Metabolomics of exercise pulmonary hypertension are intermediate between controls and patients with pulmonary arterial hypertension

Abstract

Mechanisms underlying pulmonary arterial hypertension (PAH) remain elusive. Pulmonary arterial hypertension and exercise PH share similar physiologic consequences; it is debated whether they share biologic mechanisms and if exercise PH represents an early phase of pulmonary arterial hypertension. We conducted an observational study to test if there is a graded metabolic disturbance along the severity of PH, which may indicate shared or disparate pathophysiology. Individuals referred to an academic medical dyspnea center with unexplained exertional intolerance underwent invasive cardiopulmonary exercise testing. We identified controls with no hemodynamic exercise limitation, individuals with exercise PH (mean pulmonary arterial pressure (mPAP) < 25 mmHg at rest but ! 30 mmHg during exercise without pulmonary venous hypertension) and pulmonary arterial hypertension (mPAP > 25 mmHg at rest without pulmonary venous hypertension) (n ¼ 26 in each group). Unbiased metabolomics with chromatography mass spectrometry was performed on pulmonary arterial blood at rest and peak exercise. Random forest analysis and hierarchical clustering were used to quantify metabolite prediction of group membership and rank metabolites which were significantly different between groups. Compared to controls, pulmonary arterial hypertension subjects exhibited perturbations in pathways involving glycolysis, TCA cycle, fatty acid and complex lipid oxidation, collagen deposition and fibrosis, nucleotide metabolism, and others. The metabolic signature of exercise PH was uniquely between that of control and pulmonary arterial hypertension subjects. Accuracy predicting control, exercise PH, and pulmonary arterial hypertension group was 96%, 90%, and 88%, respectively, using paired rest-exercise metabolic changes. Our data suggest the metabolic profile of exercise PH is between that of controls and patients with pulmonary arterial hypertension.

Metabolic Reprogramming of the Right Ventricle and Pulmonary Arteries in a Flow-Associated Pulmonary Arterial Hypertension Rat Model

“…Moreover, integrated analysis was carried out to explore shared differential metabolites as well as dysregulated metabolic pathways in PAs and the RV. Metabolic reprogramming of PAH has been previously characterized in animal models ,,, and patients. − It should be noted that most of these studies were designed to assess the metabolic profile in one particular tissue or sample, such as blood (plasma/serum), the lungs, or the RV tissue. Izquierdo-Garcia et al have used NMR-based metabolomics together with the technique of 18F-FDG PET imaging to characterize the metabolic profile in the heart and lung tissues in a PAH mouse model.…”

Influence of atorvastatin on metabolic pattern of rats with pulmonary hypertension

“…The differences of biologic mechanisms between exercise pulmonary hypertension and PAH were analyzed using metabonomics. They found that PAH group presented perturbations in several pathways such as collagen deposition, fatty acid, and glycolysis [ 16 ]. In addition, metabolomic profiles were conducted to differentiate PAH and idiopathic PAH [ 17 ].…”

Vital capacity and valvular dysfunction could serve as non-invasive predictors to screen for exercise pulmonary hypertension in the elderly based on a new diagnostic score

“…[8][9][10][11] However, before standardised treatment can be initiated, a precise and reliable definition of exPH is needed, since it seems to be a unique pathological entity, with patients displaying different alterations in biochemical pathways than resting PH patients and healthy controls. 12,13 Additionally, the kinetics of hemodynamic recovery seem to vary between different types of PH and exPH. 14 Several factors appear to limit the cardiovascular response to increased right ventricular (RV) afterload during exertion.…”