Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension.

Zongye Cai,Daphne Merkus,Eric Boersma,Theo Klein,Christophe Guignabert,Siyu Tian,Laurie W Geenen,Dirk J Duncker,Karin A Boomars,Yolanda B De Rijke,Annemien E Van Den Bosch,Irwin K M Reiss,Ly Tu

doi:10.3390/jcm9051248

Abstract

Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2–139.9), 118.9 (109.3–147.7), 118.3 (106.8–130.1) versus 108.0 (102.3–115.2) pM, respectively, p all <0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32–58) months. Kaplan–Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2–4 (Mean survival times were 46 (95% CI: 30–65) versus 68 (58–77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1–11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.

Highlights

Pulmonary hypertension (PH) is a severe disease with a wide spectrum of underlying etiologies [1]
A total of 64 consecutive treatment-naïve adult patients with pulmonary hypertension (PH), including 43 patients with Pulmonary arterial hypertension (PAH) (Group 1) and 21 patients with chronic thromboembolic PH (CTEPH) (Group 4), diagnosed by right heart catheterization according to the guidelines between May 2012 and October 2016 were included as PH group in this prospective observational cohort study [19,20]
After correction for potential confounders, plasma melatonin still distinguished PH patients and controls, it only distinguished PAH patients but not CTEPH patients and controls (Table 3). These results indicated that plasma melatonin was only an independent risk factor for PAH, but not for CTEPH

Summary

Introduction

Pulmonary hypertension (PH) is a severe disease with a wide spectrum of underlying etiologies [1]. An increasing number of studies demonstrated that exogenous melatonin exerts protective effects in cardiovascular diseases [5,6,7], respiratory diseases [8], and cancers [9] It was already shown in 2007 that chronic hypoxia induced PH was associated with the loss of the pulmonary vasorelaxation effect of melatonin [10], while supplementation of melatonin could prevent chronic hypoxia induced PH via anti-proliferative and anti-inflammatory effects [11,12], as well as through inhibiting oxidative stress [13,14,15], restoring nitric oxide production [11], and increasing angiogenesis [16]. Melatonin was found to be cardio-protective in monocrotaline-induced PH by improving RV function and inhibiting cardiac fibrosis [16]

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