Potential Treatment for Cardiac Fibrosis Found

Researchers at Beth Israel Deaconess Medical Center (BIDMC) have found an explanation to the origins of cardiac fibrosis. They have also found a potential method of reversing this heart condition. The findings have been reported in the latest edition of the journal Nature Medicine.

Cardiac fibrosis is a stiffening of the heart muscle. It can result in a number of cardiac diseases including heart failure. Fibrosis happens when the natural wound-healing process of our body gets disrupted.

Normally, fibroblasts – special cells for healing wounds – cover the wounded area with layers of collagen protein. These layers form a scar which enables wounds to heal. However when the fibroblasts are not working normally, matrix proteins such as collagen are produced in excessive amounts. This causes pathological scarring or fibrosis.

When it happens in the heart, the muscle becomes stiff and inflexible. This robs the heart of its ability to properly relax and function. So far it is not known was exactly is the reason behind excessive collagen protein production.

“Fibrosis can develop in any organ in the body,” explained Dr. Elisabeth Zeisberg, lead author of the study and a scientist in the Division of Matrix Biology at BIDMC. “While it’s known that fibroblast cells are responsible for cardiac fibrosis, the source of these fibroblasts has remained unknown until now.”

Dr. Zeisberg and senior author Dr. Raghu Kalluri, PhD, Chief of the Division of Matrix Biology at BIDMC hypothesized that the mechanism behind the excessive production might be a specialised form of epithelial-mesenchymal transition (EMT) known as endothelial-mesenchymal transition.

“Our laboratory has had a longstanding interest in the area of organ fibrosis and the origin of fibroblasts in this setting,” explained Dr. Kalluri, who is also Associate Professor of Medicine at Harvard Medical School (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.”

To confirm their hypothesis, the researchers used knockout mice. In the first part, they genetically marked the endothelial cells in the mice and then induced cardiac fibrosis in the animals. It was observed that during cardiac fibrosis, the endothelial cells were actually converting into activated fibroblasts. These fibroblasts were in turn depositing scar material and thereby restricting the normal functioning and electrical conduction of the heart.

For the second part of their study, the researchers used rhBMP7 protein, a morphogenic molecule present in bones to check if it could reverse the EndMT process. If the process can be reversed, it can restrict the development of fibroblasts and thereby bring about an improvement in heart function. They found that rhBMP7 can indeed reverse the cardiac fibrosis process.

This finding by the researchers offers the possibility of a therapeutic target for cardiac fibrosis. “The rhBMP-7 protein was quite impressive in its ability to recover the function of damaged hearts,” said Dr. Kalluri. “These findings provide compelling proof that the process of fibrosis can be reversed in the heart and offer the possibility of new therapies for patients who have developed cardiac fibrosis as the result of myocardial infarction, hypertension, valvular diseases or heart transplantation.”

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