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ARRA Investments in Peripheral Arterial Disease (PAD)


Public Health Burden
Atherosclerotic PAD affects 8-12 million adults in the United States.  Prevalence increases with age; as many as 20 percent of individuals over 75 years of age have PAD.  The spectrum of PAD manifestations is broad, ranging from no symptoms to leg pain with walking (claudication), pain at rest, kidney impairment, and tissue damage that may necessitate limb amputation.

Diagnosis
Public awareness of PAD is low.  Screening tests have not become routine.  A diagnosis of PAD, however, carries a significantly heightened risk for adverse cardiovascular events including death, myocardial infarction, and stroke.  Therefore, early diagnosis of PAD is an important public health goal. Projects of four ARRA-funded grants address diagnostic tools for PAD and include research to:
  • Screen large numbers of individuals with and without PAD to identify behavioral profiles and biomarkers specifically linked to PAD.  Dietary and lifestyle data acquired over 20 years on thousands of men and women in the Health Professionals Follow-up Study and Nurses’ Health Study will be examined.  Additionally, stored blood samples from the participants will be tested for markers related to endothelial cell function, oxidative stress, inflammation, and kidney function.  The resultant information should help to improve scientific understanding of PAD initiation and progression, thereby enabling its earlier diagnosis.1
  • Develop and validate magnetic resonance imaging (MRI) methods to measure skeletal muscle blood flow at peak exercise without the need for a contrast agent.  Such methods could be very useful in diagnosing PAD and safely assessing short- and long-term responses to standard and experimental treatments.2
  • Develop a rapid, noninvasive MRI protocol to allow earlier detection of changes associated with PAD, such as a reduced ability of blood vessels to expand and contract with changes in pressure and a reduced flow of blood through small vessels after exercise or other flow stimuli.3
  • Develop an easy-to-use, accurate Doppler probe (a device that emits and detects ultrasonic waves) to monitor vascular blood flow during dialysis treatment.  Such a probe could evolve into a technology for more routine, economical monitoring of peripheral blood flow in patients with PAD and could help determine appropriate timing for interventional limb salvage.4
Treatment
Current treatment options for PAD beyond cardiovascular risk factor modification are few—exercise, cilostazol (a vasodilator drug), and revascularization (surgical bypass of an occluded blood vessel or opening of an occluded artery by balloon dilation and/or stenting).  No compelling evidence exists for choosing one treatment over another in most cases of PAD; however, the annual number of revascularization procedures has soared in recent years. Two ARRA-funded grants are exploring potential new treatments for PAD, focusing on regenerative medicine to:
  • Determine whether stimulating bone marrow release of young precursor vascular cells into the circulation will attenuate symptoms that cause difficulty walking.5
  • Screen chemicals, including small proteins that can permeate cell nuclei, for their ability to reprogram adult human cells to acquire the characteristics of pluripotent stem cells.  The ultimate goal of this research is to differentiate human induced pluripotent stem cells into endothelial cells and then test their potential for vascular regeneration in models of limb ischemia.6
Basic Research
To date, treatments of PAD are limited in number and, often, in magnitude of beneficial effect.  To establish a basis for future new PAD treatments, NIH ARRA funds also will support basic investigations to:
  • Increase understanding of the factors, such as enzymes, that promote calcification of the medial layer of arteries, a common condition in chronic kidney disease.  This research will likely yield insights about similar vascular calcification in PAD, often in association with diabetes, that complicates revascularization procedures.7
  • Examine endothelial cell structures, such as the tiny openings called fenestrae that facilitate exchange of fluids and solutes across endothelial cells that line blood vessels.  Disruption of normal permeability may occur in conditions such as inflammation and atherosclerosis and therefore may yield insights about PAD.8



  1. 1R01HL091874-01A1 -- Endothelial Dysfunction, Oxidative Stress and Risk of PAD -- Mukamal, Kenneth (MA)
  2. 2R01HL075792-06 -- Comprehensive Magnetic Resonance in PAD -- Kramer, Christopher (VA)
  3. 1RC1HL099861-01 -- Integrated MRI-Based Examination for Evaluation of PAD -- Wehrli, Felix (PA)
  4. 1RC1HL101881-01 -- VF Doppler Smart Sensor for Dialysis and Vascular Applications -- Weitzel, William (MI)
  5. 1RC2HL101515-01 -- Phase II study: Mobilization of Progenitor Cells in PAD -- Quyyumi, Arshed (GA)
  6. 1RC2HL103400-01 -- NCE-based Strategy for Nuclear Reprogramming and Regenerative Medicine -- Cooke, John (CA)
  7. 1RC1HL101899-01 -- Leads and Target Validation for Vascular Calcification in CKD -- Millan, Jose Luis (CA)
  8. 1R01HL092085-01A1 -- Structure and Function of Endothelial Fenestrae -- Stan, Radu (NH)


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