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Microvessel Oxidative Stress Predicts Changes in Leg Function of Patients with Peripheral Arterial Disease after Supervised Exercise Therapy

Open AccessPublished:June 10, 2022DOI:https://doi.org/10.1016/j.jvssci.2022.05.007

      Objective

      To evaluate baseline oxidative stress in the microvessels of patients with peripheral arterial disease (PAD) (1) in association with heme oxygenase-1 (HO-1), a critical cytoprotective molecule for oxidative stress (2) as a predictor of the functional and pathophysiologic changes that occur in response to 6 months of supervised exercise therapy (SET). We hypothesized that accumulated oxidative stress in the microvessels of PAD at baseline would predict changes in walking performance, myofiber pathology, and limb function at the end of a 6-month program of SET.

      Methods

      Twelve claudicating patients received six months of SET per the American College of Cardiology/American Heart Association guidelines. Before and after SET, patients were evaluated for leg biomechanics, overground walking capacity (6-minute walking distance [SMWD]), and maximum walking time on a treadmill. Subsequently, their more affected calf muscle was biopsied for quantification of HO-1 and oxidative stress (carbonyl content) in both myofibers and microvessels. We evaluated the association between HO-1 expression and carbonyl content with correlation and multiple regression.

      Results

      HO-1 expression and Carbonyl content were strongly associated in the microvessels (n = 1400; r = 0.98; P < .001). Increasing the carbonyl content in the microvessels of each patient was associated with increasing HO-1 expression. In a subset of patients, HO-1 expression increased more slowly with increasing carbonyl content. Pre-SET oxidative stress in microvessels was a significant predictor of SET mediated change in SMWD (r = –0.75; P = .012) and plantarflexion torque (r = 0.8571; P = .0065).

      Conclusions

      Carbonyl content (oxidative stress) in microvessels of each patient was positively associated with HO-1 expression. However, in a subset of patients, HO-1 expression increased more slowly with increasing carbonyl content. Baseline oxidative stress in the microvessels, which may be a function of the quality of HO-1 expression, was a significant predictor of SET-mediated change in the SMWD and plantarflexion torque. The data suggest that microvessel oxidative damage may contribute uniquely to calf muscle pathology and leg dysfunction in patients with PAD.