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At the heart of innovation

A rat heart is drained of its cells and then reinfused with new cells and reanimated.

U heart experts honor the past as they create a new future in cardiac care

University of Minnesota scientists have ushered in the new millennium with cardiovascular breakthroughs that could be mistaken for science fiction. One research team created a beating heart in the laboratory by removing all the cells from a dead rat heart and then seeding the remaining scaffolding with live, immature heart cells. Across campus, surgeons are using tremor-free robotic arms to perform coronary artery bypass surgery, eliminating the need for an open-chest procedure; and preventive cardiologists are detecting cardiovascular disease in its earliest, still silent forms. Just as renowned University heart surgeon C. Walton Lillehei, M.D., Ph.D., and his colleagues were at the vanguard of their field more than half a century ago, a new cadre of University clinicians and scientists is forging cardiovascular medicine’s new future.

“There is no question that we walk in the footsteps of legends. This institution has a huge history, and that’s benefited us,” says Daniel Garry, M.D., Ph.D., director of the University’s Division of Cardiology and head of the Lillehei Heart Institute (LHI). “But we also have had tremendous recent accomplishments—not just within the past several decades but months, weeks, even days ago—that’s what we’ll build from when we look 5 or 10 years ahead.”

As director of the Division of Cardiology and head of the Lillehei Institute, Daniel Garry, M.D., Ph.D., is leading University heart researchers and clinicians as they help shape the future of cardiovascular medicine.

Leading-edge basic research that holds real promise for patients drew Garry, who received his M.D. and Ph.D. in cell biology and neuroanatomy from the University of Minnesota and completed his residency here in internal medicine, back to the University in 2007. Most recently, he had been director of the Cardiovascular Regeneration and Stem Cell Center at the University of Texas Southwestern Medical Center.

“I saw the opportunity to take my interests in stem cell biology and regenerative medicine to a translational level,” says Garry, who now holds the St. Jude Medical Cardiovascular Chair in Biomedical Engineering.

In his laboratory, Garry investigates the molecular networks that direct stem cells to form heart cells—both during organ development and following an injury.

As head of the cardiology division and LHI, he leads the clinicians and scientists who make the University a premier institution for cardiovascular care and research. Here are some examples of the pioneering work that’s keeping the division at the forefront.

Expanding boundaries

Lab team Stefan Kren, Brian Breviu, Doris Taylor, Ph.D., and Thomas Matthiesen used a process called decellularization to remove all of the cells from a cadaver rat heart and then reanimated it with new heart cells.

In January, Doris Taylor, Ph.D., director of the University’s Center for Cardiovascular Repair, her lab team, and research associate Harald Ott, M.D. (now a surgical resident at the Harvard Medical School), created a beating rat heart from a cadaver organ.

In a process known as decellularization, the team removed all of the cells from the rat heart, leaving only the scaffolding that Taylor calls the extracellular matrix. When the researchers populated the matrix with newborn rat heart cells, the organ came back to life; in a little over a week, it was contracting enough to pump blood out of the aorta.

Taylor and her team have since transplanted the heart into the abdomen of a rat to show it could live and survive. And it has.

“A lot of this is really fairly simple, but maybe the reason it hasn’t been done before is that no one thought it could be done—or maybe no one was willing to give it a shot,” says Taylor, who holds the Medtronic Bakken Chair in Cardiovascular Repair. “Nature is pretty darned smart, and if you just let it do its job and get out of the way, it seems to figure out what to do.”

The clinical implications of Taylor’s research—the latest in a series of research firsts achieved in this lab—transcend the boundaries of her discipline. “By having proof of this concept, we’ve opened a new door in the field of organ transplantation,” she says. “You can now imagine a scaffold for virtually any organ, and we’re committed to creating the first one. We are years away, not decades away, from having this happen in humans.”

Mechanized marvels

Meanwhile, as such laboratory-based discoveries advance, surgeons are using state-of-the-art devices to treat patients whose hearts can’t wait.

In 2003, cardiac surgeon [Kenneth Liao, M.D.,](http://www.surg.umn.edu/Faculty_Alpha/liao_kenneth_k/home.html) head of the minimally invasive cardiac surgery program and surgical director of heart transplantation, performed Minnesota’s first coronary artery bypass graft (CABG) surgery using robotic arms. Free of tremors and ultra-precise in their movements, the arms eliminate the need to open the chest and touch the aorta. Instead, surgeons make small incisions in the rib cage, then direct the arms’ movements with handheld controls on a console. Patients undergoing the procedure have a quicker recovery and shorter hospitalization than those who undergo traditional open-chest surgeries.

Minimally invasive heart procedures performed by surgeons such as Kenneth Liao, M.D., have especially benefited patients who otherwise may have been too fragile for surgery.

In April 2007, Liao teamed up with Gladwin Das, M.D., director of interventional cardiology, to perform the first hybrid procedure, which involves treating the left side of a diseased heart with CABG and the right side with stents.

“Before hybrids, we would do both left and right repair with open-chest surgeries, and that was difficult for some patients, especially those over 80,” says Liao. “Now, we can completely and effectively treat the disease without opening the chest—and without using the heart-lung machine.” So far, the team, one of only a few performing the hybrid procedure nationwide, has completed nearly a dozen.

Patients suffering from heart failure are among those benefiting most from the University’s mechanical support technologies. With wait lists for heart transplants sometimes topping two years in the Midwest, finding alternative therapies can be critical.

Enter Lyle Joyce, M.D., Ph.D., director of mechanical support in the University’s Division of Cardiothoracic Surgery. Joyce, who assisted in the first permanent implantation of the Jarvik total artificial heart in 1982, is a nationally known expert in left ventricular assist devices (LVADs), mechanical pumps that are implanted in the abdomen and then wired to an external, camcorder-sized battery pack to improve the function of ailing hearts.

Since Joyce’s arrival, the division has become one of the leading cardiac ventricular assist programs in the country, performing up to 60 LVAD procedures a year.

“Patients with heart failure don’t stay stable during the two- to three-year waiting period for a heart,” Joyce says. “They get sicker and sicker, so the best alternative to a transplant becomes an LVAD.”

Joyce and his team are leaders in testing LVADs as “destination” (permanent) therapy rather than as a bridge to a heart transplant. As part of a multicenter trial, the University’s

LVAD team, which also includes Sara Shumway, M.D.; Ranjit John, M.D.; and Liao, recently demonstrated the efficacy of the newer-generation HeartMate II LVAD as a destination therapy.

“For patients, having LVADs as a destination therapy means being able to go home and never having to worry about being readmitted for congestive heart failure,” says Joyce.

Other cardiac conditions also benefit from mechanical support devices. To stabilize acutely ill patients who need an emergency CABG or angioplasty, Das is investigating a temporary device known as a percutaneous LVAD. With one type, called a TandemHeart, surgeons direct a catheter into the heart, then use an external pump to move blood through the heart.

With another type, called the Impella, a small pump is placed on a catheter and inserted into the heart through the artery. Both devices are new—the Impella is still investigational—but Das is impressed with their potential to improve patient care.

“With these new percutaneous devices, we will be able to aggressively treat critically ill patients who might otherwise not make it,” he says.

Prevention as the best medicine

Jay Cohn, M.D., is looking at heart disease from an entirely different angle: When and how does it develop, and can it be prevented?

Daniel Duprez, M.D., Ph.D., believes the Rasmussen Center for Cardiovascular Disease Prevention’s risk-taking system is proving to be a better predictor of heart disease risk than traditional measures.

When Cohn stepped down as head of the University’s cardiology division in 1996, his career was anything but over. For years, he had been thinking about better ways to predict cardiovascular disease. Now he was ready to apply what he’d learned to prevention.

“It was a natural evolution for me because, as you begin to understand all the nuances of disease, you recognize the virtue of early detection,” explains Cohn. “Over the years, as I was developing new approaches to treating advanced heart disease, I became convinced there was potential for the disease to be recognized well before patients became sick.”

Over the next few years, Cohn searched for tests that could detect early disease in asymptomatic individuals. Eventually, he selected 10 noninvasive tests that measure the structure and function of the heart and blood vessels—such as stages of thickening in the heart or the vessel walls, reduced arterial elasticity, and changes in the retinal vessels.

In 2000 he led the launch of the Rasmussen Center for Cardiovascular Disease Prevention. It’s the only such center in the world to use this combination of tests to find abnormalities—or markers—that lead to heart disease.

“These are not tests that reveal cardiovascular risk factors, such as high cholesterol or high blood pressure,” says Cohn. “These tests actually measure the stages of cardiovascular disease progression that lead to heart attacks, strokes, heart failure, and other lethal conditions. This makes them far more valuable and sensitive than traditional risk-factor analyses.”

Since the Rasmussen Center opened, more than 1,500 patients have walked through its doors. Having data from so many patients has allowed Cohn’s colleague Daniel Duprez, M.D., Ph.D., the center’s research director, to measure the effectiveness of the Rasmussen disease-scoring system, a 1-10 scale. So far, he’s found that patients with a Rasmussen disease score of 0 to 2 (low risk) had no morbid cardiac event within the three-year follow-up, while those with risk scores of 6 or more (high risk) had an extremely high rate of events.

“We’re finding that the Rasmussen score is much more predictive of cardiac events than the traditional risk factors of age, blood pressure, blood sugar, smoking status, and cholesterol,” says Duprez, who holds the Donald and Patricia Garofalo Chair in Preventive Cardiology.

Duprez and Cohn also are searching for effective treatments for high-risk, asymptomatic patients who don’t meet clinical protocol criteria for certain medications. In one study, Duprez and his team used the angiotensin II receptor blocker valsartan (which dilates the blood vessels, reducing blood pressure) to slow the progression of cardiovascular disease in patients who had either prehypertension or hypertension but no symptoms of heart disease. They found that the drug significantly lowered patients’ Rasmussen scores after just six months.

Next, Duprez plans to test the ability of a beta blocker combined with an angiotensin-converting enzyme to lower the disease scores and reduce the risk of heart attacks.

In the genes

Jennifer Hall, Ph.D., director of the cardiovascular translational genomics program, is looking for genes that could be increasing Rasmussen Center patients’ risk.

Jennifer Hall, Ph.D., is investigating whether certain genes are associated with an increased risk for cardiovascular disease.

In the past five years, human genome researchers have identified 10 to 15 areas in human DNA associated with increased risk of heart attack, atrial fibrillation, and cholesterol and lipid disorders. One such marker is a mutation in chromosome 9, region p21, or “9p21.”

Hall and others in her lab will be analyzing blood samples from about 1,500 Rasmussen Center patients—with and without early-stage heart disease—to determine whether 9p21 is associated with increased risk for cardiovascular disease. Over the next two to five years, Hall hopes to enroll 5,000 or more patients in this study.

“We are working with Dr. Duprez to enroll more patients so we can identify more sensitive genetic markers that either put you at risk for or protect you from heart disease,” she explains.

Collaborating with Duprez and his team at the Rasmussen Center benefits her research, says Hall. “Dr. Duprez has an edge over other clinics because he is using more sensitive clinical markers for heart disease.

“That allows us to look even deeper for new regions in the human genome,” she says. “Once we identify those regions, we can try to identify which genes are involved and how we can target these genes and signaling pathways for therapy tailored to the individual.”

Shaping the future

“Our success comes from a continuum of collaboration—from basic researchers looking at the molecular aspects of heart disease to those who are implanting devices to treat heart failure,” says Herbert Ward, M.D., Ph.D., C. Walton and Richard C. Lillehei Professor and chief of cardiothoracic surgery. “At every point, we are asking questions and finding solutions to advance this field.”

“It makes for a rich environment,” agrees Garry. “In 10 years, the therapies that we have for heart disease will be radically different from what they are today, and I think we will be able to say that we pioneered these advances.”

By Jeanne Mettner

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