Search

BACKGROUND The age of patients with pulmonary arterial hypertension (PAH) has increased, with registries now reporting mean ages of 50 to 65 years old. Limited data exist on age-related differences in hemodynamic and functional assessments in PAH. METHODS Adults with PAH in the Pulmonary Hypertension Association Registry were divided into 3 groups (18–50, 51–65, and >65 years old). Analysis of variance and chi-square testing were used to assess for baseline differences. Linear regression was used to examine the association of age with continuous hemodynamic and functional variables. RESULTS A total of 769 patients with mean age of 56 ± 16 years were included. Older patients had more connective tissue disease–associated PAH and less drug-associated PAH. In linear regression models, each year of increased age was associated with shorter 6-minute walk distance (−3.37 meters; 95% CI, −3.97 to −2.76), lower mean pulmonary arterial pressure (−0.21 mm Hg; 95% CI, −0.27 to −0.15), and lower pulmonary vascular resistance (−0.06 Wood units; 95% CI, −0.09 to −0.04). Pulmonary arterial compliance, cardiac index, right ventricular stroke work index, and percent predicted 6-minute walk distance were unrelated to age; resistance-compliance time was negatively related to age (−3 milliseconds per year; 95% CI, −4 to −2). CONCLUSIONS Relative to their pulmonary vascular resistance, older patients have lower pulmonary artery compliance and worse right ventricular performance. Based on these findings, we suspect that age influences right ventricular loading conditions and the response of the right ventricle to increased afterload.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a complex disease that lacks adequate therapies. Recognition that endothelial and smooth muscle cell hyper-proliferation contribute to the pathophysiology has drawn parallels to cancer biology and highlighted shared alterations in growth signaling and metabolism. Similar to the Warburg Effect described in malignancies, smooth muscle and endothelial cells exhibit a phenotype of aerobic glycolysis in the setting of PAH. Objective: We hypothesize that in an animal model of increased pulmonary blood flow and early pulmonary vascular disease, smooth muscle cells from the central pulmonary arteries will exhibit metabolic alterations similar to the Warburg Effect. DESIGN/METHODS: Fetal lambs underwent surgical placement of an aortopulmonary shunt resulting in a postnatal increase in pulmonary blood flow. Smooth muscle cells (PASMCs) from the central PAs were isolated for analysis. Extracellular flux analysis was used to measure concurrent oxygen consumption and extracellular acidification. Targeted metabolites were measured using HPLC-mass spectrometry. Results: PASMCs from the shunted animals exhibit faster growth and a shorter calculated doubling time (29.5 vs. 45.2 hours). PASMCs derived from shunted animals had a 55% decrease in oxygen consumption rate and a 59% decrease in extracellular acidification rate. This is accompanied by a relative decrease in the mitochondrial membrane potential in the shunt cells compared to controls. Metabolic analysis shows increases in the PPP metabolites erythritol, S7P and R5P/X5P, decreases in the glycolytic metabolites Fru1,6BP and PEP, decreased malate in the TCA cycle and accumulation of acetyl-CoA in shunted cells compared to controls. Conclusions: PASMCs from lambs with pulmonary overcirculation and early PAH have a phenotype of hyper-proliferation and altered metabolism. The low rate of oxygen consumption and extracellular acidification suggest concurrent decreases of both mitochondrial respiration and glycolytic flux. Targeted metabolite analysis suggests increased glucose entry into the pentose phosphate shunt rather than glycolysis and relative depletion of TCA cycle intermediates may underlie these observed changes.