Expert Q&A with Alan Dardik, MD, PhD

Will growing new blood vessels be a palpable reality in the foreseeable future? And if so, what do you envision as the greatest potential of such capability from the clinical perspective?

There is no question in my mind that therapeutic angiogenesis will be here soon. Indeed, hardly a journal goes by that we don’t see another study describing another small series of patients. But what we need are the results of randomized trials. The first reports were just described at last June’s Society for Vascular Surgery meeting, and now we await the published results. However, to put things in perspective, we have to understand the difference between angiogenesis and arteriogenesis. Angiogenesis is the building of small blood vessels, such as capillaries, from preexisting blood vessels. Arteriogenesis is the building of larger blood vessels, such as collateral vessels. Therapeutic angiogenesis is the therapeutic use of building small vessels and the focus of much of today’s therapy. I suspect that therapeutic angiogenesis will be suitable for small-vessel disease such as diabetes or Beurgher’s disease. But many questions remain — the best drug to use, the best stem cells to use, how to give them, where and when — all remain to be optimized. However, therapeutic arteriogenesis is still far away from trials and may never be here. I envision therapeutic arteriogenesis as appropriate for patients with severe tissue loss who need large quantities of inflow delivered in a quick time frame — this just isn’t ready yet. For now, that remains the role of conventional and endovascular surgery.

You and your team at Yale are doing exciting research in the areas of intimal hyperplasia and failure modes of arterialized veins. Can you briefly summarize what findings and new understandings you have so far achieved?

My research team is trying to understand why vein grafts fail. However, our approach is a bit different than that taken by many other laboratories, most of whom focus on preventing smooth muscle cell proliferation and/or migration into the thickened neointima. We are concentrating on how successful vein grafts adapt to the arterial circulation. We all know that vein grafts thicken in response to the arterial environment of pressure and flow. How the vein graft senses just exactly how much to thicken, is what we are trying to understand. I think we want to control a very finely balanced system in the context of advanced patient comorbidities. As I mentioned, our approach is a bit different. We are taking some lessons from the early embryo, and trying to understand how some embryonic genes are working in the adult. My laboratory focuses on Eph-B4. Eph-B4 is one of the embryonic determinants of our venous system, and it works in concert with Ephrin-B2, one of the determinants of our arterial system. We have found that when surgeons operatively place a vein graft into the arterial circulation, Eph-B4 goes away, but Ephrin-B2 does not turn on. In other words, the vein stops being a vein, but it does not turn into an artery. We are trying to understand and control this process. I am pleased that we are making some progress, but clinical trials are still a bit down the road.

What are your findings thus far in your research on the role of age in response to carotid angioplasty?

We are studying this problem as well; our laboratory is also interested in examining some of the patient factors that affect the outcome of what vascular surgeons do. Age is one of these factors. We have found that aged rats have an exaggerated injury response to carotid angioplasty, much more so than younger rats. We have found that this response may reflect differences in the immune system between young and aged animals, which we know reflects the situation in young and elderly humans. The data point us to a role for the immune system in the composition of the carotid plaque. Interestingly, we recently published that these same immune cells appear in the circulation in patients with critical ischemia, and then disappear following successful surgical bypasses. I hope that we are making some important connections between the immune system and the vascular system. Needless to say, this is an exciting direction. If any of your readers want to help us in our research, please let me know.

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Dr. Alan Dardik trained at Yale, the University of Pennsylvania, and the Johns Hopkins Hospital before his appointment to the Yale faculty in 2001. Dr. Dardik concentrates his clinical practice in vascular surgery at the VA Connecticut where he is the Chief of the Vascular Surgery section, focusing his practice on teaching of medical students, residents, and fellows. The Dardik laboratory studies the healing and function of blood vessels and synthetic blood vessel substitutes that are used in patients having vascular bypass surgery. We are currently trying to understand the fundamental molecular mechanisms by which vein graft adaptation results in positive remodeling and successful adaptation to the arterial environment, yet often proceeds, in the long-term, to neointimal hyperplasia and graft failure. The laboratory is R01 funded from the NIH NHLBI and, as part of Yale's Interdepartmental Program in Vascular Biology and Therapeutics, is located on the 4th floor of the Amistad building. Members of the Dardik laboratory include surgery residents from Yale and St. Mary’s Hospital as well as postdoctoral fellows from Japan, China, and India. E-mail: alan.dardik@yale.edu