressures [7,36,41,53], as well as with studies from our laboratory showing that plasma ET-levels are elevated in type II PH in swine, secondary to myocardial infarction [25] or due to pulmonary vein stenosis [58]. Furthermore, wedge ET-1 levels were shown to be higher than pulmonary arterial ET-levels and correlated with PVR in patients with combined pre-and post-capillary but not isolated post-capillary HFpEF-PH [7,36], suggesting that the higher ET-1 levels in patients ET A and ET B receptors are expressed in the pulmonary circulation under both physiological and pathophysiological circumstances [15]. ET A is only present on vascular smooth muscle cells, mediating vasoconstriction, whereas ET B is present on both the vascular smooth muscle cell and the endothelial cells, mediating vasoconstriction and vasodilation, respectively.…”

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

“…Perhaps there is a need to fine-tune and identify which subgroups of HF patients would have the greatest benefit from drugs interfering with ET pathways. In that regard, ET-1 and its fragments have shown some potential as valuable biomarkers among HFpEF patients with pulmonary hypertension or pulmonary dysfunction as its levels were associated with the degree of pulmonary hemodynamic derangements, reduced functional reserve of the right ventricle, diminished cardiac output and impaired cardiac response to exercise and peak oxygen consumption[ 274 , 275 ]. Even in the general population, elevated plasma ET-1 levels were in strong relation with elevated pulmonary artery systolic pressures on the echocardiogram and correlated with mortality and incident HF[ 276 ].…”

Kcnk3 dysfunction exaggerates the development of pulmonary hypertension induced by left ventricular pressure overload

“…To date, most of the molecular pathways associated with PH-LHD are assumed to be common with PAH namely endothelial dysfunction, mitochondrial dysfunction, exacerbated inflammation 11 . In PH-LHD, endothelial dysfunction is at least characterized by an increased endothelin-1 (ET-1) production in the pulmonary vasculature 12 , as well as in AAC-induced PH in rat 4 . ET-1 inhibits KCNK3 function in PASMC through Rho kinase-mediated phosphorylation 13 , linking one of the main modulators of PH-LHD (ET-1) and KCNK3-dysfunction.…”