Curious at Heart: A Focus on Diastolic Heart Failure
Research initiated by Margaret Redfield, M.D., has made Mayo a focal point nationally for the study of diastolic heart failure. Mayo researchers are working on novel therapies for this devastating disease for which there are currently no available treatments.
Margaret M. Redfield, M.D., is particularly excited about one of her clinical trials. The study will test whether the drug Viagra can improve blood flow in patients with diastolic heart failure, a major cause of morbidity and mortality that results from the stiffening of the left ventricle. It's a promising approach since Viagra specifically enhances and dilates blood vessels during exercise. The study was selected by the National Institutes of Health (NIH) for funding as part of the Heart Failure Clinical Research Network, a consortium of investigators at nine sites across the country.
"Work done in our lab and elsewhere has shown the drug may also decrease hypertrophy (enlargement) and fibrosis of the heart," says Dr. Redfield. "It may improve symptoms of diastolic heart failure."
An early interest in stiff heart
As a cardiologist, Dr. Redfield was accustomed to seeing patients with symptoms of heart failure, including shortness of breath, extreme fatigue and swelling of the limbs. But in the mid-1990s, she began to wonder about the cases that didn't fit the textbook definition of the disease. The typical patient with systolic heart failure had flaccid coronary muscle that had ceased to pump effectively. But Dr. Redfield was seeing patients whose heart muscles were unusually stiff, incapable of relaxing after each pump. The stiff-heart version, known as diastolic heart failure, was believed to be rare. So why, Dr. Redfield wondered, was it appearing so often in the clinic?
She did what any passionately curious clinician-investigator would do: She went after answers. What she found in her landmark epidemiological studies is that the diastolic form of the disease was more widespread than anyone could have guessed, accounting for more than half of all cases of heart failure. But she also went back to the lab and began to build a picture of this little-understood condition. Over the years, her investigations — from wet-lab studies, to model systems in animals, to clinical studies in humans — have helped define the disease and have led her to a critical moment. "My hope," she says, "is that we may now be able to find a cure."
Serving today as Mayo's chair of cardiovascular research, Dr. Redfield long had a knack for enterprising thinking, especially when she came up against obstacles. As a college student in South Dakota, she had a keen interest in science and planned to be a nurse anesthetist like her older sister.
But when her sister came home from a conference one summer and reported having heard the field would soon be phased out of existence, Dr. Redfield quickly shifted gears and reformulated her next semester to go pre-med. What she loved most was learning "physiology and how things in the body work," she recalls, and by the time she had enrolled at Tulane University School of Medicine, she felt certain she wanted to head into either cardiology or nephrology.
But it was a stint in the lab after her first year of residency that changed her career. "I'd never done any research before and had no thought I ever would," she says, "but I loved it, and was inspired as each step built on what I'd learned." She became intent on a career that would weave together patient care and cardiology research.
As she incorporated lab work in her training, her investigative skills were immediately evident, recalls cardiologist John C. Burnett, M.D., who became an early mentor. "She was a star from the beginning, with a very precise, meticulous, analytical approach to asking scientific questions," he says. Dr. Burnett's lab focused on the study of natriuretic peptides, signaling proteins that act like hormones on the heart and are depleted in diastolic heart failure. With him, she contributed to understanding the biological and therapeutic mechanisms of the peptides and won Mayo's Balfour Award for outstanding research during her fellowship.
At the same time, she came into contact with a key tool. Mayo cardiologists were among the first to use echo Doppler to assess the relaxing and stiffening of the heart. "Here was a test that Mayo had brought to a whole generation of cardiologists," she says. The test pointed her toward her own research tack, and she showed in studies how echo Doppler could be used to diagnose diastolic heart failure.
A seminal study
But her curiosity had also been piqued about broader questions, in particular, about the prevalence of this lesser known disease. She realized she had another tool at her disposal at Mayo: the Rochester Epidemiology Project, an NIH-funded database of medical records from patients within Olmsted County.
"Because this database covered an area that was medically isolated — nearly all patients got all their medical care right here — we could find out how many people had new-onset heart failure," she explains, "and then we could look back and ask how many had echoes, and we could see what their heart function had been." As she plumbed the medical records, she showed that diastolic heart failure was not only a major public health concern, but was becoming increasingly common. What's more, even the milder cases were predictive of death.
The work, published in the Journal of the American Medical Association in 1998, quickly changed the landscape for the entire field, says cardiologist Barry A. Borlaug, M.D. That publication, along with another she published in the Journal of the American College of Cardiology, has been cited hundreds of times. "Her work got people fired up about this condition, as they should be," he says, adding that she showed the disease, prevalent in the elderly, occurs most commonly in women. "She's the kind of doctor who sees something in the clinic and doesn't just say, 'That's interesting.' She wants to know why."
A link to pulmonary hypertension
Such was the case a few years later, when Dr. Redfield looked through the chart of a patient diagnosed with pulmonary hypertension — high blood pressure in the lungs. Dr. Redfield wondered again whether diastolic heart failure might be involved. Following up on this suspicion with a study of patients in the cardiac catheterization lab, she determined diastolic heart failure to be a cause of pulmonary hypertension and published extensively on the significant connection. "A lot of people are writing about it now, but the whole understanding of this phenomenon was triggered by her observation," Dr. Borlaug says.
Developing animal models
Dr. Redfield continued to wonder what it was that defined the disease she was seeing in patients. She headed into the lab to develop the first animal models to simulate diastolic heart failure. She found the disease causes blood vessels and the heart to become scarred, rife with inflexible collagen and potentially other factors, which makes them unable to relax. Using sophisticated techniques, including echocardiographic measurements and minute catheters that can thread into a mouse heart smaller than a pea, she set out to measure pressure and heart volume and to characterize the diseased pumping.
"It's a highly technical process, and we didn't know at the start whether we would be able to accomplish it and what pressure-volume analysis would tell us," she acknowledges. "But with these models, we're able to learn about the deficiencies in heart function and then test whether our therapies can improve it." She's gone on to explore the disease on a molecular level, detecting a structural protein, called titin, that's present in abnormal form in cardiac muscle cells and impinges on normal contraction.
But all along, the investigations that dared to bridge lab experiments, epidemiological investigations and clinical studies have brought Dr. Redfield back to thinking about her patients. Though numerous treatments exist for systolic heart failure, no therapy exists for diastolic heart failure. So five years ago, Dr. Redfield's research took a turn to look for effective treatments.
"I do the research because I'm curious. I'd do it even if it didn't pay," she adds with a laugh. "But the more I've understood about the physiology of this disease, the more I've wanted to do something about it." The latest phase has been the most challenging.
One early tack homed in on her molecular findings, using a drug aimed to limber up vascular tissue by targeting the abnormal titin protein. At first, it seemed the drug improved blood vessel function in the experimental model, but disappointingly, it didn't affect the heart. In another approach, based on her research with Dr. Burnett, she's exploring how infusions of natriuretic peptides might help. With cardiologist Horng Chen, M.D., she began a major clinical study to look at whether low doses of the peptides — given in injections under the skin — might help the kidney in acute heart failure and improve patients' prognosis.
Yet another approach: With molecular biologist Stephen J. Russell, M.D., Ph.D., she's introducing genes to bolster the effect of natriuretic peptides. The idea is to use a virus as a vector — a system through which genes are delivered into target cells — in this case, the genes overexpress molecular receptors, tiny docking points on cell surfaces where the natriuretic peptides become functional. In animal models, they've found that the viral vectors deliver the genes effectively to the heart, and Dr. Redfield has developed new animal models with which they hope to refine treatment and move on to human studies in five to 10 years.
All of this work has made Mayo a focal point nationally for the study of this disease. "Hopefully we'll find that the Viagra studies will work," she says. "If it doesn't, we'll go back to the drawing board." The cardiologist in her adds, "And we'll keep at it until we find the best means to treat this disease."
— July 2011