Abstract
Abstract Background Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms may be 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 pulmonary arterial hypertension (PAH) patients and their clinical significance are still unknown. Methods and results Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in treatment-naïve PAH patients (n=43) and healthy controls (n=111). Melatonin levels were higher in PAH patients when compared with controls (Median 118.9 [IQR 109.3–147.7] versus 108.0 [102.3–115.2] pM, P<0.001) (Figure 1A). The overall mortality was 26% (11/43) during a median long-term follow-up of 42 [IQR: 32–58] months. When PAH patients were stratified into 4 groups according to the quartiles of melatonin levels, the mortality from below 1st quartile to above 4th quartile was 55% (6/11), 10% (1/10), 0% (0/12), and 40% (4/10), respectively (Figure 1B). Kaplan-Meier analysis further showed that patients with melatonin levels below the 1st quartile (<109.3 pM) had a worse long-term survival than patients with melatonin levels above the 1st quartile (Mean survival times were 46 [95% CI: 30–65] versus 68 [58–77] months, Log-rank, p=0.026) (Figure 1C). Conclusion Endogenous melatonin levels were increased in treatment-naïve PAH patients, and lower levels of melatonin were associated with worse long-term survival in patient with PAH, however, whether exogenous melatonin supplements may be effective as a therapeutic strategy in human PAH remains to be established. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.
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
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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