AU researcher targeting enzyme in chronic heart disease

MICHAEL HOLAHAN/STAFF Dr. Zsolt Bagi photographed at his Augusta University laboratory in Augusta. The particular enzyme he is interested in was involved in clinical trials for other chronic inflammatory diseases, such as arthritis.

The double whammy of aging and obesity seems to trigger a growing form of heart failure that is difficult to diagnose and treat. But targeting a certain enzyme that seems to be key to the chronic inflammation from aged fat could lead to a new kind of targeted therapy, a researcher at Augusta University said.

 

Heart failure doesn’t have the sinister reputation of other well-known killers such as cancer but can be just as deadly, said Dr. Zsolt Bagi, an associate professor in the Vascular Biology Center at AU. A 2010 review in the journal BioMed Central Cancer found the five-year survival rate of all cancers was 43 percent while the survival rate for heart failure was 26-52 percent.

“It is a similar morbidity, mortality issue to cancer,” Bagi said.

In particular, he is looking at a growing form of heart failure that at first blush doesn’t look like heart failure. It is called heart failure with preserved ejection fraction, whose hearts still pump out greater than 50 percent or somewhat close to normal while other heart failure patients are often well below that. These patients often lack the blockages in major blood vessels or previous heart attacks that can lead to heart failure but suffer some of the same symptoms.

The patients might see a cardiologist, who looks at the major blood vessels and can’t find a problem, Bagi said. But the patients are suffering from coronary microvascular dysfunction, a disease of the very thin blood vessels in the heart that are about the width of a strand of hair. It is increasingly prevalent in older patients and in particular in women, who in Europe make up 60 percent of the patients with this disease, Bagi said.

Both the American Heart Association and the National Institutes of Health have called for more study of the disease and Bagi recently published his findings in the heart association journal Arteriosclerosis, Thrombosis and Vascular Biology.

“Our study is really trying to understand how this small blood vessel disease can contribute to this very different form of heart failure,” he said. “The treatments for this kind of disease are very limited.”

Bagi studied blood vessels and fat tissue taken during open heart surgery and found a decreased ability to dilate in those who were older and obese. Those tissues were more likely to secrete inflammatory factors that could contribute to that and Bagi zeroed in on a particular enzyme called ADAM17 known to increase the amount of a particular inflammatory protein called TNF-alpha. The enzyme appeared to be most active in older patients who also lacked a protein known to be reduced with age.

In order to confirm it, Bagi worked in mouse models, using older and younger mice, and found that transferring the fat from older mice to younger mice could effectively transfer the disease and quickly.

“Within a week, the aged fat transferred to young animals increased the blood level of inflammatory cytokines, such as TNF and damaged the small blood vessels in the mouse heart,” Bagi said.

The particular enzyme he is interested in was involved in clinical trials for other chronic inflammatory diseases, such as arthritis, but the drug wasn’t specific enough and the patients developed significant side effects. But now there are those who have developed much more specific therapies, known as monoclonal antibodies, against the enzyme, Bagi said.

“There is a revival of this field and they have developed selective antibodies against this enzyme,” he said. “These are very promising in chronic diseases.”

They will most likely be tried first against arthritis and Bagi thinks clinical trials could begin this year. He hopes he has provided some evidence they should also be tried against heart disease.

“The idea of this paper was really to identify ADAM17 as a drug target,” Bagi said. “A monoclonal antibody against this would be nice.”

Reach Tom Corwin at (706) 823-3213 or tom.corwin@augustachronicle.com

Topics:
 

More

Mon, 12/11/2017 - 22:42

Burke County seeks burglary suspect