Summary

Heart disease is the number one killer of men and women worldwide. In 2005, over one third of all death in the world will be due to a cardiovascular condition, and in America alone over one million Americans will suffer a heart attack. The poor prognosis associated with heart disease, seen particularly with elderly patients, stems from the irreversible loss of heart cells which causes organ failure. Current treatment provides relief, but does not lead to a definitive cure. The new frontier in cardiovascular medicine lies in developing individualized diagnostics to predict a person's susceptibility to heart disease, and then preventative treatment or a cure through regeneration of the ailing heart muscle.

Preventing and Curing Disease - One way or the other, they're out to save your heart.

Why certain individuals develop heart disease while others do not remains a mystery not fully explained by conventional risk factors, such as elevated blood pressure or high cholesterol. Andre Terzic, M.D., Ph.D., and his colleague, Timothy M. Olson, M.D., Director of the Cardiovascular Genetics Laboratory, are delving into our genomic makeup to discover causes of heart disease we didn't know existed. By interrogating the body's genetic roadmap, they have uncovered key pathways of cardiac protection that when defective precipitate disease. Their investigative teams are further probing those genomic cues to offer an "early warning system" to individuals before irreparable heart conditions develop.

"…stem cells present an opportunity for reparative therapy with stable benefit in heart attack."
Andre Terzic, M.D., Ph.D.

"Inherent cardiac protection is the first line of defense," says Dr. Terzic. "Understanding the roots of the heart's natural resilience will in turn revolutionize the way we can predict and ultimately prevent disease." To that end, Drs. Olson and Terzic recently discovered a DNA-based mechanism that makes some hearts susceptible to failure. Thanks to their research (published in the journals Proceedings of the National Academy of Sciences and Nature Genetics) we now better understand how stress affects heart cells. By linking disease to a problem in how our hearts manage stress, their work opens a new avenue in molecular diagnostics.

"There was a great deal of excitement about this discovery," as Dr. Olson described sharing the "Eureka moment" with Dr. Terzic.

Dr. Olson's laboratory performed "high-throughput" genetic tests on blood samples from patients with unexplained heart muscle disease. This large-scale screening identified mutations in a gene that normally produces protein to defend against stress. Armed with additional knowledge emerging from the bench, Dr. Terzic's team reproduced the mutations in his laboratory and observed the consequences at the molecular level. That's how it was discovered that the mutations create a defect in a key protective structure in heart cells called the ATP-sensitive potassium channel. Normally, this potassium channel balances proper flow of calcium and potassium in the heart. Too little calcium and the heart will have problems with contractions; too much can damage cells and lead to heart failure. Potassium helps keep the electrical system in sync with heart demands, and the calcium at a safe cellular level. If the potassium channel isn't working properly, a stress load can turn from a minor annoyance to a death sentence.

"In our laboratory we investigate the hereditary factors that can affect the mechanical or electrical function of the heart."
Timothy Olson, M.D.

"By discovering how this mechanism should properly operate," says Dr. Terzic "we can now raise awareness of risk in patients carrying a predisposition for malfunction. We hope to be able, one day, to intervene and alter or compensate for this defect, removing the risk altogether."

The thirty or so people who work jointly with Drs. Terzic and Olson span departments, each offering a valued expertise or skill that is integral to the team's success. "The reason for investigating this gene in patients in the first place," says Dr. Olson "was based on Dr. Terzic's work in the laboratory defining the critical role for protective pathways in the heart."

This interdisciplinary research is a major reason why Mayo Clinic investigators can speed the process of discovery and bring their findings to the aid of patients faster than at many traditional research institutions.

"The patient is the continuous focus of our investigative work that often begins with discovery at the bench with cells or genes," says Dr. Terzic. "Through translation of fundamental research, our goal is to apply discovery science into clinical practice."

Cure through Regeneration

You will rarely see Andre Terzic stand completely still. He moves quickly, deftly, making sure you will grasp the complexity of the heart's machinery.

"Come look at these cardiac cells," he calls to a visitor. "Do you think you can focus through the microscope?" he asks a TV cameraman. The walls of the lab are a gallery for colored images of a research world invisible to most patients - intracellular structures or examples of diseased cardiac tissues. It's graphic proof of cutting-edge research dedicated to decreasing the burden of heart disease.

"Some organs can repair themselves when they are damaged," teaches Dr. Terzic. "Your hair or nails grow back when cut. Your skin grows new epidermal cells to heal cuts or wounds. The heart can't do that very well. It has a limited capacity for self-renewal. Even if a patient recovers from a heart attack, the organ still bears a scar and original function is diminished."

Until now.

Dr. Terzic and his colleagues (in a study published in the American Journal of Physiology) showed that rodent stem cells can transform into new cardiac muscle and heal a damaged heart. In other words, diseased hearts of animals, when treated with stem cells regenerated themselves into healthy hearts - without weakness or scarring.

Undifferentiated stem cells were directly injected into muscle tissue following a simulated heart attack. The stem cells responded to environmental cues and quickly changed into heart muscle cells - and began to pulse and grow. Within three weeks the researchers saw improved heart function in the damaged area. The repairs did not deteriorate over time. In fact, the treated heart displayed an improved response to imposed load and no evidence of abnormal heart rhythm. According to all tests and follow-up observations, such treated animals were healthy again. It was as if they were never ill.

This heart "repair kit" holds enormous promise for research in humans and for long-term management of cardiac disease. Dr. Terzic says the possibility of reducing disability or death from heart attacks is real. The potential of regenerating damaged organs provides an opportunity to cure heart disease and improve public health.

With a rich tradition of excellence in the investigation and care of patients with heart disease at Mayo Clinic, the J. Willard, Jr. and Donna Marriott Program for Heart Disease Research Program provides a comprehensive, multidisciplinary approach dedicated to improve diagnosis, prevention, and treatment of cardiovascular disease. Drawing from Mayo's expertise in population sciences, genomics and proteomics, and experimental and translational medicine, this state-of-the-art program capitalizes on current and emerging technologies to transform therapeutic treatments from symptomatic relief to repair of the diseased heart.

Andre Terzic, M.D., Ph.D., is the Marriott Family Professor in Cardiovascular Research at Mayo Clinic. He has integrated advanced technology with a focus on clinical problems addressed at a fundamental level. Dr. Terzic has pioneered pathogenomic research of maladaptation in heart disease, and the application of cardioprotective and cardioregenerative therapies.