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Molecular Cardiology: New Effort to Fight Old Problem

By William Allstetter

HeartIn spite of many advances in cardiac medicine, heart failure and sudden cardiac death have remained thorny problems. Approximately 400,000 people in the United States die from heart failure each year and 200,000 die from sudden cardiac death. Half of all people with heart attacks die from sudden cardiac death before reaching the hospital. Yet, the basic causes of these problems remain poorly understood.

Dr. Andrew Marks, the Clyde and Helen Wu Professor of Molecular Cardiology, thinks that molecular biology may reveal the causes and, ultimately, treatments for these difficult problems. Dr. Marks came to P&S in 1997 to create and direct the molecular cardiology program. Since then, he has investigated the basic science of muscle contraction and developed collaborations with several P&S scientists to answer questions raised by the specific problems of heart failure and sudden cardiac death. He has received grants worth more than $1 million annually in direct costs and $600,000 in indirect costs. In August 1998 his laboratory published a major paper in the journal Science describing calcium release inside muscle cells, a finding that helps explain the efficient contraction of muscles and may eventually shed light on heart failure.

“This is a very exciting time in cardiovascular medicine,” says Dr. Paul Cannon, the Hatch Professor of Medicine and chief of cardiology. “The cardiovascular diseases are being redefined in genetic and molecular terms.”

Dr. Cannon chaired the search committee that hired Dr. Marks. He says the committee sought a top molecular biologist who could not only do his own research but also could contribute skills and knowledge of molecular biology to the research questions being posed by other P&S investigators. Dr. Marks’ curriculum vita clearly qualifies him as a top scientist. In addition to publishing more than 50 peer-reviewed papers in less than 15 years, Dr. Marks was elected in 1995 to the American Society of Clinical Investigation, recognition at a relatively young age that he is a “quality scientist who will be a longtime contributor to the field,” according to Dr. Myron Weisfeldt, Bard Professor and Chairman of Medicine. He also has spoken and chaired sessions at the prestigious Gordon Conferences.

“His science was quite excellent,” says Dr. Cannon. “The search committee also saw potential interactions with other investigators. People were eagerly talking about potential collaborations before the interview process was over.”

Dr. Robert Kass, professor and chairman of pharmacology, was one of the search committee members eagerly discussing collaborations. Dr. Kass has studied ion channels in the cell membrane that contribute to cardiac arrhythmias. Although cardiac arrhythmias have been linked to several mutations in genes that code for these channels, it is not clear exactly how mutant channels cause the rapid and erratic muscle contraction that results in sudden cardiac death.

Dr. Marks studies the calcium channels on the sarcoplasmic reticulum inside the cell. They release calcium in response to an electrical signal generated by the flow of ions through the ion channels studied by Dr. Kass. The two researchers have developed a theory about how these two sets of ion channels may interact to cause arrhythmias and sudden cardiac death and have begun research to test their hypothesis.

Dr. Marks also works with cardiac physiologist Dr. Daniel Burkhoff, assistant professor of medicine, and others to better understand intriguing findings resulting from the use of the left ventricular assist device. LVAD is a mechanical pump that temporarily assists a failing heart while a patient waits for a heart transplant. Until recently, heart failure has been seen as an inexorable process of declining pumping ability leading to death. But about five years ago doctors learned that a heart helped by the LVAD regains some ability to function. Although the heart eventually resumes its decline after the LVAD is removed, the temporary improvement provides a ray of light in an otherwise hopeless situation.

“That really changes the way you think about heart failure and therapy for it,” says Dr. Burkhoff. “We should be able to strive for much more, not only palliative care, but a cure.”

In the process of installing the LVAD, surgeons remove about two cubic centimeters of heart tissue. If a patient is lucky enough to receive a transplant, surgeons remove the rest of the heart. Drs. Burkhoff and Marks are studying the differences in heart tissue before and after the LVAD is installed. They have seen that the number of calcium channels inside the heart cells increases after the LVAD has helped the heart pump for a few weeks. They are also investigating the differential expression of genes in the weak and recovered hearts to learn more about the processes that cause the recovery.

Dr. Andrew Marks
Dr. Andrew Marks
Dr. Marks also collaborates with Dr. Jeanine D’Armiento, assistant professor of medicine, on possible extracellular causes of heart failure. In a number of diseases, including heart failure, the heart increases its production of metalloproteinases, enzymes that break down collagen in the extracellular matrix. The degradation of the collagen causes changes in the heart muscle cells that weaken their ability to contract. Dr. D’Armiento has developed a mouse that overexpresses one of the metalloproteinases. At about one year these mice begin to lose heart function, mimicking heart failure in humans. She is trying to identify the signaling pathway altered through the overexpression of the metalloproteinases, while Dr. Marks is studying how the changes in collagen alter the function of calcium channels within the heart muscle cells.

“I think it is very important to study these mice through an integrated approach, and Dr. Marks has helped do that,” says Dr. D’Armiento.

In the August paper in Science, Dr. Marks and Dr. Steven Marx, assistant professor of medicine, who came with Dr. Marks from Mount Sinai, showed how an electrical signal received by muscle cells is converted efficiently to calcium release. Half the calcium channels inside the cell are sensitive to changes in the electrical charge within the cell. But the other half aren’t. For efficient contraction and relaxation, all the calcium channels must open and close at the same time. Previous theories suggested the channels opened in a two stage manner: An electrical signal caused half the calcium channels to release calcium, which in turn triggered the other half of the calcium channels to open. Drs. Marx and Marks showed that large clusters of the channels, both electrically sensitive and insensitive, are mechanically linked. A single calcium channel can trigger a whole cluster of channels, both sensitive and insensitive to electrical charge, to open at the same time, making for a more coordinated release of calcium and stronger muscle contraction. That work was done in skeletal muscles. Preliminary results have shown that the same holds true for muscle cells in the heart.

Dr. Marks is recruiting two more investigators to join him in the molecular cardiology program. But he has otherwise finished most of the tasks associated with setting up the program. He is now poised to turn his attentions more fully on his own laboratory and the research he wants to do there. The Science paper was in all likelihood only the first of many that researchers in the program will produce to reveal the molecular basis for the function and malfunction of the heart muscle.

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