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Inflammatory and Proliferative Cytokines in PAH: Genotypic Characterization and Effects of Pharmacotherapy

A. Khanna

Gautam Ramani

J. Xu

J. Frederick

F. Janowick

Myung Park


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Conference: 2010 International PHA Conference and Scientific Sessions

Release Date: 06.24.2010

Presentation Type: Abstracts

Khanna A, Ramani G, Xu J, Janowick F, Fredrick J, Park M.
University of Maryland, Baltimore MD, USA

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular smooth cell proliferation and increase in pro-inflammatory states. Both inflammation and transforming growth factor-b (TGF-β) has been known to play a pivotal role in the regulation of cellular growth and the pathogenesis of PAH. However, the precise contribution of pro- and anti inflammatory cytokines and TGF-b and therapeutic interactions in PAH patients remain poorly understood.

METHODS: Patients with WHO Group I PAH and hemodynamically significant PAH with chronic thromboembolic disease (CTEPH) were prospectively evaluated. Blood samples were collected and analyzed. Genotype analysis was performed using a cytokine genotype system from One Lambda (Los Angeles, CA) and TGF-β levels were quantified using a ELISA kit from Promega (Madison, WI). Patient demographics, functional status, and pharmacologic treatment were collected.

RESULTS: 27 patients were enrolled [age 54 ± 16 years, 19 (70%) women, 60 % functional class III]. 11 patients had idiopathic pulmonary arterial hypertension (IPAH), 13 patients had associated PAH (APAH), and 3 patients had chronic thromboembolic pulmonary hypertension (CTEPH). The genotypic pattern of PAH patients was highly consistent. 100 % and 93% of patients, respectively, displayed genotypes for high production of the pro-inflammatory cytokines TNF-alpha and IL-6. In contrast, 100% of patients demonstrated genotypes for either low or intermediate producing IL-10 cytokine. 85% of patients expressed the high TGF-β producing genotype. Circulating levels of TGF- β were significantly higher in PAH patients compared to controls (32.8 ± 2.29 ng/mL vs. 16.66 ± 3.1 ng/mL p < 0.0001). Among PAH patients, circulating levels of TGF-β were significantly higher in African Americans than Caucasians (38.9 ± 3.03 ng/ml vs. 28.6 ± 2.93 ng/ml, p < 0.03). There were no correlations between TGF-β levels and functional class, 6 minute walk test, or invasive hemodynamic measurements. Interestingly, treatment with continuous infusion prostacyclin therapy was associated with lower TGF-β levels (36.28 ± 3.2 ng/mL vs 27 ± 2.1 ng/mL, p=0.04).

DISCUSSIONPatients with PAH demonstrate an inherently pro-inflammatory genotype, which may contribute to disease development and progression. TGF-β levels are elevated in both IPAH and APAH, and therapy with continuous infusion prostacyclin analogues appears to have a beneficial effect in reducing the levels. Further studies are warranted to better determine the implication of modulating TGF- β and inflammatory cytokines in progression in PAH patients.