Peripheral Artery Occlusive Disease Clinical Trials, Diagnosis, and Treatment

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Peripheral Artery Occlusive Disease

In medicine Peripheral Artery Occlusive Disease (PAOD), also known as peripheral vascular disease (PVD) and peripheral artery disease (PAD) is a collator for all diseases caused by the obstruction of large peripheral arteries, which can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or thrombus formation. It causes either acute or chronic ischemia.

Current Research

For current research articles click - here

Classification

Peripheral artery occlusive disease is commonly divided in the Fontaine stages:

I: mild pain on walking ("claudication")

II: severe pain on walking relatively shorter distances (intermittent claudication)

III: pain while resting

IV: loss of sensation to the lower part of the extremity

V: tissue loss (gangrene)

Symptoms

Claudication - pain, weakness, or cramping in muscles due to decreased blood flow

Sores, wounds, or ulcers that heal slowly or not at all

Noticeable change in color (blueness or paleness) or temperature (coolness) when compared to the other limb

Diminished hair and nail growth on affected limb and digits.

Causes

Smoking - tobacco use in any form is the single most important modifiable cause of PAD internationally. Smokers have up to a tenfold increase in relative risk for PAOD in a dose-related effect. Exposure to second-hand smoke from environmental exposure has also been shown to promote changes in blood vessel lining (endothelium) which is a precursor to atherosclerosis.

Diabetes Mellitus - increased risk of PAOD 2-4X by causing endothelial and smooth muscle cell dysfunction in peripheral arteries. Diabetics account for up to 70% of nontraumatic amputations performed, and a known diabetic who smokes runs an approximately 30% risk of amputation within 5 years.

Dyslipidemia - elevation of total cholesterol, LDL cholesterol, and triglyceride levels each have been correlated with accelerated PAOD. Correction of dyslipidemia by diet and/or medication is associated with a major improvement in short-term rates of heart attack and stroke. This benefit is gained even though current evidence does not demonstrate a major reversal of peripheral and/or coronary atherosclerosis.

Hypertension - elevated blood pressure is correlated with an increase in the risk of developing PAD, as well as in associated coronary and cerebrovascular events (heart attack and stroke).

Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, homocysteine, and fibrinogen.

Risk of PAOD also increases if the patient is: over the age of 50, African American, male, obese, or has a personal history of vascular disease, heart attack, or stroke.

Diagnosis

Upon suspicion of PAOD, the first-line test is the ankle brachial pressure index (ABPI/ABI) which is a measure of the fall in blood pressure in the arteries supplying the legs. A reduced ABPI (less than 0.9) is consistent with PAOD. Values of ABPI below 0.8 indicate moderate disease and below 0.5 severe disease.

If ABI's are abnormal the next step is generally a lower limb doppler ultrasound examination to look at site and extent of atherosclerosis at the femoral artery. Other imaging can be performed by angiography, where a catheter is inserted into the femoral artery and selectively guided to the artery in question and then used to inject radiodense contrast agent whilst an X-ray is taken. Any stenosis of the arteries can be identified and treated at the same time by balloon angioplasty if the stenosis is over a short segment (<3cm). However if the artery is occluded or there is diffuse disease present, then arterial bypass surgery may be required.

Modern multislice computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography. CT provides complete evaluation of the aorta and lower limb arteries without the need for an angiogram's arterial injection of contrast agent.

Therapy

Dependent on the severity of the disease, the following steps can be taken:

Conservative measures include Smoking cessation (cigarettes promote PAOD and are a risk factor for cardiovascular disease). Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves. Medication with aspirin, clopidogrel and statins, which reduce clot formation and cholesterol levels, respectively can help with disease progression and address the other cardiovascular risks that the patient is likely to have.

Angioplasty (PTA or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery.

Plaque excision, in which the plaque is scraped off of the inside of the vessel wall.

Occasionally, bypass grafting is needed to circumvent a seriously stenosed area of the arterial vasculature. Generally, the saphenous vein is used, although artificial (Gore-Tex) material is often used for large tracts when the veins are of lesser quality.

Rarely, sympathectomy is used - removing the nerves that make arteries contract, effectively leading to vasodilatation.

When gangrene of toes has set in, amputation is often a last resort to stop infected dying tissues from causing septicemia.

Arterial thrombosis or embolism has a dismal prognosis, but is occasionally treated successfully with thrombolysis.

Associations

Many PAOD patients also have angina pectoris or have had myocardial infarction. There is also an increased risk for stroke.

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Peripheral_artery_occlusive_disease)

Findings From Current Research

Pharmacological Interventions for Peripheral Artery Disease

Authors: Duprez DA.

University of Minnesota, Cardiovascular Division, Medical School, VCRC-Room 270, Minneapolis, MN 55455, USA. dupre007@umn.edu

Peripheral arterial disease (PAD) encompasses the vascular diseases caused primarily by atherosclerosis and thromboembolic pathophysiological processes that alter the normal structure and function of the aorta, its visceral arterial branches and the arteries of the upper and lower extremities. PAD is associated with an increased risk for cardiovascular morbidity and mortality. The goals for pharmacological therapy in PAD should focus on reducing cardiovascular risk, improving walking distance and preventing critical limb ischaemia. Exercise training plays a key role in the therapeutic assessment, as well stopping smoking. Antiplatelet therapy (aspirin) should be given to every PAD patient if there are no contraindications. Neither their combination nor anticoagulant therapy has shown additional benefit in PAD patients. Several pharmacological agents have been developed to improve the functional state of the claudicant and to relieve the symptoms. Many studied drugs have shown either no, a small or a potential benefit. With future development of new drugs for PAD, there is an absolute need for very strict well-designed protocols in order to evaluate the claudication distance, the progression of the disease and the reduction in cardiovascular morbidity and mortality. New developments should focus on improvement of endothelial function, vascular repair and enhancement of collateral circulation.

Journal: Expert Opin Pharmacother. 2007 Jul;8(10):1465-77.
Adapted from PubMed; click here to access full journal article.

Peripheral Artery Tonometry Demonstrates Altered Endothelial Function in Children with Type 1 Diabetes

Authors: Haller MJ, Stein J, Shuster J, Theriaque D, Silverstein J, Schatz DA, Earing MG, Lerman A, Mahmud FH.

Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL, USA.

Objectives: To assess the ability of reactive hyperemia-peripheral artery tonometry (RH-PAT) to serve as a surrogate marker of endothelial dysfunction in children with type 1 diabetes (T1D). Research Design and Methods: Forty-four children with T1D [age 14.6 +/- 2.7 yr; duration of diabetes 6.01 +/- 4 yr; range of diabetes duration 1-16 yr; and hemoglobin A1c (HbA1c) 8.34 +/- 1.2%] and 20 children without diabetes (age 14.1 +/- 1.5 yr) underwent RH-PAT endothelial function testing after an overnight fast. Height, weight, body mass index (BMI), blood pressure (BP), fasting lipid profile, and glucose level were determined in each child. Children with T1D underwent a second RH-PAT study 4 wk after their initial study to determine the intrapatient variability of the technique. Results: Children with T1D had endothelial dysfunction as evidenced by lower mean RH-PAT scores (1.63 +/- 0.5) when compared with children without diabetes (mean RH-PAT score 1.95 +/- 0.3) (p = 0.01). Repeat RH-PAT scores were predicted by initial RH-PAT scores (p = 0.0025). Mean intrapatient standard deviation of RH-PAT score was 0.261 and mean coefficient of variation was 14.8. Variations in RH-PAT score were not explained by differences in glucose, HbA1c, BMI, systolic BP, diastolic BP, or lipids. Conclusions: Although larger validation studies are required, RH-PAT is a promising non-invasive technique to assess endothelial function in children with T1D. Non-invasive measures of endothelial dysfunction may provide the additional risk stratification data needed to justify more aggressive primary prevention of cardiovascular disease in children with T1D.

Journal: Pediatr Diabetes. 2007 Aug;8(4):193-8.
Adapted from PubMed; click here to access full journal article.

Genetic Susceptibility to Peripheral Arterial Disease: A Dark Corner in Vascular Biology

Authors: Knowles JW, Assimes TL, Li J, Quertermous T, Cooke JP.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif; Stanford Human Genome Center, Department of Genetics, Stanford University School of Medicine, Palo Alto, Calif.

Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects approximately 12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibility to PAD is likely contributed by sequence variants in multiple genes, each with modest effects. Although many of these variants probably alter susceptibility both to PAD and to coronary artery disease, it is likely that there exists a set of variants specifically to alter susceptibility to PAD. Despite the prevalence of PAD and its high societal burden, relatively little is known about such genetic variants. This review summarizes our limited present knowledge and gives an overview of recent, more powerful approaches to elucidating the genetic basis of PAD. We discuss the advantages and limitations of genetic studies and highlight the need for collaborative networks of PAD investigators for shedding light on this dark corner of vascular biology.

Journal: Arterioscler Thromb Vasc Biol. 2007 Jul 26
Adapted from PubMed; click here to access full journal article.

The Effect of the Introduction of MR and CT Angiography on the Utilization of Catheter Angiography for Peripheral Arterial Disease

Authors: Levin DC, Rao VM, Parker L, Frangos AJ, Sunshine JH.

Department of Radiology, Thomas Jefferson University Hospital and Jefferson Medical College, Philadelphia, Penn, USA. david.levin@mail.tju.edu

PURPOSE: To determine whether the utilization rate of diagnostic catheter angiography (DCA) for peripheral arterial disease (PAD) has been affected by the utilization in recent years of magnetic resonance angiography (MRA) and computed tomographic angiography (CTA). METHODS AND MATERIALS: Medicare Part B data sets for 2000 to 2004 were reviewed to study utilization trends in the Current Procedural Terminology, 4th ed., codes for DCA, MRA, and CTA of peripheral arteries. The Medicare physician specialty codes were used to indicate procedures performed by radiologists, cardiologists, surgeons, and other physicians. Utilization rates per 100,000 Medicare beneficiaries were calculated. RESULTS: Between 2000 and 2004, the total utilization rate of all 3 types of angiographic procedures for PAD rose from 789 to 969 per 100,000 (+23%). The rate for DCA dropped slightly, from 767 to 761 per 100,000, whereas the rate for MRA and CTA together increased from 23 to 208 per 100,000. Almost all MRA and CTA were performed by radiologists. Among radiologists, the DCA utilization rate dropped from 486 to 334 per 100,000 (-31%); among cardiologists and surgeons together, the DCA rate increased from 228 to 387 per 100,000 (+70%). The total utilization rate of all diagnostic angiographic procedures for PAD among radiologists increased by 3%, compared with much higher rate increases among cardiologist and surgeons. CONCLUSION: Among radiologists, a substitution effect occurred, in that noninvasive procedures such as MRA and CTA progressively replaced an invasive procedure, DCA. However, the rapid increase in DCA utilization among cardiologists and surgeons led to an increase in the overall utilization rate of angiographic procedures for diagnosing PAD. Increasing self-referral for an invasive procedure such as DCA among these two specialties is of concern at a time when less expensive, noninvasive alternatives are readily available.

Journal: J Am Coll Radiol. 2007 Jul;4(7):457-60.
Adapted from PubMed; click here to access full journal article.

Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway

Authors: Senthilkumar A, Smith RD, Khitha J, Arora N, Veerareddy S, Langston W, Chidlow Jr JH, Barlow SC, Teng X, Patel RP, Lefer DJ, Kevil CG.

Departments of Cardiology, Pathology, and Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport; the Department of Molecular and Cellular Pathology and Center for Free Radical Biology, University of Alabama at Birmingham; and the Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, New York.

Background--Peripheral artery disease (PAD) is a prevalent cardiovascular disorder that results in tissue ischemia which can progress to critical limb ischemia. Restoration of tissue perfusion in the setting of chronic ischemia through stimulation of arteriogenesis and angiogenesis remains a key therapeutic target for PAD. However, experimental therapeutics, including growth factor and gene therapy, have had little clinical success indicating the need for a better understanding of molecular pathways required for therapeutic angiogenesis. METHODS AND RESULTS: Here we report that phosphodiesterase-5 inhibition by sildenafil significantly increases vascular perfusion, tissue blood flow, and vascular density during chronic ischemia of the mouse hind limb. Importantly, sildenafil therapy did not alter any of these parameters in nonischemic limbs. Sildenafil increased tissue cGMP levels independently of increases in nitric oxide production, and sildenafil therapy stimulated angiogenesis in ischemic limbs of eNOS(-/-) and iNOS(-/-) mice. Lastly, sildenafil-mediated angiogenic activity was blocked by inhibition of protein kinase G using the PKG antagonist DT-3. CONCLUSIONS: These data demonstrate that sildenafil therapy results in increased angiogenic activity through a PKG-dependent pathway that is independent of nitric oxide production or NOS activity and identify the angiogenic therapeutic potential of sildenafil for critical limb ischemia.

Journal: Arterioscler Thromb Vasc Biol. 2007 Jun 21
Adapted from PubMed; click here to access full journal article.

Prognostic Value of Ankle-Brachial Index and Dobutamine Stress Echocardiography for Cardiovascular Morbidity and All-Cause Mortality in Patients with Peripheral Arterial Disease

Authors: Thatipelli MR, Pellikka PA, McBane RD, Rooke TW, Rosales GA, Hodge D, Herges RM, Wysokinski WE.

Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

BACKGROUND: Peripheral arterial disease (PAD) is associated with an excessive risk for cardiovascular events and mortality. To determine measures prognostic of adverse events, ankle-brachial index (ABI) was compared with dobutamine stress echocardiography (DSE) in patients referred to our vascular center for the evaluation of PAD. METHODS: The medical records of consecutive patients referred for the concurrent evaluation of PAD and coronary artery disease (CAD) between 1992 and 1995 were reviewed for subsequent cardiovascular events and death. RESULTS: Among 395 patients (mean age, 69.7 +/- 9.6 years; 40% women), 341 had abnormal ABI and 268 had abnormal DSE (95 fixed and 173 stress-induced wall motion abnormalities). During a mean follow-up of 4.7 years, 27.3% of patients experienced a cardiovascular event, and 39.4% died. By multivariate analysis, ABI provided the strongest prediction of all-cause mortality (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.36 to 4.05; P = .002). Conversely, DSE with inducible or fixed wall motion abnormalities showed no association with cardiovascular events or increased mortality in multivariate analysis. The only DSE variable independently predictive of mortality was decreased left ventricular ejection fraction (<50%) at peak stress (HR, 1.70; 95% CI, 1.22 to 2.36; P = .002). Statin and aspirin therapy, but not beta-blockers, were protective. There was no relation between ABI and wall motion index score at rest or after stress. CONCLUSIONS: In high-risk patients referred to our vascular center for the evaluation of PAD, the assessment of ABI provided a strong independent prediction of all-cause mortality. Therefore, proper interpretation of this simple, affordable, and reproducible measure extends beyond the assessment of PAD severity. Although a poor left ventricular response to dobutamine was also predictive, other echo variables were not.

Journal: J Vasc Surg. 2007 Jul;46(1):62-70; discussion 70. Epub 2007 Jun 20
Adapted from PubMed; click here to access full journal article.

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