Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis

Peripheral artery disease (PAD) is a manifestation of atherosclerosis that produces progressive narrowing and occlusion of the arteries supplying the lower extremities. The most common clinical manifestation of PAD is claudication, i.e., a severe functional limitation identified as gait dysfunction and walking-induced leg muscle pain relieved by rest. The standard therapies for claudication include the medications cilostazol and pentoxifylline, supervised exercise therapy and operative revascularization. Recent data demonstrated that 24 weeks of treatment with the angiotensin-converting enzyme (ACE) inhibitor Ramipril produces improvements in the walking performance of patients with claudication that are higher than those of cilostazol and pentoxifylline and similar to those produced by supervised exercise therapy and operative revascularization. The mechanisms by which Ramipril therapy produces this impressive improvement in the functional capacity of claudicating patients remain unknown. The Investigators hypothesize that treatment of claudicating PAD patients with Ramipril will improve walking performance and quality of life by improving the myopathy of the gastrocnemius. Improved myopathy is a consequence of reduced oxidative damage, reduced TGF-β1 production by vascular smooth muscle cells and reduced collagen deposition in the affected gastrocnemius.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Arterial Disease
• Intervention / Treatment: Drug: Ramipril

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Holly DeSpiegelaere; Phone Number: 402-995-4171; Email: Holly.DeSpiegelaere@va.gov

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • Recruiting
      • VA Medical Center
      • Contact: Holly DeSpiegelaere; Phone Number: 402-995-4171; Email: Holly.DeSpiegelaere@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

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 significantly limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology,
4. Current use of either ACE inhibitors or angiotensin II receptor blockers,
5. Chronic kidney disease with estimated Glomerular Filtration Rate < 30 ml/min/1.73 m2,
6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ramipril Treatment; 6 months treatment with the medication Ramipril	Drug: Ramipril; Ramipril therapy will start at 2.5mg/day for 1 week. Then 5mg/day for 1 week and will be increased to 10mg/day by the third week. The patients will stay on Ramipril 10mg/day for 22 weeks.; Other Names: Altace

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Claudication Distance	Maximum walking distance in meters per Gardner protocol	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-minute Walking Distance	Maximum Distance in meters the patient can walk in 6 minutes on a flat, hard surface	6 months
Initial Claudication Distance	The distance in meters the patient can walk before he experiences claudication pain, per Gardner protocol	6 months
Average Daily Steps Taken	Monitored with an accelerometer at home	6 months
Leg hemodynamics measured as Ankle Brachial Index (ABI)	Ratio of the blood pressure at the level of the ankle to the blood pressure at the level of the arm	6 months
Leg hemodynamics measured as Calf muscle hemoglobin oxygen saturation	Measured with Near Infrared Spectroscopy	6 months
Myofiber Oxidative Damage	Myofiber content of HNE adducts and protein carbonyls	6 months
Myofiber Morphology, Cross-Sectional Area	Area in square microns, measured by immunofluorescence microscopy	6 months
Myofiber Morphology, Roundness	Measured as ratio of major axis in microns to minor axis in microns	6 months
Myofiber Morphology, Solidity	Measured as the ratio of myofiber area in square microns to the area of a fitted convex hull in square microns	6 months
Muscle Fibrosis, Muscle TGF-β1	Measured as the sum of the products of mean pixel intensity (in gray scale units) and area (in square microns) of each TGF-β1 labeled event divided by the total area (in square microns) of the tissue sample analyzed. Measured by immunofluorescence microscopy.	6 months
Muscle Fibrosis, Total collagen deposited.	Measured as the area-weighted mean pixel intensity (in gray scale units) of all the collagen labeled events per tissue sample. Measured by bright-field microscopy.	6 months
Microvascular Fibrosis, Capillary wall thickness.	Measured in microns by immunofluorescence microscopy of vessels labeled for collagen.	6 months
Capillary density.	Number of capillaries per unit area (in square microns) of the tissue sample analyzed.	6 months
Quality of life measured by the Walking Impairment Questionnaire	measured by the Walking Impairment Questionnaire	6 months
Quality of life measured by the Medical Outcomes Study Short Form 36 Healthy Survey	measured by the Medical Outcomes Study Short Form 36 Healthy Survey	6 months
Leg biomechanics measured as Vertical ground reaction force	measured as Vertical ground reaction force	6 months
Leg hemodynamics	measured as Calf blood flow via contrast-enhanced ultrasound	6 months
Leg hemodynamics measured as Calf blood flow via stress ABI testing	measured as Calf blood flow via stress ABI testing	6 months
Myofiber Mitochondrial Respiration, measured by polarography	measured by polarography	6 months
Muscle Mitochondrial Function, measured by spectrophotometry	measured by spectrophotometry	6 months
Serum biomarker of fibrosis, serum procollagen type I c-peptide in picograms of peptide per ml	serum procollagen type I c-peptide in picograms of peptide	6 months
Serum biomarker of fibrosis, serum procollagen type III n-terminal peptide in picograms of peptide per ml	serum procollagen type III n-terminal peptide in picograms of peptide per ml	6 months
Plasma biomarker of fibrosis, plasma TGF-β1 in picograms per ml	plasma TGF-β1 in picograms per ml	6 months

Collaborators and Investigators

• Sponsor: University of Nebraska
• Investigators: Principal Investigator: Iraklis I Pipinos, MD, University of Nebraska; Principal Investigator: George P Casale, PhD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2016
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: June 17, 2016
• First Submitted That Met QC Criteria: July 21, 2016
• First Posted (Estimated): July 22, 2016

Study Record Updates

• Last Update Posted (Estimated): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Claudication; Peripheral Arterial Disease; Myopathy; Ramipril; Angiotensin-converting enzyme
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Ramipril
• Other Study ID Numbers: 0139-16-ET; 00991 (Other Identifier: VAMC-IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No