TUCSON, Arizona — A study led by a physician-scientist at the University of Arizona College of Medicine – Tucson 's Sarver Heart Center identified a drug candidate that appears to reverse the progression of a type of heart failure in mouse models, which could lead to expanded treatment options for humans. The results were published in the journal Cell Metabolism .
Heart failure occurs when the heart doesn't pump blood properly. In about half of cases, the muscle is weak and has difficulty pumping. The rest result from a stiff muscle, a type called heart failure with preserved ejection fraction, or HFpEF.
The research team found that a key ingredient in triggering heart failure with preserved ejection fraction is an enzyme that escapes into an area of the cell where it's not normally found. Once there, it reacts with another enzyme to convert glucose, a type of sugar, into harmful byproducts that set off a chain reaction, ultimately reducing the heart's elasticity.
"Nobody had shown this before. It makes sense, because HFpEF is associated with diabetes, which is a major risk factor. The continuous sugar overload causes cell dysfunction," said senior author Hossein Ardehali, MD, PhD, associate director of the Sarver Heart Center, associate dean for translational research, director of the Translational Research Program and the Irving J. Levinson professor of cardiology at the U of A College of Medicine – Tucson.
After uncovering the connection between the harmful glucose byproducts and the stiff heart muscle characteristic of HFpEF, the team identified a molecule that neutralized the glucose byproducts, reversing heart failure in mouse models.
To learn more about what causes HFpEF, Ardehali's team, which includes researchers from Northwestern University, the University of California San Diego and the University of Pennsylvania, developed the first mouse model of spontaneous HFpEF. They peered inside endothelial cells, which line the blood vessels, to follow these cells on their journey from healthy to dysfunctional and identify what activates the disease state.
The reactions between enzymes, glucose and other molecules that occur in endothelial cells can be likened to a factory's assembly line. The machinery in a healthy heart produces functioning widgets, but in HFpEF, someone has thrown a wrench into the machinery, resulting in defective widgets. Just as a car built with defective parts won't run well, a heart built with defective molecules won't pump blood well.
"When we are young, the heart relaxes and blood goes into it," Ardehali said. "As we get older, the heart becomes stiff. It's not elastic anymore, so blood doesn't go into the heart easily. That can cause heart failure — one of the most common causes of death and hospitalization in this country."
Until recently, there were no treatments for HFpEF other than cardiac rehabilitation, which involves exercise, lifestyle changes and stress reduction. Within the past few years, a new class of diabetes drugs, SGLT2 inhibitors – sold under brand names including Invokana, Farxiga, Jardiance and Steglatro – have been found to benefit HFpEF patients as well, but patients need more options. The researchers hope their drug candidate will ultimately expand the therapeutic toolkit.
The next step is to perform additional lab tests to confirm the drug candidate works as expected, after which they plan to evaluate it in humans.
"We hope that this drug can be used in patients and reduce the incidence of HFpEF. I'm hoping we can turn it into clinical practice," Ardehali said. "We are excited – this could potentially be a new treatment for HFpEF."
This work was supported in part by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health, under award nos. HL127646, HL140973, HL138982 and HL155953; the NIH's National Eye Institute under award no. R01EY032609, and the American Heart Association under award no. SP0065527. Additional funding was provided by the Ledcuq Foundation and the BrightFocus Foundation.
