Circulating Angiogenic Modulatory Factors Predict Survival and Functional Class in Pulmonary Arterial Hypertension

Abstract

The diagnosis of pulmonary arterial hypertension (PAH) is frequently delayed. We hypothesized that circulating angiogenic modulatory protein levels might correspond with vascular remodeling activity and serve as sensitive biomarkers of PAH. Levels of soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR1), N-terminal brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and other biomarkers were measured in peripheral blood from 97 PAH patients, 16 first-degree relatives of idiopathic or heritable pulmonary arterial hypertension (HPAH) patients, and 56 controls, and correlated with disease, functional class, hemodynamic parameters, exercise capacity, and transplant-free survival. Endoglin expression was analyzed in lung tissues of six individuals with idiopathic or HPAH and four individuals without PAH. Levels of sEng, sVEGFR1, CRP, and NT-proBNP were elevated in Group I PAH of diverse etiologies, with sEng performing better than NT-proBNP in detecting PAH (receiver operator characteristic-area-under-the curve [ROC-AUC] of 0.82 ± 0.03 vs. 0.71 ± 0.05, P = 0.016). While sEng, sVEGFR1, and NT-proBNP correlated with New York Heart Association (NYHA) class, sEng levels were more sensitive than NT-proBNP in detecting NYHA Class I-II disease (ROC-AUC of 0.88 ± 0.05 vs. 0.67 ± 0.08, P = 0.028). sEng, sVEGFR1, CRP, and NT-proBNP predicted transplant-free survival by univariate Cox regression. After adjusting for NT-proBNP levels, each of the other three markers predicted transplant-free survival. In multivariate analysis, sEng and CRP were independent predictors of survival. Endoglin expression was markedly enhanced in the microvascular endothelium and endovascular lesions of PAH versus control lung tissues. Circulating angiogenic proteins sEng and sVEGFR1 are sensitive markers of prognosis and function in Group I PAH, including mildly symptomatic disease, and may provide unique noninvasive data reflecting underlying remodeling activity.

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

“…74 The second paradox that characterizes the SuHx rat model is that the proliferative lung microangiopathy is paired with the antiangiogenic environment of the failing RV.…”

Is Elevated Circulating Galectin-3 Level A Predictor of Pulmonary Artery Hypertension Development and Progression?

“…Although clinical features, hemodynamic parameters, echocardiography patter, multi-spiral computer tomography findings, exercise capacity, and anti-nuclear antibody profiles were found as powerful factors predicted a development of PAH due to several diseases [8], the reliability, sensitivity, specificity and predictive value are derived from PAH patients with different comorbidities and specific complications associated with CTD, congenital heart disease and respiratory disease might be unacceptable [9]. In this context, taken into consideration pathophysiological heterogeneity of PAH to risk stratification based on biological markers (N-terminal pro-brain natriuretic peptide, red cell distribution width, soluble endoglin, growth differentiation factor-15, interleukin-6, soluble vascular endothelial growth factor receptor-1, C-reactive protein, pentraxin 3) reflected several faces of nature evolution of the disease might be useful and appears to be attractive [10][11][12][13]. Although several biomarkers are widely investigated for risk stratification around patients with PAH, there are several limitations to clinical use associating with higher biological variability and cost, low specificity, lack direct evidence regarding prediction of clinical status and outcomes.…”

Inflammation in chronic thromboembolic pulmonary hypertension: accomplice or bystander in altered angiogenesis?

“…These casual but intriguing observations certainly present an element of conundrum since on one hand vascular channels and recanalisation are thought to be driven by growth factors such as VEGF [30], and on the other hand angiogenic modulatory proteins with inflammatory properties (e.g. soluble endoglin and VEGF receptor-1) are elevated in PAH and predict poor outcome [25]. Importantly, from a mechanistic standpoint, the attempt by the authors to link inflammation, altered angiogenesis and clinical outcome (a tall order to be sure) falls somewhat short in this clinical study for the obvious limitations an observational clinical study presents.…”

“…Similarly, various markers of inflammation such as cytokines and chemokines are expressed in human disease, as well as in animal models of PH, in the lung tissue or in the circulation [16][17][18][19][20][21], and circulating antibodies have been detected [11,[22][23][24]. Many of these inflammatory biomarkers can predict survival [13,25,26].…”