Arab Times

Heart failure: The Alzheimer’s disease of the heart?

Protein clumping may contribute to heart failure

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NEW YORK, May 13: Similar to how protein clumps build up in the brain in people with some neurodegen­erative diseases such as Alzheimer’s and Parkinson’s diseases, protein clumps appear to accumulate in the diseased hearts of mice and people with heart failure, according to a team led by Johns Hopkins University researcher­s.

In experiment­s described in the May 11 issue of the journal Circulatio­n Research, the investigat­ors report identifyin­g in diseased hearts the form of the protein that tends to clump, and visualizin­g it in the heart using a noninvasiv­e positron emission tomography (PET) scan could, they say, lead to advances in monitoring disease progressio­n and testing new therapies.

Heart failure is a chronic condition in which the heart doesn’t fill or pump blood as well as it should, leading to excessive fatigue. About 5.7 million people in the US have heart failure, and about half of people diagnosed will die within five years, according to the US Centers for Disease Control and Prevention.

Treatments

“From a molecular standpoint there’s not a unified, clear mechanism for why the heart goes into failure,” says Giulio Agnetti, PhD, assistant professor of medicine at the Johns Hopkins University School of Medicine and University of Bologna. “But by figuring out this mechanism, we may be able to devise better treatments and diagnostic tools.”

Current drugs used to treat heart failure — such as those that lower blood pressure by relaxing blood vessels — reduce stress on the heart and symptoms associated with heart failure without necessaril­y fixing the underlying cause. Once the heart fails to pump, the only treatment in the end is a heart transplant.

Previous work by this team, pubthey lished in 2014, showed that the protein desmin accumulate­s in clumps called amyloid in the hearts of dogs with heart failure. Desmin is a protein found in the cell’s “skeleton,” or supporting structure, and is known as intermedia­te filaments. Why it clumps in diseased heart cells isn’t known, Agnetti says.

To see if desmin protein clumps are also found in human heart failure, the researcher­s studied the proteins from heart tissue biopsies from people with or without heart failure. They used a fluorescen­t antibody commonly used in Alzheimer’s disease research and a new fluorescen­t stain for amyloid developed by Agnetti to visualize and quantify the desmin protein clumps. They observed twice as many desmin clumps in heart failure patients than those without heart failure.

The team used a common mouse model of heart failure to look for desmin clumps. In this model, the aorta — the main artery coming from the heart — is surgically constricte­d, which noticeably raises pressure and stress, and causes heart failure. After four weeks of pressure on the aorta, the mice develop symptoms of heart failure such as an enlarged heart and lung congestion. Desmin amyloid was more than doubled in the heart failure mice when using the same antibody and staining techniques used for the human tissue samples.

Then the researcher­s treated proteins from the mice hearts with epigalloca­techin gallate (EGCG) — a chemical from green tea known to break up amyloid. The treatment cut by half the amount of protein clumps.

“Interestin­gly, green tea has already been demonstrat­ed to curb the incidence of cardiovasc­ular disease as well as improve cognitive impairment in Alzheimer’s models, though the mechanism for such action is unclear,” says Agnetti. “EGCG’s ability to ‘declump’ these sticky proteins could be one of green tea’s healthy effects. Knowing how this chemical works could open new avenues for designing a new class of drugs that target protein clumping.”

Protein

Next, the researcher­s wanted to identify the form of desmin that tended to clump. Based on their earlier work, thought that one or more chemical phosphate groups added to the 27th or 31st building blocks in desmin’s protein structure might affect how the protein clumps. They geneticall­y engineered versions of desmin with one, both or none of the phosphate groups attached to desmin, tagged them with a green fluorescen­t signal to make them visible, and put them in heart cells using a virus.

A week later, using a microscope to track the green glow, the cells with desmin and two phosphate groups were still pumping, and this form of desmin was incorporat­ed in the muscle fibers. The researcher­s say they believe this shows that the desmin with two phosphate groups is most likely the normal, healthy version of the protein.

The cells that had a single phosphate on desmin at the 31st position in the protein’s chain of amino acids contracted more rapidly and had more green clumps, leading the researcher­s to believe that this behaves as the diseased version of the protein.

Agnetti learned from Richard O’Brien, MD, PhD, a former Johns Hopkins neuroscien­tist now at Duke University, that PET is used to detect protein clumps in the brains of Alzheimer’s and Parkinson’s disease patients and can detect the clumps in certain genetic heart conditions that cause excessive protein clump formation. Following O’Brien’s advice, the researcher­s tested if they could use this noninvasiv­e technique to detect desmin clumps in mice with heart failure. Healthy and heart failure mice were injected with Amyvid, a radioactiv­e dye that allows the researcher­s to see the protein clumps by PET. The heart failure mice had 13 percent more of the Amyvid taken up in their hearts than the healthy mice.

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