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Male Gender Predisposes PAH Patients to Reductive Stress and Disease Progression

Olga Rafikova

Ankit Desai

Ruslan Rafikov

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 06.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1041

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Background

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by increased pulmonary vascular resistance leading to right ventricular failure. Previous studies indicated that while females are more susceptible to PAH, male patients have a lower survival rate. Nevertheless, the particular mechanisms responsible for the worse prognosis in males are not clear. Male vascular cells were shown to be more prone to necrotic cell death compared to those derived from females. We now hypothesize that an ongoing pulmonary vascular necrosis in males mediates a redox shift of plasma environment toward more reduced, i.e., induces reductive stress, which contributes to PAH progression.

Methods

In this study we analyzed the plasma samples collected from three different patient cohorts - 1) patients with a diagnosis of Group I PAH (PAH cohort); 2) patients that were diagnosed with non-PAH lung diseases (lung cohort); and 3) patients that were diagnosed with acute or chronic heart disease (heart cohort). All patients were prospectively recruited from the University of Arizona (UA). All subjects provided written consent to participate in this study with the approval of the UA institutional human subjects review board.

Results

As a surrogate for vascular necrosis, we compared circulating high mobility group box 1 (HMGB1) levels, a damage-associated molecular patterns (DAMP) molecule released from necrotic cells, in male and female PAH patients, as well as in patients from lung and heart cohorts. Male, but not female, PAH patients had significantly elevated levels of plasma HMGB1 comparing to gender-matched patients from lung and heart cohorts. Next, we used RedoxSys® Diagnostic System to evaluate the redox state of patient plasma. In strong accordance with previously published findings, there was a significant “oxidative shift” in male and female patients from lung cohort compared to other patient cohorts. Patients of either gender from the heart cohort had a reduced plasma state that could be explained, in part, by a previously reported history of myocardial damage or ischemic heart disease. However, in the PAH cohort, there was an evident gender disparity: female PAH patients exhibited significantly more oxidized plasma compared to heart cohorts, while males possessed a slightly more reduced plasma state. Importantly, there was also a distinct gender difference in the correlation between the redox parameters and markers of RV dysfunction. While in females, brain natriuretic peptide (BNP), an established marker of heart failure, was elevated in response to oxidative changes, males demonstrated a significant correlation of elevated BNP levels with increasing reductive stress levels. In particular, in male patients, every 1 µC of increase in total antioxidant activity resulted in 81% rise of BNP levels. Since RV dysfunction is the primary survival determinant in patients with PAH, our results suggest that the reductive stress is a potential marker for RV dysfunction and may contribute to the poor survival of males with PAH.

Conclusions

This study reveals a predisposition of the male gender to reductive stress, which could contribute to the progression of PAH in males. This discovery inaugurates a novel concept of gender-specific redox pathobiology in PAH.