Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis
Rui‐Sheng Wang, Shi Huang, Stephen W. Waldo, Edward Hess, Madhura Gokhale, Shelsey W. Johnson, Katarina Zeder, Gaurav Choudhary, Jane A. Leopold, William M. Oldham, Gábor Kovács, Matthew S. Freiberg, Ryan J. Tedford, Bradley A. Maron, Evan L. Brittain
Abstract
Abstract Rationale Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006–September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998–December 20, 2013). Measurements and Main Results From an N of 4,737 complete case patients with mPAP of 19–24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9–61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ≥19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7–73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570–1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ≥3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ≥3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2–69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671–3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55–0.62; P < 0.001) and 49% (95% confidence interval, 0.38–0.69; P < 0.001) improvements in survival were observed for PAC ≥3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ≥3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.