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).

Objectives: 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.

Keywords: diastolic pressure gradient; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; isolated post-capillary pulmonary hypertension; pulmonary arterial hypertension.

Figure 1. Flow Diagram for Patient Categorization

This schematic represents the initial dataset and subsequent exclusions. The disease classification is according to the 5^th World Symposium on Pulmonary Hypertension. All units are mm Hg, unless stated otherwise. Cpc-PH = combined post-capillary and pre-capillary pulmonary hypertension; COPD = chronic obstructive pulmonary disease; DPG = diastolic pressure gradient; ICD-9 = International Classification of Diseases, 9^th edition; ILD = interstitial lung disease; Ipc-PH = isolated postcapillary pulmonary hypertension; mPAP = mean pulmonary artery pressure; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; PAWP = pulmonary arterial wedge pressure; RHC = right heart catheterization; WHO = World Health Organization.

Figure 2. Unadjusted Survival Analysis for Patients With Cpc-PH, Ipc-PH, and PAH

Unadjusted survival between Cpc-PH, Ipc-PH, and PAH is no different (p>0.05 by log rank test). Abbreviations as in Figure 1.

Central Illustration. Cpc-PH and PAH Patients: Clinical and Genetic Similarities

Despite a similar prevalence of systemic, vascular, and cardiac comorbidities, Cpc-PH patients develop more severe pulmonary vascular disease at a younger age than Ipc-PH patients. When compared with Ipc-PH patient controls, we identified 141 SNPs shared between Cpc-PH and PAH patients. These SNPs were associated with genes that are highly expressed in lung tissue and involve gene ontology groups previously implicated in PAH pathophysiology, such as cytoskeletal structure and function. Cpc-PH = combined post-capillary and pre-capillary pulmonary hypertension; Ipc-PH = isolated post-capillary pulmonary hypertension; LV = left ventricular; PAH = pulmonary arterial hypertension; SNP = single-nucleotide polymorphism.