The first VCRN project seeks to improve the success rate of procedures to open blocked arteries in the leg for patients suffering from peripheral artery disease (PAD). PAD is estimated to affect over 200 million people world-wide, a 25% increase in the last decade associated with aging and the global epidemic of diabetes. PAD is caused by atherosclerosis in the arteries of the leg that can cause significant pain and inability to walk, as well as potential amputation and death. In the US, PAD affects 10 million Americans including 20% of those over 65, with higher hospital treatment costs than stroke and coronary heart disease, requiring hundreds of thousands of surgeries each year. Despite this, research in PAD has lagged far behind that in coronary and cerebrovascular diseases, resulting in major existing gaps in medical knowledge, diagnostics, and therapeutics specific to this large and growing burden of disease.
Primary treatments used to restore blocked blood flow in PAD (angioplasty, stenting, bypass surgery) have a failure rate as high as 50% within two years due to a cascade of events that include inflammation, cell growth, and scar tissue formation. Despite technical advances, this rate has remained essentially unchanged due to inadequate knowledge of the biology that drives vessel healing in humans. Breakthrough research in this area will require multi-center, multi-disciplinary collaboration. Failure typically results from recurrent narrowing (restenosis), and multiple lines of evidence suggest that the magnitude and duration of the inflammatory responses to vascular injury is a critical determinant. Identification of the critical biomarkers defining this injury response in PAD patients will provide new opportunities for targeted treatments to improve outcomes. We propose to develop a transformational research platform to address this gap, powerfully accelerated by the first comprehensive effort to collect blood, tissue samples, and clinical and imaging data from PAD patients undergoing these procedures.
Our long-term goal is to define biochemical and genetic determinants of vascular healing that will enable improved clinical management, and will suggest new treatment targets to improve patient outcomes in advanced PAD. Our short-term goal is to establish the first integrated clinical database and biobank from PAD patients undergoing vascular interventions, allowing for biochemical mapping of inflammation and resolution pre- and post-intervention, and their correlation with outcomes. Successful implementation of this singular collaborative research program will create a unique, long-term research asset and drive novel, clinically relevant discoveries in vascular medicine for years to come.
We are beginning with a pilot program with five clinical sites to: verify the patient recruitment, biosample and data collection processes, and generate initial candidate molecules to be confirmed by subsequent studies. Once this is complete, we will be able to expand the number of sites and leverage the network and biobank for translational research studies in vascular disease.
Increasing evidence suggests that normal healing requires a specific sequence and timing of gene activation, with production of specific proteins and bioactive lipids that may promote or resolve inflammation. Our prior work has demonstrated the importance of systemic inflammation in PAD patients undergoing surgical revascularization, the measurement of novel lipid mediators of inflammation and resolution in patients with vascular disease, and the identification of a genetic polymorphism associated with leg bypass surgery outcomes (PubMed: J Vasc Surg. 2013 Jan 9. doi:pii: S0741-5214(12)02432-9). To learn more about this pilot study click here.
The pilot study protocol follows that for PREDICT-PVI (Understanding Restenosis: Genomic and Proteomic Determinants of Peripheral Vascular Intervention). The study protocol has already been IRB approved at three sites, and enrollment initiated. Initial samples from UCSF and the SFVA have been processed, received, and validated within the electronic tracking system and integrated database.
The overall goal of PREDICT-PVI is to identify biomarkers related to vascular healing after leg arteries blocked by peripheral artery disease (PAD) are opened. Patients are being enrolled in two groups: one focused on vein bypass surgery and the other focused on restenosis in arteries treated by endovascular means (angioplasty, atherectomy, stenting). Demographic, clinical, and procedural data will be collected as a baseline. Clinical and imaging data will be obtained over the follow up period in accordance with standard post-procedural surveillance practices. Blood samples will be obtained for genomic DNA and plasma biomarkers at 3-4 time points. The genetic and proteomic strategy will be hypothesis-based testing of specific candidate genes/proteins that are considered potential candidates based on other related clinical or basic laboratory investigation. In the vein bypass study, a biopsy sample of the vein conduit will be obtained at the time of initial surgery for potential uses such as immunostaining or transcriptional analysis to examine baseline gene expression patterns.