New protein shows potential for treating systolic heart failure

Virginia TechOct 16 2024

The heart is a muscle like no other, beating 60 to 100 times per minute on average, around the clock. But when it grows weak, it can lead to serious problems: from debilitating shortness of breath and swelling in the legs and feet, to fluid in the lungs and even death.

In systolic heart failure, which affects more than 32 million people globally, the muscle loses the ability to squeeze hard enough to push oxygenated blood from the heart's left ventricle through the body via the circulatory system.

The current treatments cardiologists use manage the symptoms of systolic heart failure and are crucial for improving patients' quality of life. However, these therapies don't directly address the underlying problem -; the weakened heart muscle itself. High mortality and hospitalization rates of patients with systolic dysfunction persist. My goal is to find ways to restore heart muscle function, including improving its energy metabolism."

Junco Warren, cardiovascular scientist in the Center for Vascular and Heart Research at the Fralin Biomedical Research Institute at VTC

Warren has identified a protein with the potential to do just that.

In a study published this month the American Journal of Physiology, Warren and her lab show for the first time that a protein known as PERM1 effectively regulates both energy and the heart's ability to contract. The study suggests the protein could be a new therapeutic approach to systolic heart failure.

In recent decades, scientists have developed several drugs aimed at improving heart muscle contraction. But many of the drugs have faced challenges in significantly improving long-term health, and most failed to improve survival in clinical trials, according to a review in the European Journal of Heart Failure.

These drugs intended to either increase the force of the heart's contractions or improve the efficiency of muscle fiber contractions, said Warren, who is also an assistant professor in Virginia Tech's Department of Human Nutrition, Foods, and Exercise in the College of Agriculture and Life Sciences. However, both approaches increase energy utilization and can actually worsen patient outcomes.

Systolic heart failure results from a vicious cycle, she said. The heart muscle grows weak, and that in turn inhibits the mitochondria – the energy producers in cells – from doing their job, which further weakens the muscle. 

According to Warren's findings, a protein called PERM1 regulates both parts of that vicious cycle. PERM1 is found in the heart and skeletal muscles and is known to regulate mitochondrial function. Because the protein is found in muscles that contract, Warren and her team found that the protein might also affect muscle contraction.

"The heart is a unique organ. It beats 24 hours, seven days a week, no rest," Warren said. "So, the heart's metabolism must be different from other organs."

In the study, the researchers delivered the protein into the hearts of healthy mice using a disarmed virus, called adenovirus. Viruses are effective vehicles because they are designed to find their way into difficult places in the body.

The study found that the protein regulated the mitochondrial function, as was known, but also improved the heart's ability to contract.

The research was conducted in healthy hearts, so the next step is to see if the protein has the same impacts in a failing heart.

"Now we are applying this method in failing hearts to see if delivering PERM1 via adeno-associated virus -; a method commonly used for gene therapy -; is able to bring back cardiac function and mitochondrial function," Warren said. "That would further suggest that it may be a new therapeutic to treat systolic heart failure by simultaneously addressing the weakness in the muscle and energy production by the mitochondria."

The study was funded by the National Institutes of Health, the American Heart Association, and the Seale Innovation Fund at the Fralin Biomedical Research Institute.