Ramipril Treatment of Claudication
| Status: | Recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 90 |
| Updated: | 11/2/2018 |
| Start Date: | October 2015 |
| End Date: | March 31, 2020 |
| Contact: | Holly DeSpiegelaere |
| Email: | Holly.DeSpiegelaere@va.gov |
| Phone: | 402-995-4171 |
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.
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.
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.
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:
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.
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