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

May 09, 2018

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 U.S. have heart failure, and about half of people diagnosed will die within five years, according to the U.S. Centers for Disease Control and Prevention.

"From a molecular standpoint there's not a unified, clear mechanism for why the heart goes into failure," says Giulio Agnetti, Ph.D., 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, published 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 'de-clump' 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."

Next, the researchers wanted to identify the form of desmin that tended to clump. Based on their earlier work, they 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, M.D., Ph.D., 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.

"PET imaging of protein clumps may be eventually used in patients to identify structural changes in the heart as the disease progresses, and this information likely holds prognostic value," says Peter Rainer, M.D., Ph.D., a former postdoctoral fellow at Johns Hopkins who is now at the Medical University of Graz in Austria. "It could be used as a nice measure of the effect of an intervention to halt or reverse disease progression."

In future experiments, the research team plans to confirm its results in more human tissue samples. The investigators also hope to identify a drug or small molecule to prevent desmin from forming clumps.

"There is a lot of emphasis placed on the role of genes in modern times, but we're born with our genes and at present we can do very little about the ones we have," says Agnetti. "I think the next step is to follow up with the proteins that are dynamically modified in response to environment, which places a larger emphasis on lifestyle intervention to help prevent diseases. Natural compounds like EGCG in green tea and modified dietary interventions could play a role in keeping us healthy."
-end-
Additional authors include Nazareno Paolocci, Peihong Dong, Yuchuan Wang, Catherine Foss, Steven An, Martin Pomper and Gordon Tomaselli of Johns Hopkins; Matteo Sorge of the University of Turin; Justyna Fert-Bober, Ronald Holewinski and Jennifer Van Eyk of Cedars-Sinai; Alessandra Baracca and Giancarlo Solaini of the University of Bologna and Charles Glabe of the University of California, Irvine.

The study was funded by grants from the National Heart, Lung, and Blood Institute (R01 HL107361 and P01 HL107153), the American Heart Association (2SDG9210000 and 16IRG27240002) and the Magic That Matters Foundation.

Johns Hopkins Medicine

Related Heart Failure Articles from Brightsurf:

Top Science Tip Sheet on heart failure, heart muscle cells, heart attack and atrial fibrillation results
Newly discovered pathway may have potential for treating heart failure - New research model helps predict heart muscle cells' impact on heart function after injury - New mass spectrometry approach generates libraries of glycans in human heart tissue - Understanding heart damage after heart attack and treatment may provide clues for prevention - Understanding atrial fibrillation's effects on heart cells may help find treatments - New research may lead to therapy for heart failure caused by ICI cancer medication

Machining the heart: New predictor for helping to beat chronic heart failure
Researchers from Kanazawa University have used machine learning to predict which classes of chronic heart failure patients are most likely to experience heart failure death, and which are most likely to develop an arrhythmic death or sudden cardiac death.

Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.

Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population

Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.

Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.

Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.

Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.

How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.

Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.

Read More: Heart Failure News and Heart Failure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.