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

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.