Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Damico, Rachel; Kolb, Todd M.; Valera, Lidenys; Wang, Lan; Housten, Traci; Tedford, Ryan J.; Kass, David A.; Rafaels, Nicholas; Gao, Li; Barnes, Kathleen C.; Benza, Raymond L.; Rand, James; Hamid, Rizwan; Loyd, James E.; Robbins, Ivan M.; Hemnes, Anna R.; Chung, Wendy K.; Austin, Eric D.; Drummond, M. Bradley; Mathai, Stephen C.; Hassoun, Paul M.

doi:10.1164/rccm.201409-1742oc

Cited by 94 publications

(110 citation statements)

References 64 publications

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“…The significant correlation of endostatin concentration with established prognostic markers such as RAP, CI, NT-proBNP, 6MWD, and uric acid in our IPAH patient cohort implies that endostatin itself could be a prognostic marker and predict heart failure in severe IPAH. This is supported by the association of circulating endostatin with mortality in patients with PAH (9) and chronic heart failure (16). In addition to its potential as a prognostic tool, therapeutic applicability of endostatin has also been demonstrated (48).…”

Section: Discussionmentioning

confidence: 94%

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

Hoffmann

Marsh

Pieper

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alterations in extracellular matrix (ECM) have been implicated in the pathophysiology of pulmonary hypertension. Here, we have undertaken a compartment-specific study to elucidate the expression profile of collagens and their processing enzymes in donor and idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries. Predominant intimal, but also medial and perivascular, remodeling and reduced lumen diameter were detected in IPAH pulmonary arteries. Two-photon microscopy demonstrated accumulation of collagen fibers. Quantification of collagen in pulmonary arteries revealed collagen accumulation mainly in the intima of IPAH pulmonary arteries compared with donors. Laser capture-microdissected pulmonary artery profiles (intima+media and perivascular tissue) were analyzed by real-time PCR for ECM gene expression. In the intima+media of IPAH vessels, collagens (COL4A5, COL14A1, and COL18A1), matrix metalloproteinase (MMP) 19, and a disintegrin and metalloprotease (ADAM) 33 were higher expressed, whereas MMP10, ADAM17, TIMP1, and TIMP3 were less abundant. Localization of COLXVIII, its cleavage product endostatin, and MMP10, ADAM33, and TIMP1 was confirmed in pulmonary arteries by immunohistochemistry. ELISA for collagen XVIII/endostatin demonstrated significantly elevated plasma levels in IPAH patients compared with donors, whereas circulating MMP10, ADAM33, and TIMP1 levels were similar between the two groups. Endostatin levels were correlated with pulmonary arterial wedge pressure, and established prognostic markers of IPAH, right atrial pressure, cardiac index, 6-min walking distance, NH2-terminal pro-brain natriuretic peptide, and uric acid. Expression of unstudied collagens, MMPs, ADAMs, and TIMPs were found to be significantly altered in IPAH intima+media. Elevated levels of circulating collagen XVIII/endostatin are associated with markers of a poor prognosis.

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Section: Discussionmentioning

confidence: 94%

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

Hoffmann

Marsh

Pieper

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…We identified 141 SNPs that were differentially expressed between PAH and Cpc-PH versus Ipc-PH controls. After exclusion of SNPs not associated with any known genes, 75 exonic SNPs remained (Online Tables 9 and 10), including 2 genes previously associated with PAH progression (COL18A1)(27) and modulation (SMCR7)(28). These 75 exonic SNPs in 73 genes were associated with an additional 68 genes by eQTL mapping using the GTEx database, yielding a total of 141 genes associated with shared risk for both Cpc-PH and PAH versus Ipc-PH (Online Table 11).…”

Section: Resultsmentioning

confidence: 99%

Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension

Assad

Hemnes

Larkin

et al. 2016

Journal of the American College of Cardiology

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166

201

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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.

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“…The inclusion criteria, exclusion criteria, and clinical assessments and therapy were published previously (25). Data were collected prospectively from the JHPH Program, which maintains a registry.…”

Section: Pah Patient Cohortsmentioning

confidence: 99%

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

Yang¹,

Nies²,

et al. 2016

Am J Respir Crit Care Med

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ORCID IDs: 0000-0001-9273-4578 (J.Y.); 0000-0001-5453-425X (M.K.N.). AbstractRationale: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival.Objectives: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival.Methods: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker.Measurements and Main Results: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and higher levels of N-terminal pro-brain natriuretic peptide. HDGF was a strong predictor of mortality, with an unadjusted hazard ratio of 4.5 (95% confidence interval, 1.9-10.3; P = 0.003 by log-rank test). In multivariable Cox proportional hazards models, elevated HDGF levels predicted decreased survival after being adjusted for age, PAH subtype, invasive hemodynamics, and N-terminal pro-brain natriuretic peptide.Conclusions: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH. HDGF may add additional value in PAH risk stratification in clinical trials and may represent a potential target for future PAH drug development.

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Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Cited by 94 publications

References 64 publications

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

Clinical and Biological Insights Into Combined Post- and Pre-Capillary Pulmonary Hypertension

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

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