BOSTON -- A report led by researchers at Beth Israel Deaconess Medical Center (BIDMC) helps explain the origins of cardiac fibrosis, a stiffening of the heart muscle that leads to a variety of cardiac diseases, most notably heart failure.
The animal study, which appears today in the Advance Online Publication of Nature Medicine, also demonstrates that a bone morphogenic molecule known as rhBMP7 can reverse the cardiac fibrosis process, offering the possibility of a therapeutic target for this debilitating condition.
"Heart disease is the number-one cause of death in the Western world," explains the study's lead author Elisabeth Zeisberg, MD, a scientist in the Division of Matrix Biology at BIDMC and an Instructor of Medicine at Harvard Medical School (HMS). "And most people who suffer from heart disease have developed scarring of the heart tissue, known as fibrosis."
Fibrosis develops when the body's natural wound-healing process goes awry. Under normal conditions, specialized cells known as fibroblasts deposit layers of collagen protein to form a scar and thereby enable wounds to heal. However, in abnormal circumstances - and for unknown reasons - excessive production of matrix proteins, such as collagen, results in pathological scarring, or fibrosis. In the heart, the buildup of matrix leaves the organ stiff and inflexible, unable to properly relax and function.
"Fibrosis can develop in any organ in the body," explains Zeisberg. "While it's known that fibroblast cells are responsible for cardiac fibrosis, the source of these fibroblasts has remained unknown until now."
Zeisberg and senior author Raghu Kalluri, PhD, Chief of the Division of Matrix Biology at BIDMC, speculated that a specialized form of epithelial-mesenchymal transition (EMT) known as endothelial-mesenchymal transition might be the mechanism behind this turn-of-events.
"Our laboratory has had a longstanding interest in the area of organ fibrosis and the origin of fibroblasts in this setting," explains Kalluri, who is also Associate Professor of Medicine at HMS. "We have previously demonstrated that in the kidney, liver and the lung, epithelial cells under stress can convert into fibroblasts via epithelial-mesenchymal transition."
So, using knockout mice in which endothelial cells had been marked genetically, the investigators confirmed that during cardiac fibrosis, these cells were indeed converting into activated fibroblasts, which were depositing scar material and impeding the proper function and electrical conduction of the heart.
In the second part of the study, the investigators turned to the rhBMP7 protein to determine if it could successfully reverse the EndMT process and thereby reduce the development of fibroblasts and lead to the improvement of heart function.
"The rhBMP-7 protein was quite impressive in its ability to recover the function of damaged hearts," says Kalluri. "These findings provide compelling proof that the process of fibrosis can be reversed in the heart and offers the possibility of new therapies for patients who have developed cardiac fibrosis as the result of myocardial infarction, hypertension, valvular diseases or heart transplantation."
This study was funded, in part, by research grants from the National Institutes of Health and the Novartis Corporation.
In addition to Zeisberg and Kalluri, coauthors include BIDMC investigators Michael Zeisberg, MD, and Julie McMullen, PhD; Oleg Tarnavski, PhD, and Seigo Izumo, MD, of Novartis Institute for Biomedical Research; Adam Dorfman, MD, and William Pu, MD, of Children's Hospital Boston; Erika Gustafsson, PhD, of Lund University, Sweden; Anil Chandraker, MBBS, Xueli Yuan, PhD, and and Mohamed Sayegh, MD, of Brigham and Women's Hospital; Anita Roberts, PhD, of the National Cancer Institute; and Eric Neilson, MD, of Vanderbilt University.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.