Use of Entresto Sacubitril/Valsartan for the Treatment of Peripheral Arterial Disease

This study proposes the use of Entresto (sacubitril/valsartan) to test the effects on pain free walking duration on patients with peripheral arterial disease, a condition caused by decreased blood flow to the muscles in the legs.

Current approaches for the treatment of peripheral arterial disease (PAD) lack the success observed in the treatment of other forms of vascular diseases. A potential reason for this may be that available treatments do not target the pathological mechanisms implicated in the development of PAD. These mechanisms include obstruction of aortic-iliac arteries and its branches due to the formation of atherosclerotic plaques and mitochondrial and microvascular dysfunction. Although blood flow improves following surgical revascularization, pain free and maximal walking duration does not improve to the same degree. This suggests that in addition to blood flow obstruction, mitochondrial and microvascular dysfunction are significant factors implicated in the development of PAD. Therefore, any treatment designed for patients with PAD should be aimed at improving mitochondrial and microvascular function. In this regard, natriuretic peptides (NP) have been shown to increase mitochondrial and microvascular density and these two findings have been associated with increases in oxygen consumption and perfusion of skeletal muscles. The Investigator proposes that an increase in endogenous natriuretic peptides by inhibiting the enzyme that degrades it in blood will increase mitochondrial and microvascular function and this will be associated with an increase in maximal and pain free walking duration. To test this hypothesis the investigators have designed a double blind randomized controlled clinical trial providing sacubitril/valsartan for 12 weeks trial period.The improvements in mitochondrial and microvascular function will be measured using magnetic resonance (MR) spectroscopy and functional MR imaging and an exercise stress test will be used to assess maximal and pain free walking duration. This trial will provide patients with PAD with a non-surgical, cause-specific treatment option.

Time in minutes on a standardized treadmill test to initiation of pain and time until pain requires patient to stop walking

Post-contraction measures of mitochondrial and microvascular function using MR spectroscopy and functional MRI

Inclusion Criteria: Subject with symptoms of intermittent claudication, such as exercise-induced pain, cramps, fatigue, or other equivalent discomfort, involving large muscle groups of the leg(s) (calf, thigh, buttocks), relieved by rest. Ankle-brachial index ≤ 0.90 acquired according to the American Heart Association guidelines. Highest ankle pressure reduced by at least 25 mm Hg after exercise compared to resting pressure (or loss of previously present Doppler signal for both the posterior tibial and anterior tibial arteries immediately after exercise if arteries were incompressible). Patients on medical treatment for PAD without significant improvement in intermittent claudication within the last 6 months. Exclusion Criteria: Age < 18 and > 80 years. Patients with physician diagnosed chronic kidney disease or heart failure stage II or IV or unstable angina. Echocardiographic evidence of cardiomyopathies and pulmonary hypertension. Patients that have received cancer treatment within the last year (except skin cancer). Severe limitations in mobility due to osteomuscular disorders present at time of interview. Dementia or other mental disorders that prevent patients from following a research protocol present at time of interview Patients engaged in an exercise rehabilitation program within the past 6 months. Patients schedule to undergo an arterial revascularization procedure during the study or have undergone one within the past 6 months. Inconsistent maximal walking distance on the treadmill test.