At each beat a heart's blood vessels, which are embedded in its surface, alternately stretch and contract, with some vessel segments bending or twisting in the process. All those push-pull, twist-turn motions substantially change the mechanics and chemistry of the arteries in ways that are not completely known, according to the engineers.
Such conformational changes, if they could be thoroughly understood, would provide doctors with a new set of "geometric risk factors" that might predict the early onset of atherosclerosis. Atherosclerosis is the development of restrictions and blockages in arteries that can lead to heart disease.
"We're trying to understand the development and origins of the disease", stated Morton Friedman, a biomedical engineering professor who leads the Cardiovascular Simulations Laboratory at Duke's Pratt School of Engineering. "We're also trying to identify people who might be predisposed to it. If we can understand why it happens, that may help us find ways to stop it or slow down its progress. The traditional risk factors for cardiovascular disease - high cholesterol, high blood pressure, smoking, diabetes, obesity - only explain about 50 percent of the disease's incidence. So other factors must be involved."
While other research teams have probed living vessels of the heart for ties to heart disease, Morton Friedman thinks the focus on dynamic geometry is pretty much that of his team. Professor Friedman was already searching for such geometric risk factors in cardiac vessels when he came to Duke in 2001 from the Ohio State University. Transferring with him were Hui Zhu, now a Duke assistant research professor of biomedical engineering, and Yun Liang, now among Professor Friedman's graduate students at Pratt.
Hui Zhu, whose training is in electrical engineering, is an expert in getting the most out of the images provided by two technologies used to visualize the interiors of blood vessels in live, beating hearts. The first technique, called biplane cineangiography, uses X-rays and an injected dye to create a kind of two-dimensional moving picture of blood flowing inside vessels. The second method, intravascular ultrasound, enables researchers to visualize the wall thicknesses of those vessels, as well as providing some idea of what the walls are made of.
Yun Liang, meanwhile, is enhancing the ultrasound information by extending it to the third dimension. And Hui Zhu is also an expert at statistically analysing images to determine whether certain vessel geometries can be linked to indications of early atherosclerosis.In an article in the December 2003 issue of the research journal Arteriosclerosis, Thrombosis and Vascular Biology, Professor Friedman and Hui Zhu described their use of all these tools to find statistical links between the thickness of vessel walls and how the arteries curve and twist during a heartbeat.
"These thickness variables are of particular interest, because wall thickening is an important part of the atherosclerotic process", the two Duke researchers wrote. In the early stages of a developing blockage, the wall of a diseased coronary artery "actually grows outward to maintain the opening", Professor Friedman explained, "but eventually that so-called compensatory enlargement becomes insufficient."
The growth of such obstructions is a complex process, according to Professor Friedman. First, fatty materials called lipids enter the wall from the blood. Those deposits induce an "inflammatory response" by blood cells that collect and die in the same place. Other cells then accumulate there too. These accumulations form the deposits called plaque, which Professor Friedman described as "a whole mishmash of fibrous materials, lipids, dead cells, calcium and cholesterol crystals".
In some cases, the end result is a plug that fills most of the vessel opening known as the lumen. But "in most cases that lead to heart attack that's not what happens", he added. "In most of those cases the plaque is fragile. As a result it ruptures. And in breaking it exposes all this junk to the blood. Then a clot forms that actually blocks the vessel."
Professor Friedman noted that certain enzymes attack plaque, making it weaker and more vulnerable to rupturing. "It could be that the flexing of vessels as the heart beats could have a role in deciding which plaques are more likely to rupture", he stated. "If we got to the point where we really could understand what is going on, perhaps we could identify people whose arterial dynamics or geometry put them at greater risk."
Under their newly funded four-year NIH research, Professor Friedman's team will investigate the validity of several hypotheses with collaborators at Duke Medical Center, Vanderbilt and Texas A&M universities and the University of Texas/Southwestern Medical Center. One hypothesis holds that "the local geometry and motion" of disease-prone vessel segments "has a significant influence on the initiation, progression and stability" of atherosclerosis. Another proposes that "different features of artery geometry and motion play influential roles at different stages in the development of coronary artery disease".
The Duke team will apply its visualization and analytical techniques to cineangiogram and intravascular ultrasound images of living human patients provided by several of their collaborators. Only some of those scanned vessels will be diseased, as Professor Friedman stressed. "In addition to the diseased cases, we are developing a catalogue of coronary artery motion on the normal human heart so we can start to identify what is normal and what is not", he stated.
To do detailed studies that would be inappropriate in living human patients, the engineers will also apply these techniques to laboratory mice that have been genetically modified to predispose the animals to developing atherosclerosis. "Over a reasonably short period of time we can get lesions in the mice that look a lot like human lesions", Professor Friedman concluded. "Their coronary anatomy is close enough."