Oxidative Stress Is Associated With Increased Pulmonary Artery Systolic Pressure in Humans

Abstract

Oxidative stress contributes to the development of pulmonary hypertension in experimental models, but this association in humans is unknown. We investigated the relationship between pulmonary artery systolic pressure measured by echocardiography and plasma aminothiol oxidative stress markers, with the hypothesis that oxidative stress will be higher in those with pulmonary hypertension. A group of 347 patients aged 65±12 years from the Emory Cardiovascular Biobank underwent echocardiographic assessment of left ventricular ejection fraction and pulmonary artery systolic pressure. Plasma aminothiols, cysteine, its oxidized form, cystine; glutathione, and its oxidized disulphide (GSSG) were measured and the redox potentials (Eh) of cysteine/cystine and glutathione/GSSG couples were calculated. Non-normally distributed variables were log transformed (Ln). Univariate predictors of pulmonary artery systolic pressure included age (p<0.001), gender (p=0.002), mitral regurgitation (p<0.001), left ventricular ejection fraction (p<0.001), left atrial size (p< 0.001), diabetes (p=0.03), Plasma Ln cystine (β=9.53, p<0.001), Ln glutathione (β =-5.4, p=0.002), and Eh glutathione (β =0.21, p=0.001). A multivariate linear regression model adjusting for all confounding variables demonstrated that Ln cystine (β=6.56, p=0.007), mitral regurgitation (β= 4.52, P<0.001), statin use (β =-3.39, p=0.03), left ventricular ejection fraction (β=-0.26, p=0.003), and age (β=0.17, p=0.003) were independent predictors of pulmonary artery systolic pressure. For each 1% increase in plasma cystine, pulmonary artery systolic pressure increased by 16%. This association persisted in the subgroup with preserved left ventricular ejection fraction (≥50%) and no significant mitral regurgitation. Whether treatment of oxidative stress will improve pulmonary hypertension requires further study.

Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

“…A recent study of 347 patients who received TTE revealed that pulmonary artery systolic pressure was correlated with the oxidative stress markers cysteine, mitral regurgitation, statin use, left ventricular ejection fraction and patient age (21). ROS promote smooth muscle contraction by triggering elevated cytosolic free Ca 2+ concentrations.…”

Oxidative Stress: A Unifying Paradigm in Hypertension

“…Nevertheless, there is clear evidence that ROS production is increased in patients with essential hypertension, renovascular hypertension, malignant hypertension, salt-sensitive hypertension, cyclosporine-induced hypertension, and preeclampsia. [63][64][65] Population-based observational studies reported an inverse relationship between plasma antioxidants and blood pressure, and clinical studies have shown that systolic and diastolic blood pressures correlate positively with biomarkers of oxidative stress (plasma TBARS and 8-epi-isoprostanes) and negatively with antioxidant levels in patients with hypertension. 66,67 Plasma levels of asymmetric dimethylarginine (endothelial NOS inhibitor) and the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid, a marker of ROS production, were inversely correlated with microvascular endothelial dysfunction and elevated blood pressure in hypertensive patients.…”

Association between MDR1 gene polymorphism and clinical course of pediatric pulmonary arterial hypertension

“…On the other hand, P-gp facilitates transmembrane intracellular transport of various toxins, de- creasing the intracellular concentration of toxic compounds (16). The role of inflammation and oxidative stress in PAH pathogenesis is supported by many studies (3)(4)(5)(30)(31)(32). Cytokines, growth factors and shear stress represent endogenous activators of NADPH (nicotinamide adenine dinucleotide phosphate oxidase), which is a molecular complex that generates ROS (2).…”

“…Pulmonary arterial hypertension (PAH) is a hemodynamic and pathophysiological condition with multiple etiologies characterized by chron-ic and progressive remodelling of small pulmonary arteries, resulting in increased pulmonary vascular resistance (PVR) (1). Evidence suggests that inflammation, nitrogen oxides and oxidative stress contribute to the development and progression of lesions in the pulmonary vasculature (2,3). The reactive oxygen species (ROS) are an important mediator of vascular tonus, their excess generation being involved in the pathogenesis of PAH (4,5).…”