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Blocking a pathway to heart failure

The study may help explain how aging can affect heart muscle, pictured here, and contribute to heart failure. Dr_Microbe / iStock / Thinkstock

More than 5.6 million adults in the United States are living with heart failure. Heart failure means that the heart can’t pump enough blood to meet the body’s needs. People with heart failure may feel very tired, have swollen feet, and feel short of breath.

The leading causes of heart failure are conditions that can damage the heart, such as high blood pressure and diabetes. Heart muscle, like other muscles of the body, can also weaken with age.

Previous studies have associated the activin type II receptor (ActRII) pathway with muscle wasting and other aging-related conditions. A team led by Drs. Jason Roh and Anthony Rosenzweig of Massachusetts General Hospital set out to more closely investigate this pathway in heart failure. The study, which was supported by multiple NIH components, appeared in Science Translational Medicine on March 6, 2019.

The research team analyzed blood components from healthy adults and those with heart failure. They found that ActRII activity was higher in older adults and in people with heart failure. They also found that ActRII activity was higher in heart muscle cells of mice with heart failure.

The researchers then tested the role of activating ActRII on heart muscle cells. One of the proteins that binds to ActRII is called activin A. Older mice had about three times as much activin A in their blood as younger mice.

When the scientists injected young, healthy mice with activin A, ActRII was activated, and heart function declined. At the same time, there was a drop in a protein called SERCA2a, which is important for heart muscle cell function.

Next, the team tested a treatment approach for heart failure. They used a drug known as CDD866 to block ActRII. CDD866 can bind to the receptor and prevent activin A from activating it. CDD866 blocked activin A from causing a drop in SERCA2a. Inhibiting the ActRII pathway in this way improved heart function in tests with several different groups of mice with heart failure.

These results help explain how aging might contribute to heart failure. They also suggest a potential therapeutic approach.

“It is becoming increasingly clear that the ActRII pathway is involved in many of the chronic diseases associated with aging—such as heart failure, muscle loss, and neurovascular diseases,” Rosenzweig says. “The results of this study need to be validated in larger animal models before being tested in human heart failure.”

—by Geri Piazza