Effects of Tetrahydrobiopterin (BH4) on Leg Blood Flow, Mitochondrial Function and Leg Performance in Patients With Peripheral Artery Disease

UNOmaha

Nitric oxide has been shown to be an important regulator within the cardiovascular system, responsible for regulation of blood flow, blood pressure and vascular growth. Cardiovascular diseases show a reduced ability of the peripheral blood vessels to dilate due to decreased levels of NO with concomitant increased levels of oxidative stress, which is extremely detrimental to patients with PAD, as the limited oxygen delivery to skeletal muscles ultimately results in claudication and reduced physical ability. However, this reduced oxygen delivery and utilization may be able to be improved as previous studies have revealed that tetrahydrobiopterin (BH4), is an important cofactor responsible for NO production. Furthermore, recent studies have shown that endothelial BH4 levels are associated with the vascular pathophysiological response to hypoxia, as it directly mediates endothelial nitric oxide synthase regulation and reduces superoxide production. Additionally, acute administration of BH4 was shown to improve vascular function, specifically, endothelial mediated vasodilatory function, in patients with systemic vascular and coronary disease, as well as six minute walking distances in patients with hypertension. Therefore, the purpose of this proposed study will be to examine the effects of BH4 on vascular function, oxidative stress and leg performance in patients with PAD. This study will examine patients with a classification of stage 1 or stage 2 peripheral artery disease who demonstrate a history of exercise-limiting claudication. Blood vessel oxygen transfer capacity in the leg will be assessed in the femoral and popliteal arteries with ultrasound, and blood vessel dilatory ability will be assessed in the brachial artery with flow-mediated dilation. Skeletal muscle mitochondrial function will be measured with near infrared spectroscopy, and ROS levels will be analyzed through blood samples. Leg function will be measured with an isokinetic dynamometer.

2019-07-01

2019-07-01

2019-10-01

Withdrawn

Early phase I

Inclusion Criteria: 1. be able to give written, informed consent 2. demonstrate positive history of chronic claudication 3. have a history of exercise limiting claudication 4. have an ankle/brachial index \< 0.90 at rest 5. have a stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks. 6. be between 50-85 years old Exclusion Criteria: 1. rest pain or tissue loss due to PAD (Fontaine stage III and IV) 2. acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma 3. walking capacity limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology

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2023-08-15