My research focuses on the role of arterial calcification in lower-extremity vascular disease. We are interested in the mechanisms by which smooth muscle cells in the arterial wall become phenotypically transformed into bone-like cells. This primarily occurs in patients with diabetes and renal failure.

In previous studies using cell culture systems and rodents, we showed that the matrix-degrading enzymes known as MMPs were critical factors in the development of medial artery calcification and that reducing MMP activity could prevent medial calcification in vitro and in vivo. We have been working to better understand how MMPs promote calcification and whether these inhibitors can be used in the clinical setting to prevent vascular calcification in patients. During our work on MMPs, we found that a class of bone-related factors known as bone morphogenetic proteins, or BMPs, are up-regulated during arterial calcification. Through collaborations with several investigators, we have begun to study the potential role of new synthetic small-molecule BMP inhibitors in our calcification models. The ultimate goal of our basic studies is to gain insight into mechanisms that control calcification so we can develop clinically relevant therapies for use in our patients with critical limb ischemia.

Through clinical studies we have undertaken over the last eight years, we have learned that the amount of calcification in lower extremity arteries is a better predictor of long-term amputation risk than demographic and vascular risk factors. More recently, our research has focused on the finding that extensive arterial calcium is associated with poor limb outcomes in a manner that is independent of occlusive disease. This finding is contrary to previous notions of how vascular disease affects lower extremity blood flow. Currently, we are evaluating the hypothesis that arterial calcification, perhaps by affecting vessel wall compliance, contributes to limb ischemia and increases amputation risk in vascular patients. Our ultimate goal is to develop pharmacologic therapies to decrease calcium accumulation, improve arterial wall compliance, and thus reduce amputations in patients with diabetic vascular disease.

SELECTED RESEARCH SUPPORT

Role of arterial calcification in restenosis; NIH, 2010-2015; PI: Raul Guzman, MD

Methods to reduce vein harvest injury; NIH, 2013-2016; Co-investigator: Raul Guzman, MD (PI: Joyce Chueng-Flynn, PhD)

SELECTED PUBLICATIONS

Guzman RJ, Bian A, Shintani A, Stein CM. Association of foot ulcer with tibial artery calcification is independent of peripheral occlusive disease in type 2 diabetes. Diabetes Res Clin Pract 2013;99(3):281-6.