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 (HFpEF), 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, shows 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 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, PhD, Nancy Sweitzer, MD, PhD, and colleagues at the UA Sarver Heart Center decided to investigate whether metformin could be an effective treatment for HFpEF because 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.
The researchers 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 Dr. Granzier and colleagues 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,” Dr. Granzier said. “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.”
Dr. Granzier is professor of cellular and molecular medicine and physiology at the UA College of Medicine – Tucson, UA professor of biomedical engineering and molecular and cellular biology and a member of the UA BIO5 Institute. He also is the Alan and Alfie Norville Endowed Chair in the UA Sarver Heart Center Molecular Cardiovascular Research Program.
The University of Arizona Sarver Heart Center’s 159 members include faculty from cardiology, cardiothoracic surgery, pediatric cardiology, neurology, vascular surgery, radiology, endocrinology, emergency medicine, nursing, pharmacy and basic sciences. The UA Sarver Heart Center emphasizes a highly collaborative research environment, fostering innovative translational or “bench-to-bedside” research; dedicated to innovating lifesaving patient care. If you would like to give permission for Sarver Heart Center to contact you about heart research studies, please complete a Cardiology Research Registry Information Form. The academic mission of the Sarver Heart Center encompasses for fellowship programs in cardiovascular disease, interventional cardiology, advanced heart failure and transplant cardiology, and electrophysiology.