Patients with claudication experience significant disability and are faced with limited therapeutic options that include only two FDA approved medications Pentoxifylline and Cilostazol which have at best modest effects. A recent clinical trial identified Ramipril as a promising therapeutic agent that produced improvements in walking distances several times those of Pentoxifylline and Cilostazol and similar to those produced by supervised exercise therapy and operative revascularization. The mechanism(s) by which Ramipril produced these effects is unknown. On the basis of our work on the histopathology of lower leg muscle of claudicating patients with peripheral artery disease (PAD) and its relationship to leg function, we have designed the present study aimed at determining how Ramipril produces its beneficial effects in claudicating patients. Our HYPOTHESIS is that Treatment of claudicating PAD patients with Ramipril improves walking performance and quality of life by improving the myopathy of the gastrocnemius. Improved myopathy is a consequence of reduced oxidative damage, reduced TGF-1 production by vascular smooth muscle cells and reduced collagen deposition in the affected gastrocnemius. We will test our hypothesis by implementing the following Specific Aims.
SPECIFIC AIM #1 will 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 will 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. We view vascular smooth muscle cells as the principle mediators of fibrosis in PAD muscle.
In SPECIFIC AIM #3 we will use adult human arterial smooth muscle cells (AHASMC), in vitro, to 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-1 and collagen, via stimulation of phosphoinositide-3-kinase signaling and suppression of phosphatase and tensin homologue, a master regulator of cell growth. If our hypothesis is correct, then the work in Aims #1 and #2 will demonstrate for the first time that therapy with Ramipril improves limb function and quality of life by improving the myopathy of skeletal muscles in the ischemic lower limbs. The work in Aim #3 will identify pathways by which hypoxia and Ang II collaborate to induce myopathy in ischemic muscle. Specific agents targeting these pathways could become new treatments for claudication and for more advanced stages of PAD. Finally, information from this study may identify new tools for precise staging of PAD, evaluating therapeutic interventions and identifying patients who will benefit from aggressive therapy.

Public Health Relevance

Intermittent claudication afflicts 5% of the US population older than 55 years of age and develops along with hardening of the arteries of the legs. Claudicating patients limp and can only walk very short distances because their leg muscles are damaged and their legs hurt. Our protocol evaluates the mechanisms that may produce the leg muscle damage and dysfunction of claudication and its successful completion ultimately can yield new diagnostic and treatment strategies for the care of these patients.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Joseph, Lyndon
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University of Nebraska Medical Center
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Hernandez, Hernan; Myers, Sara A; Schieber, Molly et al. (2018) Quantification of Daily Physical Activity and Sedentary Behavior of Claudicating Patients. Ann Vasc Surg :
McCamley, John D; Cutler, Eric L; Schmid, Kendra K et al. (2018) Gait Mechanics Differences Between Healthy Controls and Patients With Peripheral Artery Disease After Adjusting for Gait Velocity Stride Length and Step Width. J Appl Biomech :1-19
Schieber, Molly N; Hasenkamp, Ryan M; Pipinos, Iraklis I et al. (2017) Muscle strength and control characteristics are altered by peripheral artery disease. J Vasc Surg 66:178-186.e12