Abstract 4140630: Serum Metabolites Predict Mortality or Transplant in Pre-capillary and Combined Pre- and Post-capillary Pulmonary Hypertension in the PVDOMICS Cohort

Introduction: Efforts to stratify mortality risk in pulmonary hypertension (PH) have focused on the minority of patients in WSPH group 1. Metabolomic studies in group 1 identify histidine, polyamines, tRNA metabolites, and homoarginine as predictors of mortality. Little is known about the role of metabolomics to predict mortality in the larger group of PH patients. Question: Which serum metabolites predict a composite of mortality or transplant in pre-capillary, post-capillary, and combined pre- and post-capillary PH (Cpc-PH), irrespective of WSPH group? Aims: To identify predictive metabolites in the Pulmonary Vascular Disease Phenomics Program (PVDOMICS) cohort and understand the pathobiology relating predictors to mortality/transplant. Methods: We generated peripheral venous metabolomic data in 649 PH subjects. We defined pre-capillary PH as pulmonary vascular resistance (PVR)>2 WU and pulmonary capillary wedge pressure (PCWP)≤15 mmHg (n = 453), post-capillary PH as PVR≤2 WU and PCWP>15 mmHg (n=25), and Cpc-PH as PVR>2 WU and PCWP>15 mmHg (n = 171). We used Cox models with multiple testing correction to identify predictive metabolites in each group. We then correlated select predictors with hemodynamic, laboratory, and echocardiographic data. Results: The hemodynamic groups included a mix of WSPH groups. We identified 249 predictors in pre-capillary PH, 0 in post-capillary PH, and 7 in Cpc-PH. Homoarginine predicts mortality/transplant in pre-capillary PH (HR=0.56, p<0.001) and Cpc-PH (HR=0.59, p=0.025). In pre-capillary PH, low homoarginine is associated with high PVR (r=-0.26, p<0.001), high BNP (r=-0.49, p<0.001), RV dilation (p<0.001 for moderately dilated, p<0.001 for severely dilated vs. normal), and RV free wall longitudinal strain (r=-0.31, p<0.001). Conclusions: Many metabolites predict mortality/transplant in pre-capillary PH and Cpc-PH, including those previously identified in group 1 as well as newly identified predictors. To our knowledge, this is the first report of such predictors in hemodynamic subsets rather than in WSPH groups. Our data suggest low homoarginine contributes to increased PVR, RV failure, and mortality/transplant in pre-capillary PH. More studies on homoarginine are needed.