Dr. Agrawal has received $3.12 million in funding from the National Institutes of Health (NIH) for the five-year study to examine how a patient’s vitamin-D levels might affect whether, and how quickly, arteries start to narrow again after angioplasty and after stents have been inserted.
Agrawal said the re-narrowing is basically an inflammatory response, and vitamin D plays an important role in the immune system.
“My interest always has been to look into the role of micronutrients as to how they affect the immune system,” Dr. Agrawal told NutraIngredients-USA.
“About seven or so years ago I came across the role of vitamin D in regulating certain diseases. Vitamin D does that because certain immune cells have receptors for vitamin D. And not only the receptors, but mechanisms to covert 25-hydroxy vitamin D into an active form. That triggered my interest,” he said.
In the case of angioplasty and stents, the treatment, while lifesaving, does involve some damage to blood vessels, and the body reacts to that injury. Discovering the precise role of vitamin D in mediating that response is the goal of the new study.
“During such procedures, either angioplasty or stenting, there is always some component of mechanical injury,” Dr. Agrawal said. “That further stimulates the immune response, which further activates the immune cells that are present at the site, and those are the cells that lead to the re-closure of the arteries.”
Agrawal noted that the plaques that clog arteries are composed mainly of cholesterol and calcium. But, he added, “we’ve known for a long time that there are a lot of immune cells in there.”
“The re-closure mostly occurs at the edges of the stents where there is the most mechanical injury,” Agrawal said. Stents can close in the middle, too, when smooth muscle tissue starts to grow helter-skelter toward the center of the artery through the mesh that forms the walls of the stent. Drug-coated stents can control this to some extent, but do little to quell the buildup at the stent’s edges.
It’s a big problem. Agrawal noted that the rate of re-closure after angioplasty and stenting is high; 20-30% in the first two years and as high as 50% in the three-to-five year time frame.
In addition to the danger of re-closure, patients who have stents in place face a high risk of dangerous blood clot formation. So they often receive maintenance prescriptions of anticoagulant medication, Dr. Agrawal said, and that carries its own risks and side effects.
“If you look at the population, about 35-40 percent are vitamin D deficient. It matches very well with the incidence of coronary heart disease,” he said. It also correlates well with the percentage of patients who suffer renewed arterial blockages after treatment.
“So my goal has been to try to find something better,” he said. If a controlled study can prove the role of vitamin D in this problem of re-closure, patients can be coached to have adequate supplementation to head the problem off at the pass. Or perhaps to help prevent the plaques from forming in the first place, he said.
Pigs stand in for people
Humans, especially sick ones, are difficult subjects for nutrition studies, Dr. Agrawal said. Leaving the obvious ethical (and regulatory) problems aside, in the case of vitamin D there are variables of seasonal sunlight exposure and skin pigmentation, too many variables to adequately control for.
Fortunately, nature provides a nearly-perfect cardiovascular stand-in for humans in the form of pigs. Dr. Agrawal’s study will use a special breed of dwarf Mexican pigs called Yucatan microswine that were developed to closely mimic human atherosclerotic symptoms, and to develop arterial blockages relatively early in their lives when fed a high-fat diet. They also have the advantage of only reaching 80-100 pounds or so at maturity, making them less expensive to raise and easier to handle than conventional breeds.
“It’s not an easy model to work with. It’s really expensive, really difficult,” Dr. Agrawal said. But, he said, unlike other potentially cheaper models that have been tried, such as rabbits, results from this type of model can be applied to humans with a very high degree of confidence.
One group of swine will be fed a diet that includes adequate vitamin D3, to act as a control. Another group will be vitamin-D deficient, while the third will be supplemented. The pigs will be induced to develop atherosclerosis and then will have stents implanted and followed up for eight months thereafter. The results could shed light on what a given patient’s 25-hydroxy vitamin D level should be to insure the best hope for success for the stenting procedure.
“We are going for the molecular level,” he said. “How does it really work?"
The Holy Grail: personalized nutrition
“So far what we are calling sufficient, insufficient or deficient vitamin D levels is based on our knowledge of the musculoskeletal system. It is related to bone only. We do not know what is the normal for the cardiovascular system, or for lung function.”
Tissue for the swine in the study will be used in other projects related to vitamin D, he said, including research into fatty liver disease, reflux disease and inflammatory bowel conditions.
“My ultimate goal is to develop a personalized care for the patient,” Dr. Agrawal said. “We all know we are heading in that direction. We may have to come up with parameters for each and every patient.”
Dr. Agrawal is part of a powerful vitamin D team. The research group at Creighton, located in Omaha, Neb., includes longtime vitamin D authority Robert Heaney, MD, who began researching the vitamin there more than 25 years ago. Other researchers at the school include Joan Lappe, PhD, Robert Recker, MD, and Laura Armas, MD.