Impact of Nrf2 Activation on Macrovascular Function, Microvascular Function, Leg Function, and Walking Capacity in Patients With Peripheral Artery Disease
Peripheral artery disease (PAD) is associated with elevated oxidative stress, and oxidative stress has been implicated as the cause of reduced endothelial reactivity in individuals with PAD. Endothelial function is important because the endothelium contributes to the dilation of arteries during exercise, thereby implicating impaired endothelial function as a mechanism contributing to exacerbated exercise-induced ischemia. Therefore, the purpose of this study is to test the hypothesis that acute exogenous diroximel fumarate (Vumerity) intake will improve antioxidant capacity, thereby reducing oxidative stress and improving vascular function and walking capacity in those with PAD. During this study, participants will be administered diroximel fumarate or a placebo, and the acute effects of diroximel fumarate on vascular function and walking capacity will be assessed. Vascular function and walking capacity will be assessed with flow-mediated dilation, arterial stiffness, head-up tilt test, blood biomarkers, near-infrared spectroscopy, and a treadmill test. There will be a follow-up visit to assess blood work after diroximel fumarate.
∙ Peripheral artery disease (PAD) participants:
• Able to provide written informed consent
• 50-75 years of age
• Diagnosed as Fontaine stage II-III
• History of exercise-induced claudication
• Females must be postmenopausal (cessation of menses for \> 24 months)
• Normal renal function (serum creatinine-estimated glomerular filtration rate \>= 60 mL/min) or evidence of stable renal function within the last 6 months
• Normal hepatic function (alanine transaminase \< 87.5 U/L, alkaline phosphatase \< 260 U/L, total bilirubin 1.8 mg/dL) or evidence of stable hepatic function within the last 6 months
• Complete blood count:
‣ Females: red blood cell 4-5 trillion cells/L, hemoglobin 12-15 g/dL, hematocrit 34-45%, white blood cell count 3-10 billion cells/L, platelet count 160-380 billion/L, and normal lymphocyte count \> 700 million lymphocytes/L, or evidence of stable blood counts within the last 6 months
⁃ Males: red blood cell 4-6 trillion cells/L, hemoglobin 13-17 g/dL, hematocrit 38-49%, white blood cell count 3-10 billion cells/L, platelet count 135-320 billion/L, and normal lymphocyte count \> 700 million lymphocytes/L, or evidence of stable blood counts within the last 6 months
∙ Age-matched control participants:
• Able to provide written informed consent
• 50-75 years of age
• No evidence of peripheral occlusive disease (ankle-brachial index \> 0.90)
• Females must be postmenopausal (cessation of menses for \> 24 months)
• Normal renal function (serum creatinine-estimated glomerular filtration rate \>= 60 mL/min), or evidence of stable renal function within the last 6 months
• Normal hepatic function (alanine transaminase \< 87.5 U/L, alkaline phosphatase \< 260 U/L, total bilirubin 1.8 mg/dL ), or evidence of stable hepatic function within the last 6 months
• Complete blood count:
‣ Females: red blood cell 4-5 trillion cells/L, hemoglobin 12-15 g/dL, hematocrit 34-45%, white blood cell count 3-10 billion cells/L, platelet count 160-380 billion/L, and normal lymphocyte count \> 700 million lymphocytes/L
⁃ Males: red blood cell 4-6 trillion cells/L, hemoglobin 13-17 g/dL, hematocrit 38-49%, white blood cell count 3-10 billion cells/L, platelet count 135-320 billion/L, and normal lymphocyte count \> 700 million lymphocytes/L, or evidence of stable blood counts within the last 6 months