Melatonin Improves Quality of Life, Oxidative Stress, and Cardiovascular Function in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) Group 1 from the World Health Organization (WHO) is a rare, severe chronic, and progressive condition. Patients with PAH have increased oxidative stress (OS) and diminished antioxidant capacity. Melatonin is a potent antioxidant hormone with reported benefits in PAH animal models. We aimed to evaluate the functional, hemodynamic, and antioxidant response to a 6-month melatonin therapy in PAH Group 1 patients. Clinical evaluation was done at baseline (BT), as well as at 3 (T3) and 6 (T6) months of melatonin treatment in stable PAH Group 1 (WHO) patients. The principal endpoint was change in walking distance (WD) in the 6-min walking test (6MWT). Secondary endpoints were functional class (FC), quality of life (QoL), performance of right ventricle (RV), and plasma antioxidant capacity. This study included 19 patients. They were mainly women in WHO FC II and III. A significant improvement was noticed in perception of dyspnea, palpitations, and fatigue in concordance with the QoL improvement in the physical domain after 6 months of melatonin. This was represented by a significant fall in the total score of the PAH-SYMPACT questionnaire. In addition, the baseline heart rate was lower at the T6 follow-up. No significant changes were seen in the echocardiographic variables. However, the biochemical analysis showed significative increases in plasma total antioxidant (2.94 ± 0.13 vs. 8.41 ± 0.19) and ferric reducing (191 ± 12 vs. 256 ± 17) capacities. Overall, oral melatonin treatment improved the plasma antioxidant capacity and the QoL in this pilot study.

Keywords: FRAP; antioxidant capacity; cardiac remodeling; life quality; pulmonary hypertension; right ventricle dysfunction.

Figure 1

Experimental design. Study timeline showing assessments at baseline (BT) and treatment Months 2–6 (T2–T6), including serial evaluations of patient wellness through echocardiography, 6‐min walking test (6MWT), and blood tests measuring both plasma antioxidant capacity as melatonin levels. Source:Figure created with BioRender.

Figure 2

Flowchart illustrating the study and patients' follow‐up. The study enrolled 24 patients with pulmonary arterial hypertension, of whom 19 (79.2%) completed the 6‐month protocol. Five participants discontinued participation due to adverse events, melatonin intolerance (n = 1), fatal massive hemoptysis (n = 1), or loss to follow‐up (n = 3). Serial evaluations were conducted at baseline (BT) and monthly intervals (T2 through T6 months) with assessments including echocardiography, 6‐min walk testing, and plasma biomarkers analysis.

Figure 3

Heart rate during the 6MWT. Bar graph representing the 6 min walking test (6MWT) heart rates (HR) grouped according to the different acquisition times (initial, final, and after 1 and 5 min of recovery) during the examination of PAH patients at baseline (BT; white bars), and after 3‐ (T3; gray bars) and 6‐ (T6; black bars) month of melatonin treatment. Significant differences (Dunnett's multiple comparisons, p ≤ 0.05): *versus BT (at same acquisition time).

Figure 4

Plasma reducing and antioxidant capacity. Histograms representing the total antioxidant capacity (TAC; A) and the ferric reducing ability (FRAP; B) of the plasma in patients with pulmonary arterial hypertension at baseline (BT; white bars), and after 3‐ (T3; gray bars) and 6‐ (T6; black bars) month melatonin treatment. Values are expressed as average ± SEM, for BT, T3, and T6. Statistical difference (ANOVA, p ≤ 0.05): *versus BT; ^†versus T3.

Figure 5

PAH‐SYMPACT outcomes. Histograms display: first, cardiovascular symptoms (A); second, cardiopulmonary symptoms (B); third, physical impact (C); and fourth, cognitive/emotional impact (D) domains, along with total composite (E) scores of patients with pulmonary arterial hypertension at baseline (BT), and after 2‐ (T2), 3‐ (T3), 4‐ (T4), 5‐ (T5), and 6‐ (T6) month melatonin treatment. Data represent mean ± SEM. *p ≤ 0.05 versus BT by ANOVA with post hoc correction.

Figure 6

Plasma melatonin levels and relationship with antioxidant capacity. Histogram of plasma melatonin levels at baseline (BT), 3 months (T3), and 6 months (T6) of treatment (A). Data represent mean ± SEM. *p ≤ 0.05 versus BT by ANOVA with post hoc correction. XY‐plot of individual melatonin levels versus total plasma antioxidant capacity (TAC) in all patients (B). The dashed trend line represents the monotonic relationship (Spearman's p = 0.6090, *p ≤ 0.05), with the linear equation superimposed.