Stanford Report Online

Stanford Report, October 25, 2000
Cardiac surgeon's heart valve map parallels human genome project


Cardiovascular surgeon D. Craig Miller, MD, spends more time thinking about mapping than plumbing, but he concedes that understanding how valves in a household open and close has relevance to his longstanding, potentially lifesaving research.

The Stanford cardiovascular surgeon is immersed in a federally sponsored research project to "map" the plumbing problems that cause heart murmurs and valve leakage in the human heart.

Miller and his colleagues at Stanford and the Research Institute of the Palo Alto Medical Foundation believe that an exact map will allow heart surgeons to plan and perform more precise operations to correct ischemic mitral regurgitation (IMR). This is a difficult-to-treat condition, affecting between 1.2 and 2.1 million people in the United States, including about 400,000 who face life-threatening consequences.

"IMR remains one of the most vexing, life-threatening clinical problems remaining in cardiac surgery. It markedly limits the patient's functional well-being, and has major adverse implications for health care costs," Miller noted.

So far the team has found that heart valves seem to "have a life of their own," Miller said. Rather than reacting passively -- opening and closing in response to the rush of blood through vessels -- the valves seem to "know" in advance when to open and close, and may even send signals to each other, the 10-year research project has disclosed. Nerves, muscle fibers, mechanical interactions, and possibly even molecular receptor systems in the valves may actually anticipate the timing of blood flow. These early warning systems then modulate or "alert" the valves, telling them when and how to open and close, Miller said.

Using some 36 miniature (1 to 2 mm) metal markers placed on structures inside beating sheep hearts, Miller and colleagues are currently creating three-dimensional, nearly "real time" motion studies of normal and leaking mitral valves.

To render 3-D images of the valves, Miller takes high-speed, X-ray movies of the beating heart from two angles simultaneously. Since X-rays won't photograph soft tissue, the markers are needed to cast shadows that the camera can record, Miller explained. Experienced technicians use computers to identify, digitize and track the location of each individual marker, frame-by-frame, every 17 milliseconds. This renders a 3-D picture of all parts of the mitral valve leaflets (or flaps) as they open and close. Miller also tracks other sites in the main pumping chamber of the heart, the left ventricle.

Building the detailed pictures that result from such intricate tracking is as essential to understanding heart function as the human genome project is for understanding human genetics, Miller believes. The parallel stems from the need "to understand the plumbing and mechanics with incredible thoroughness, because ignoring or misunderstanding even the smallest detail can have deal-breaking consequences in terms of finding durable repair solutions," Miller said.

"Once the fine motion of the valve leaflets is mapped and the control mechanisms more fully characterized, this knowledge might help us understand many different cardiac valve problems in ways that are so far unseen," said fellow Stanford heart surgeon Philip E. Oyer, MD, PhD.

The marker study, said Miller, should eventually be used both to develop and to validate sophisticated computer and mechanical engineering models of cardiac mechanics and valve function.

IMR occurs when coronary blood flow to the heart is restricted, causing damage to the left ventricle because of lack of blood supply. The result is that the mitral valve leaflets remain normal, but leak. Other forms of mitral valve disease ­ prolapse or rheumatic valve disease ­ are easier to understand in an echocardiogram or during surgery, because they cause abnormal leaflets are easier to spot, Miller explained.

As anyone who has ever tried to fix a leaky faucet understands, it doesn't take a major problem with the size or placement of a fitting to cause a leak. Heart surgeons have a similar difficulty, Miller said.

"Very subtle, less than 1 - 2 mm, changes in the complex 3-D leaflet geometry, and in relationships with other structures inside the ventricle, can mean the difference between a well-functioning valve and one that leaks severely," Miller said.

Surgery to repair the valve, when possible, is often successful and preferable to replacing the valve, but cardiac surgeons remain frustrated today because they still do not know exactly why the mitral valve leaks when IMR strikes.

"It's quite silly, really, to pretend we know how to repair mitral valves that leak due to the consequences of ischemic heart disease when nobody truly understands why they leak in the first place," Miller said.

David Lai, MD, a Fellow of the Royal Australasian College of Surgeons who has spent two years as a research fellow in Miller's lab, noted that fixing heart valves is unlike plumbing, where changing a washer is a common and relatively trivial activity. In the heart, the valves are living, "smart" tissues and should be repaired rather than replaced if possible.

Miller initially received funding for such experimental studies in 1982 from the National Institutes of Health (NIH), and his $2.5 million NIH grant was recently renewed through February 2004. Nationally, less than 15 to 20 percent of applications receive such NIH funding in the current competitive environment, Miller noted. Additionally, a second, related NIH application is currently pending.

Miller, one of the busiest practicing faculty heart surgeons, has been a Stanford faculty member since 1978. He currently holds the Thelma and Henry Doelger Professorship in Cardiovascular Surgery, and focuses primarily on patients with valvular heart disease or thoracic aortic aneurysms and dissections.

His co-investigators in the current experimental work include bioengineers Neil B. Ingels, PhD and George T. Daughters, MS of the Department of Physiology and Biophysics at the Research Institute of the Palo Alto Medical Foundation, and David H. Liang, MD, assistant professor of cardiovascular medicine at Stanford.