Depletion of vitamin D aggravates pulmonary arterial hypertension

Abstract

Background. Multiple studies have reported a worldwide deficiency of vitamin D. Epidemiological studies also suggest a relationship between vitamin D deficiency and cardiovascular diseases. Pulmonary arterial hypertension (PAH) is a severe and progressive vascular disease characterized by vasoconstriction, arterial remodelling and thrombosis. Interestingly, calcitriol, the active form of vitamin D, modulates several signalling pathways affected in PAH. The aims of this study were to investigate if vitamin D deficiency may predispose to or exacerbate PAH and to analyze the vitamin D levels and its prognostic role in PAH patients.

Methods. Male Wistar rats were fed a standard or a vitamin D-free diet for five weeks. Then, rats were further divided into controls or PAH, which was induced by a single dose of SU5416 (20 mg/Kg) and exposure to hypoxia (10% O2) for 2 weeks. 25(OH)-vitamin D plasma levels were determined in 67 patients from the Spanish PAH biobank with idiopathic, hereditary or drug-induced PAH and in 100 controls.

Results. PAH rats with vitamin D-free diet showed an increase in pulmonary pressure and increased pulmonary artery muscularization compared to PAH animals with standard diet. Pulmonary arteries from vitamin D deficient rats showed endothelial dysfunction measured as acetylcholine-induced relaxation and higher contraction to serotonin. Myocytes isolated from pulmonary arteries in vitamin D deficient rats had a reduced whole voltage-dependent potassium current density and acid-sensitive (TASK-like) currents. Vitamin D free diet induced increased lung expression of survivin and downregulated kcnk3, bmp4 and bmp6. Plasma samples from the PAH biobank presented lower 25(OH)-vitamin D and higher intact parathormone than controls. PAH patients with 25-OH-vitamin D plasma values below the median (7.3 ng/ml) in the cohort showed lower values in the 6 minute walking distance test and reduced survival (p=0.015) after sampling.

Conclusions. These findings suggest a possible pathophysiological role of vitamin D deficiency in PAH.

Supported by SAF2016-77222R and SAF2014-55399-R,