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 PH (Ipc-PH) and combined post-capillary and pre-capillary PH (Cpc-PH). Little is known about the clinical or physiological characteristics that distinguish these 2 subphenotypes, and if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH). Objectives We sought to test the hypothesis that the hemodynamic and genetic profile of Cpc-PH would more closely resemble PAH than Ipc-PH. Methods We used Vanderbilt’s electronic medical record linked to a DNA biorepository to extract demographics, clinical data, invasive hemodynamics, echocardiography, and vital status for all patients referred for right heart catheterization between 1998 and 2014. We identified shared genetic variants between PAH and Cpc-PH compared with Ipc-PH using pre-existing single-nucleotide polymorphism data. Results We identified 2,817 patients with PH (13% Cpc-PH, 52% Ipc-PH, and 20% PAH). Cpc-PH patients were on average 6 years younger, with more severe pulmonary vascular disease than Ipc-PH patients, despite similar comorbidities and prevalence, severity, and chronicity of left heart disease. After adjusting for relevant covariates, the risk of death was similar between Cpc-PH and Ipc-PH (HR: 1.14, 95% CI: 0.96 to 1.35, p = 0.15) when defined by 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 Cpc-PH patients develop pulmonary vascular disease similar to PAH patients, despite younger age and similar prevalence of obesity, diabetes mellitus, and left heart disease compared with Ipc-PH patients. 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.

Hemodynamic Phenotyping of Pulmonary Hypertension in Left Heart Failure

“…36 Biological support for a Cpc-PH phenotype was recently provided by an analysis of a large database of 2817 PH patients from Vanderbilt University in Nashville. 37 In that study, patients with Cpc-PH were younger but with more severe pulmonary vascular disease than patients with Ipc-PH, despite similar comorbidities and prevalence, severity, and chronicity of LHD, and presented with 75 exonic single-nucleotide polymorphisms enriched in pathways involving cell structure, extracellular matrix, and immune function that were shared with PAH and not with Ipc-PH patients.…”

“…37,38 In the database of the Medical University of Vienna, independent predictive capability of DPG by multivariate analysis was significant in both diastolic HF (DHF)/ HF with preserved ejection fraction (EF) and systolic HF (SHF)/HF with reduced EF, even when the definition included a PVR >3 WU. However, PVR alone was a predictor of outcome in HF with reduced EF but not in HF with preserved EF (Figure 3).…”

Lack of a Tricuspid Regurgitation Doppler Signal and Pulmonary Hypertension by Invasive Measurement

“…We extracted clinical and hemodynamic data from all adult patients undergoing RHC at Vanderbilt between 1998 and 2014. The method of data extraction has been described in detail elsewhere 9, 10, 11. We included only subjects who underwent a TTE within 2 calendar days before or after RHC.…”

“…If a subject had multiple RHCs, we only included data from the first procedure in this analysis. Right ventricular (RV) size and systolic function on TTE were graded in a semiquantitative manner (ie, normal, mild, moderate, severe), as previously reported 9. These data were generated from the clinical TTE reports and thus reflect the expert opinion of the interpreting echocardiographer.…”

“…The prevalence of PH in patients without a measurable TR jet on TTE is also unknown in part because such patients are excluded from correlation studies 6. The absence of a TRV on echocardiography has been equated with an absence of significant PH, and previous studies have suggested that elevated TRV on TTE was sufficient to detect the majority of PH 7, 8, 9. Clinicians would benefit from better information regarding the risk of PH when the screening TTE cannot provide an estimate of pulmonary pressures.…”