Rationale: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown.Objectives: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung.Methods: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects.Measurements and Main Results: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P , 0.05) and peripheral blood mononuclear cells (PBMC) (P , 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P , 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P , 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P , 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups.Conclusions: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management.

Interventional cardiologists who work in cardiac catheterization laboratories are exposed to low doses of ionizing radiation that could pose a health hazard. DNA damage is considered to be the main initiating event by which radiation damage to cells results in development of cancer and hereditary disease. The aim of the present study was to assess the effects of chronic low-dose X-ray radiation exposure on somatic DNA damage of interventional cardiologists working in high-volume cardiac catheterization laboratories. For this analysis, we used peripheral lymphocytes and the assay for micronuclei (MNs), which is considered to be a reliable biological dosimeter for radiation exposure. We obtained peripheral blood from 62 physicians (mean age+/-se = 40.6+/-1.5 years): 31 interventional cardiologists (group I, exposed) and 31 age- and sex-matched clinical cardiologists (group II, nonexposed). Interventional cardiologists showed higher MN values (group I=20.5+/-1.6 vs. group II=12.8+/-1.3, P=0.001), although some overlap was apparent in the individual subject analysis. A correlation between years of professional activity and MN frequency value was detectable for interventional cardiologists (r=0.428, P=0.02) but not for clinical cardiologists (r=0.253, P=0.17). The results indicated that, overall, interventional cardiologists working in a high-volume catheterization laboratory have higher levels of somatic DNA damage when compared with clinical cardiologists working outside the catheterization laboratory. The amount of this damage varies and is only weakly related to the duration of professional exposure, which suggests that a dominant modulation of the underlying genetic substrate by environmental factors has a role in determining the harm in individual physicians.

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