Raul J. Guzman, MD
Associate Professor of Surgery, Harvard Medical School
Yujun Cai, PhD
Tonghui Lin, PhD
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 transformed into more 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 are 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, is 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.
My laboratory moved to Boston from our previous home in Nashville, Tenn. in 2013. Over the past four years, we have begun new and exciting research collaborations with several investigators on campus. We are particularly fortunate to have entered into a new collaboration with Aristidis Veves, MD, from our Division of Podiatry, Research Director of the Microcirculation Lab and Director of the Rongxiang Xu, MD, Center for Regenerative Therapeutics. We are working together to initiate studies aimed at understanding the relationship between arterial calcification and ischemia in patients with diabetes. We have recently demonstrated that the association between calcification and foot ulcers is independent of arterial occlusion. Because this association remains undefined, however, we hope to develop a large clinical data set on diabetic patients with and without foot ulcers to study this problem. We are also currently initiating new protocols that quantify arterial calcification in patients undergoing endovascular interventions. Our hope is that we can use this unique data set to gain a more precise understanding of why calcification predicts increased amputation risk.
Our basic investigations have also been stimulated by the addition of Yujun Cai, PhD, Instructor in Surgery to our team. Dr. Cai has extensive experience in studies related to the role of phosphodiesterases in vascular remodeling. His work has been published in leading vascular journals including Circulation Research and ATVB. We plan to continue his work on phosphodiesterases as they related to osteogenic SMC transformation and calcification. Our hope is that these exciting findings will translate into novel therapies to reduce arterial calcification and in improve outcomes in patients with diabetes and renal disease.
Teaching, Training, and Education
My educational contributions have primarily been in the teaching of general and vascular surgery residents in the operating room and on the inpatient wards. I also have been fortunate to mentor and supervise young surgery residents during their basic research experience. While much of my teaching is clinically oriented, I also enjoy teaching in the laboratory and, in particular, enjoy training our residents in methods of careful experimental design, execution, and interpretation of research results.
Selected Research Support
Role of MMPs in arterial calcification; NIH, NHLBI, 2017 – 2018; PI: Raul Guzman, MD (0Co-investigator Dr. Yujun Cai, PhD)
This purpose of this study is to investigate the role of MMPs in arterial calcification and the potential for a dedicated clinical trial to assess the role of MMP inhibition strategies to reduce calcification and improve outcomes in our patients with vascular disease. Our hypothesis is that MMP-3, induced by inflammation and elevated phosphate levels, promotes osteogenic transformation of vascular SMCs and medial calcification through both local and systemic effects.
Zettervall SL, Soden PA, Ultee KH, Seldon C, Oh J, McGann K, Schermerhorn ML, Guzman RJ. Elevated serum phosphate levels are associated with decreased amputation-free survival after interventions for critical limb ischemia. J Vasc Surg 2017;65(2):431-437.
Zettervall SL, Marshall AP, Fleser P, Guzman RJ. Association of arterial calcification with chronic limb ischemia in patients with peripheral artery disease. J Vasc Surg 2018;67(2):507-513.
Wise ES, Wergin JE, Mace EH, Kallos JA, Muhlestein WE, Shelburne NJ, Hocking KM, Brophy CM, Guzman RJ. Upper extremity pulse pressure predicts amputation-free survival after lower extremity bypass.
Am Surg 2017;83(7):804-811.
Lin T, Wang XL, Zettervall SL, Cai Y, Guzman RJ. Dorsomorphin homologue 1, a highly selective small-molecule bone morphogenetic protein inhibitor, suppresses medial artery calcification. J Vasc Surg 2017;66(2):586-593.