Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis

This is an interventional study of PAD patients that exhibit claudication. The purpose of this study is to determine the potential mechanisms by which Ramipril vastly improves the walking performance of these patients. The study will be achieved through these specific aims:

Specific Aim #1: Test the hypothesis that Ramipril-mediated improvements of walking parameters among patients with PAD correlate with improvements in both the morphometrics and biochemistry of myofibers in the gastrocnemius of the impaired limb.

Specific Aim #2: Test the hypothesis that Ramipril-mediated improvements of walking parameters in patients with PAD correlate with reduced fibrotic events in small vessels and microvasculature, in association with reduced generalized collagen deposition and improved tissue oxygenation, in the gastrocnemius of the impaired limb.

Specific Aim #3: Using adult human arterial smooth muscle cells (AHASMC), in vitro, the Investigators will test the hypothesis that the ACE inhibitor Ramipril, which acts as an antagonist of Angiotensin II type 1 receptor (ART1) stimulation by reducing tissue Angiotensin II (Ang II), impedes a mechanism in which Ang II stimulation of ART1 and exposure to hypoxia enhance proliferation of AHASMC and their production of TGF-β1 and collagen, via stimulation of phosphoinositide-3-kinase signaling and suppression of phosphatase and tensin homologue, a master regulator of cell growth.

If the above hypotheses are correct, Aims #1 and #2 will demonstrate for the first time that therapy with Ramipril improves the walking performance and quality of life of claudicating PAD patients by improving the myopathy in skeletal muscle of the ischemic lower limbs. The work in Aim #3 will determine the pathways by which hypoxia and Angiotensin II cooperate to induce myopathy in the ischemic muscle. Specific agents targeting these pathways could become new treatments for claudication and for the more advanced stages of PAD characterized by leg rest pain and gangrene.

Inclusion criteria

• A positive history of chronic claudication,
• Exercise-limiting claudication established by history and direct observation during a screening walking test administered by the evaluating vascular surgeon,
• Arterial occlusive disease per ankle Brachial index measurements and/or other imaging modalities,
• Stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks.

Exclusion criteria

• Rest pain or tissue loss due to PAD (Fontaine stage III and IV),
• acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma,
• Walking capacity significantly limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology,
• Current use of either ACE inhibitors or angiotensin II receptor blockers,
• Chronic kidney disease with estimated Glomerular Filtration Rate < 30 ml/min/1.73 m2,
• History of bilateral severe renal artery stenosis and 7) History of angioedema related to previous ACE-inhibitor treatment or known hypersensitivity to ramipril or other ACE inhibitors.