New Metabolites Associated With Hemodynamic Indicators of Right Ventricular-Pulmonary Vascular Dysfunction Discovered

New metabolites associated with hemodynamic indicators of right ventricular-pulmonary vascular (RV-PV) dysfunction have been discovered, according to a study recently published by the Journal of American College of Cardiology.

Previous research has pointed to a maladaptive imbalance between pulmonary vasodilators and vasoconstrictors in RV-PV dysfunction. “PV remodeling and right ventricular hypertrophy have been associated with a potential switch from fatty acid oxidation to glycolysis, which provides further motivation to apply a more global metabolite profiling approach to PH,” the authors noted. “Ultimately, metabolite profiling might highlight measures to redress metabolic derangements in RV-PV dysfunction.”

In the current study, researchers sought to determine whether metabolite profiling could identify plasma signatures of RV-PV dysfunction. They measured plasma concentrations of 105 metabolites in 71 individuals with right-sided heart catheterization and radionuclide ventriculography at rest and during exercise using targeted mass spectrometry.

They found 21 metabolites associated with 2 or more hemodynamic indicators of RV-PV function. In addition, circulating indoleamine 2,3-dioxygenase (IDO)-dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates, and purine metabolites were identified as novel associations of RV-PV dysfunction.  IDO-TM levels were inversely related to RV ejection fraction and well-correlated with exercise pulmonary vascular resistance (PVR) and PA pressure-flow response.

Two consecutive cohorts of patients underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring to assess dyspnea on exertion. A third cohort was prospectively enrolled, which consisted of patients who were diagnosed with right-sided heart cathetherization-proven pulmonary arterial hypertension (PAH) attributed to idiopathic, heritable, drug- or toxin-associated or connective tissue diseased-associated PAH.

The patients’ average age in both cohorts was 62 years, with slightly more females. Average exercise capacity was reduced in both the derivation and validation cohorts (peak V0₂=62% ± 13% predicted and 66% ± 14% predicated, respectively) in the hemodynamic profiles.

RV-PV dysfunction and IDO-TM associations not previously known were linked to pulmonary hypertension in this study. Likewise, plasma levels of tricarboxylic acid cycle metabolites (TCA-Ms) were closely related with hemodynamic indexes of RV-PV dysfunction.

“Metabolite profiling permits comprehensive, relatively unbiased investigation of metabolic pathways that potentially underlie complex phenotypes such as RV-PV dysfunction,” the researchers concluded. “Additional research is needed to characterize the pathophysiological pathways by which these and other metabolites contribute to pulmonary hypertension and dyspnea of hemodynamic origin.”

Reference

Lewis GD, Ngo D, Hemnes AR, et al. Metabolic profiling of right ventricular-pulmonary vascular function reveals circulating biomarkers of pulmonary hypertension. J Am Coll Cardiol. 2016;167(2):174-189. doi:10.1016/j.jacc.2015.10.072.