$4.5 million NIH grant supports BWH research to identify and describe mechanisms that contribute to the morbidity, progression, and outcomes of PAD.
Peripheral arterial disease (PAD) affects between eight and 12 million Americans. PAD patients may experience intermittent claudication, pain, reduced quality-of-life, and in extreme cases, they may be at risk for limb loss. Yet unlike coronary artery disease, PAD is not well understood and is probably underdiagnosed.
Recently, a team headed by Mark A. Creager, MD, and consisting of experts in cardiovascular medicine and vascular surgery from Brigham and Woman’s Hospital’s (BWH) Shapiro Cardiovascular Center, received a five-year $4.5 million NIH grant to support research in peripheral arterial disease.
The purpose of the grant is to identify and describe mechanisms that contribute to the morbidity, progression, and outcomes of PAD. The study has three components – with the common theme of inflammation, insulin resistance, and PAD – including a biomarker identification component, a medical treatment component, and an observational surgical outcomes component.
Inflammatory Signature for PAD
Paul M. Ridker, MD, MPH, Director of the BWH Center for Cardiovascular Disease Prevention, is investigating how inflammatory markers may relate to the subsequent development of PAD in 27,000 healthy women enrolled in the Women’s Health Study. Researchers took baseline blood samples, and women were queried at intervals regarding symptoms of PAD and whether they had undergone any PAD-related procedures.
In the group of women who subsequently developed PAD, researchers are looking at a variety of inflammatory markers, including C-reactive protein (CRP) to determine if and how these markers may relate to the development of PAD. Although coronary artery disease, stroke, and peripheral artery disease are all associated with atherosclerosis and inflammation, researchers believe that different markers and different phenotypes may be implicated in the development of different types of vascular disease, and they are looking for a specific inflammatory signature for PAD.
Dr. Creager says, “We are currently analyzing the results of this study and will be reporting on them. Dr. Ridker has already published the results of several studies relating the presence of CRP with subsequent development of PAD in men.”
Impact of Inflammation and Insulin Resistance on PAD
Dr. Creager is lead investigator at BWH for a multi-center randomized trial investigating whether inflammation and insulin resistance contribute to reduced walking ability in PAD patients and whether drugs that reduce inflammation and improve insulin resistance may reduce symptoms of intermittent claudication and improve walking ability.
Appropriate candidates for the study are men and women, 40 years of age or older, who have intermittent claudication due to PAD and who are not limited by other problems that affect their ability to walk on a treadmill. Patients have a baseline treadmill test and are randomized for treatment with rosiglitazone, atorvastatin, or placebo in a two-by-two factorial design protocol.
After four months of treatment, patients take another treadmill test to determine whether any treatment favorably affected their walking ability. Other tests will seek to elucidate the mechanisms of improvement and whether improvement was attributable to reduction in inflammation, improvement in small blood vessel function, and/or improvement in skeletal muscle metabolism.
Dr. Creager says, “We expect to complete this study component in 2008. This is a very exciting study and we are confident it will contribute to our understanding of the mechanisms of PAD and shift the paradigm of our thinking about the most effective therapies.”
Role of Inflammation in the Durability of Bypass Grafts for PAD
Patients with advanced PAD may have such severely compromised blood vessels that they have pain at rest, are in danger of developing ulcers and gangrene, and require surgical revascularization to avoid limb loss. Vascular surgeon Michael S. Conte, MD, has a special interest in improving the durability of surgical revascularization for PAD.
“The cornerstones of our bypass program for PAD are experienced surgeons and use of native vein. Our results are recognized in the literature as among the best in the world, but here, as in other centers, 30 to 35 percent of patients undergoing bypass experience restenosis in the graft within five years, and we do not know why,” explains Dr. Conte. Dr. Conte is BWH lead investigator for the third component of the grant, an observational study that will attempt to establish an association and perhaps suggest a causal relationship between levels of inflammation and healing patterns in patients undergoing surgical revascularization.
Patients will have blood tests to measure levels of a panel of inflammatory biomarkers as well as sophisticated imaging studies including high-resolution ultrasound and MRI in order to look at changes in the wall of the vein over time.
Frank Rybicki, MD, PhD, is directing the MR imaging portion of the study. Researchers will try to identify which patients develop an aggressive scarring response and to target specific anti-inflammatory therapies for those patients.
Multidisciplinary Care Benefits PAD Patients
Dr. Conte notes that patients with the most severe form of PAD – critical limb ischemia – may not be diagnosed until there is irreversible damage to a foot or limb. For this group of patients especially, increased awareness and early referral to a comprehensive vascular program are essential.
Dr. Creager adds, “Patients with advanced PAD are also at elevated risk for cardiovascular events, including heart attack and stroke, and benefit from an aggressive multi-specialty treatment approach including medical management and endovascular and surgical approaches. BWH was among the first centers – almost two decades ago – to establish a true multidisciplinary collaboration between vascular medicine and vascular surgery to serve PAD patients. Today the Vascular Center – part of the Brigham and Women’s Hospital Cardiovascular Center – encompasses basic and clinical research, prevention, a world-class vascular diagnostic laboratory, and multi-specialty therapeutics to serve patients with all forms of vascular disease.”
The Center sees 6,700 PAD patients annually. Clinicians perform approximately 630 diagnostic and interventional endovascular procedures and 960 surgical procedures for limb salvage, and aortic, infrainguinal, and carotid disease.
Referrals and Information
Our vascular disease specialists welcome physician inquiries and referrals. Please contact our Physician Referral Service at 1-800-MD-TO-BWH.
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