Reducing the damage of a heart attack

December 15, 2008

NEW YORK (Dec. 15, 2008) -- In the aftermath of a heart attack, the body's own defenses may contribute to future heart failure. Authors of a new study believe they have identified a protein that plays an important role in a process that replaces dead heart muscle with stiffening scar tissue. The researchers are hopeful that the findings will lead to the development of new therapies to prevent this damage.

"The body tries to fix the injury to the heart muscle by depositing the fibers, but this causes a greater problem," says Dr. Thomas Sato, co-senior author of the study and the Joseph C. Hinsey Professor in Cell and Developmental Biology at Weill Cornell Medical College in New York City. "This process, called fibrosis, causes the heart to become like steel, unable to contract and pump blood throughout the body. The result can be fatal."

Myocardial infarction causes 13 percent of deaths worldwide and is the leading cause of death in industrialized countries.

The researchers' promising findings were published online, Dec. 14, in Nature Cell Biology and will be featured in the upcoming January issue. Due to the findings' significance, the journal has selected the study as an issue highlight.

"Treatments for fibrosis in the heart are relatively limited, making it important to develop new and novel approaches to limit fibrosis," explains Dr. Craig Basson, co-author of the study, the Gladys and Roland Harriman Professor of Medicine and director of the Center for Molecular Cardiology at Weill Cornell Medical College, and attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Dr. Sato and his team removed from a mouse's genome a gene called Sfrp2, stopping the mice from producing the protein sFRP2. They found that there was less scar tissue formed in the hearts of mice without the gene, compared to normal mice that still had the gene within their DNA.

The experimental mice also had improved recovery to their heart function, which leads the authors to believe that the protein has a direct affect on muscle scarring and stiffening following myocardial infarction.

The Weill Cornell team collaborated with Dr. Daniel S. Greenspan, co-senior author and professor of pathology and laboratory medicine from the University of Wisconsin School of Medicine and Public Health in Madison, Wis. Dr. Greenspan determined how the main component of connective tissue, collagen, interacts with the sFRP2 protein, and how these molecules play a crucial role in scar formation.

"With many injuries and diseases, large amounts of collagen are formed and deposited in tissues, leading to scarring and fibrosis," says Dr. Greenspan, an expert in collagen. "Fibrosis can severely affect the functioning of the heart, lung, liver and other tissues."

Together, the researchers determined that the sFRP2 protein works by accelerating the processing of pro-collagen, a precursor of mature collagen, the main component deposited in scar tissue. Following a heart attack, fibrous collagen deposits are increased, replacing the dead muscle and leading to more scar tissue, which prevents recovery.

"Therapeutically, the findings mean that it is possible to create a drug that may one day inhibit the functioning of the protein in order to limit fibrosis within the heart," says Dr. Sato. "Doing so may aid in controlling the degree of scarring, and allow the heart to continue to function following myocardial infarction."
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Co-authors of the study include Drs. Koichi Kobayashi, Min Luo, Yue Zhang, David C. Wilkes, Chikaomi Yamada and Ting-Chun Liu, all from Weill Cornell; Drs. Gaoxiang Ge and Guorui Huang from the departments of pathology and laboratory medicine and pharmacology, at the University of Wisconsin; and Drs. Thomas Grieskamp and Andreas Kispert from the Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.

The study was supported by grants from the National Institutes of Health, the American Heart Association, the German Research Foundation and by the European Union FP6 contract "Heart Repair."

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in areas such as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, transplantation medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease and social determinants of health in an effort to unlock the mysteries of the human body in health and sickness. In its commitment to global health and education, the Medical College has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. For more information, visit www.med.cornell.edu.

NewYork-Presbyterian/Weill Cornell Medical Center

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