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Abstract 548: Microvessel Oxidative Stress And Damage And Its Relation To Muscle Degeneration And Fibrosis In The Ischemic Limbs Of Patients With Peripheral Artery Disease

2023; Lippincott Williams & Wilkins; Volume: 43; Issue: Suppl_1 Linguagem: Inglês

10.1161/atvb.43.suppl_1.548

1524-4636

Molly Schieber, Shuai Li, Matthew A. Fuglestad, Christina Shields, Julian K Kim, Ulka Sachdev, Iraklis I. Pipinos, George P. Casale,

Systemic Sclerosis and Related Diseases

We have previously documented myofiber oxidative damage and degeneration, interstitial fibrosis, and abnormal microvascular architecture in the calf muscle of patients with Peripheral Artery Disease (PAD). Our objective was to evaluate baseline oxidative stress (Heme oxygenase 1 [HO-1] expression) and oxidative damage (carbonyl adducts) in the microvessels (≤10.5 μm) of patients with PAD in association with myofiber pathology and fibrosis. We hypothesized that microvessel oxidative stress and accumulated oxidative damage in PAD muscle at baseline 1) are greater than in non-PAD control muscle and 2) are associated with myofiber pathology and fibrosis. Methods: Oxidative stress was assessed as expression of HO-1, regarded as the most important molecule protective against cellular oxidative stress. Oxidative damage was determined as abundance of cellular carbonyl adducts. The gastrocnemius was biopsied for quantification of HO-1 and carbonyl content in both myofibers and microvessels in claudicating patients with PAD (Fontaine Stage II; n=12), in patients with non-healing ulcers (Fontaine Stage IV (n=13), and in non-PAD controls (n=16; recruited from a vascular clinic by a vascular surgeon). Results: Microvessel oxidative damage was greater in Stage IV (1,616,286 gsu*μm 2 ) compared to Stage II (1,138,707gsu*μm 2 , p=0.022) and controls (817,384 gsu*μm 2 , p=0.0001), and in Stage II compared to controls (p=0.004). Oxidative stress was greater in Stage IV (273,269 gsu*μm 2 ) and Stage II patients (228,936 gsu*μm 2 ) compared to Controls (175,471 gsu*μm 2 ; p=0.0017 and p=0.0173, respectively). Oxidative damage in microvessels of controls and Stage II patients predicted myofiber oxidative damage (87,457,944 gsu*μm 2 ; r=0.688, p=0.0065) and (146,730,298 gsu*μm 2 ; r=0.685, p=0.0139), respectively, and interstitial fibrosis (r=-0.753, p=0.0047) in Stage II. Microvessel response to oxidative stress (HO-1) predicted myofiber damage (r=0.614, p=0.007) in controls. Conclusion: Microvessel oxidative damage is increased in the ischemic calf muscle of PAD patients, advances with stage, and correlates with myofiber oxidative damage and interstitial fibrosis in Stage II patients. Microvessel pathology may be a central mediator of the myopathy of PAD.