title: Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a common and morbid complication of left heart disease with 2 subtypes: isolated post-capillary pulmonary hypertension (Ipc-PH) and combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Little is known about the clinical or physiological characteristics that distinguish these 2 subphenotypes or if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH).
  
  
  OBJECTIVE
  The goal of this study was to test the hypothesis that the hemodynamic and genetic profile of Cpc-PH would more closely resemble PAH than Ipc-PH.
  
  
  METHODS
  Vanderbilt University's electronic medical record linked to a DNA biorepository was used to extract demographic characteristics, clinical data, invasive hemodynamic data, echocardiography, and vital status for all patients referred for right heart catheterization between 1998 and 2014. Shared genetic variants between PAH and Cpc-PH compared with Ipc-PH were identified by using pre-existing single-nucleotide polymorphism data.
  
  
  RESULTS
  A total of 2,817 patients with PH (13% Cpc-PH, 52% Ipc-PH, and 20% PAH) were identified. Patients with Cpc-PH were on average 6 years younger, with more severe pulmonary vascular disease than patients with Ipc-PH, despite similar comorbidities and prevalence, severity, and chronicity of left heart disease. After adjusting for relevant covariates, the risk of death was similar between the Cpc-PH and Ipc-PH groups (hazard ratio: 1.14; 95% confidence interval: 0.96 to 1.35; p = 0.15) when defined according to diastolic pressure gradient. We identified 75 shared exonic single-nucleotide polymorphisms between Cpc-PH and PAH enriched in pathways involving cell structure, extracellular matrix, and immune function. These genes are expressed, on average, 32% higher in lungs relative to other tissues.
  
  
  CONCLUSIONS
  Patients with Cpc-PH develop pulmonary vascular disease similar to patients with PAH, despite younger age and similar prevalence of obesity, diabetes mellitus, and left heart disease compared with patients with Ipc-PH. An exploratory genetic analysis in Cpc-PH identified genes and biological pathways in the lung known to contribute to PAH pathophysiology, suggesting that Cpc-PH may be a distinct and highly morbid PH subphenotype.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address: tufik.r.assad@vanderbilt.edu.
authors.forename: Tufik R
authors.initials: TR
authors.lastname: Assad
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Larkin
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Glazer
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Vanderbilt Center for Translational and Clinical Cardiovascular Research, Vanderbilt University School of Medicine, Nashville, Tennessee; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Quinn S
authors.initials: QS
authors.lastname: Wells
authors.affiliation: Vanderbilt Center for Translational and Clinical Cardiovascular Research, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Farber-Eger
authors.affiliation: Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Quanhu
authors.initials: Q
authors.lastname: Sheng
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee; Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Harrell
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.affiliation: Vanderbilt Center for Translational and Clinical Cardiovascular Research, Vanderbilt University School of Medicine, Nashville, Tennessee; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Evan L
authors.initials: EL
authors.lastname: Brittain
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D006328:Cardiac Catheterization; D004452:Echocardiography; D005260:Female; D005838:Genotype; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000453:epidemiology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D015996:Survival Rate / Q000639:trends; D013714:Tennessee / Q000453:epidemiology
chemical_list: D015415:Biomarkers
keywords: diastolic pressure gradient; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; isolated post-capillary pulmonary hypertension; pulmonary arterial hypertension