Immune system cells linked to heart failure

November 13, 2006

The immune system and, more specifically, cells recruited from it are key players in the muscle dysfunction that results in some forms of heart failure, said Baylor College of Medicine researchers in a report that appears online in the Proceedings of the National Academy of Sciences.

Dr. Mark Entman, professor of medicine at BCM as well as scientific director of the DeBakey Heart Center, and colleague Dr. Sandra Haudek, instructor in the section, studied mice subjected to short, daily occlusion of the left anterior coronary artery. The short occlusions did not cause cardiac cell damage but resulted in inappropriate deposition of fibrous tissue in the heart. Over time, this weakens the heart-pumping chamber or left ventricle.

"This mimics a disorder seen in patients," said Entman. "The mice develop a cardiomyopathy (a disorder of the heart muscle) resulting from coronary insufficiency that is very similar to that seen in clinical coronary disease."

In the experimental mice and human patients there were elevated levels of a particular immune system protein called monocyte chemoattractant protein -1, or MCP-1, which attracts immune system cells called monocytes to the site of the heart muscle injury. Entman, Haudek and their colleagues found that the cells that were attracted became fast-growing fibroblasts that were smaller and more spindle-shaped than the usual ones.

Normal fibroblasts play a role in wound-healing, but these caused fibrosis or excess fibrous tissue in the heart muscle, preventing it from doing its job and resulting in cardiomyopathy. These fibroblasts are unusual because they originate from stem cells that are usually progenitors of blood-related cells (hematopoietic cells).

In a second part of the study, the researchers found that treatment with a protein called serum amyloid P (SAP) actually prevented production of these fibroblasts and the resulting fibrosis when given to the mice before and during the time period of coronary occlusion. SAP, they discovered, actually binds to a cellular receptor called Fc gamma, which is the gamma globulin receptor.

"Thus, we identified two ways to link cardiac fibrosis to the immune system," said Entman. "The monocytes become fibroblasts and the Fc gamma receptor regulates the process. Ischemic cardiomyopathy is the leading cause of death in patients with coronary artery disease. This study suggests some therapeutic targets which might mitigate its progression."
Others who participated in this research include Drs. Ying Xia, Peter Huebener, John M. Lee, Signe Carlson, JoAnn Trial and Nikolaos G. Frangogiannis of the DeBakey Heart Center at BCM and The Methodist Hospital and Jeff R. Crawford, Darrell Pilling and Richard H. Gomer of the Howard Hughes Medical Institute, department of biochemistry and cell biology at Rice University.

Funding for this research came from National Heart, Lung, and Blood Institute, The Medallion Foundation, The Methodist Hospital Foundation, the Howard Hughes Medical Institute and The Robert A. Welch Foundation.

Baylor College of Medicine

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