Scientists 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). The study (“Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance”), which was published 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 around the body.
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure–volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber,” wrote the investigators.
“Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham-operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance.
“Using phospho-site-specific antibodies, we assay the phosphorylation of titin’s PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin’s stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness.”
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, it 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, there are currently no drugs available to treat HFpEF.
A team at the Sarver Heart Center at the University of Arizona 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 that the drug reduced left ventricular stiffness, thereby improving the animals’ capacity for exercise.
The scientists determined that 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 Henk L. Granzier, Ph.D., a professor in the department of physiology at the University of Arizona. “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.”