Researchers at the University of Arizona have discovered that metformin, a drug commonly used to treat type 2 diabetes, might also be used to treat heart failure with preserved ejection fraction, a condition predicted to affect more than 8 percent of people age 65 or older by 2020.
The study, published Dec. 19, in the Journal of General Physiology, showed that metformin relaxes a key heart muscle protein called titin, allowing the heart to properly fill with blood before pumping it throughout the body.
Nearly half of all heart failure patients are considered to have heart failure with preserved ejection fraction, or HFpEF, in which the heart can properly contract but, because the wall of the left ventricle is stiffer than normal, fails to fully relax between beats, reducing its capacity to fill with blood. This reduces blood supply to the rest of the body, leading to shortness of breath with exertion and difficulty exercising.
HFpEF is more common in women, and other risk factors include hypertension, old age and obesity. Unlike other forms of heart failure, however, no drugs are available to treat HFpEF.
Henk Granzier, who holds the Alan and Alfie Norville Endowed Chair in the UA Sarver Heart Center Molecular Cardiovascular Research Program, and Sarver Heart Center Director Dr. Nancy Sweitzer, chief of cardiology in the UA Department of Medicine, led the team that investigated whether metformin could be an effective treatment for HFpEF. The drug has been shown to increase left ventricular dilation and lower the rate of heart failure in diabetes patients.
The researchers gave metformin to mice with HFpEF-like symptoms and found the drug reduced left ventricular stiffness, thereby improving the animals' capacity for exercise. Granzier and his colleagues determined that in these mice, metformin relaxes the left ventricle by making a heart muscle protein called titin more compliant. Titin acts like a molecular spring that helps the muscle recoil after it is stretched, and titin’s stiffness can be tweaked by enzymes that add phosphate groups to the protein’s spring-like elements.
One of these elements, known as the N2B element, contains abnormally few phosphate groups in HFpEF patients, making titin extra stiff. But the researchers found that metformin treatment increased the number of phosphate groups in the N2B element of mouse titin, causing the protein, and the heart muscle as a whole, to become more compliant.
"We therefore conclude that metformin is a potential therapy for patients with HFpEF," said Granzier, who is a is professor of cellular and molecular medicine and physiology at the UA College of Medicine – Tucson, a professor of biomedical engineering and molecular and cellular biology, and a member of the UA BIO5 Institute. "Because the drug is already approved and well-tolerated in humans, using it to target titin stiffness presents a unique opportunity for immediate translation to the clinic."
A version of this article originally appeared on the UA Health Sciences website: https://opa.uahs.arizona.edu/newsroom/news/2018/ua-scientists-discover-diabetes-drug-could-be-used-treat-common-heart-failure