Developing a child-centric approach to treating heart failure is no easy task. For one thing, the underlying causes of decreased cardiac function in children vastly differ from those in adults. While most adults with heart failure have suffered a heart attack, heart failure in children is more likely the result of congenital heart disease (CHD), or a structural defect present at birth that impairs heart function. And most therapies designed for adults haven’t proven equally effective in children.
Stimulating heart muscle cells to regenerate is one way cardiac researchers at Boston Children’s Hospital’s Translational Research Center hope to restore function to children’s ailing hearts. In this area, children actually have an advantage over adults: their young heart cells are better suited for regrowth.
Reporting in the April 1 Science Translational Medicine, Brian Polizzotti, PhD, and Bernhard Kuhn, MD, demonstrate that not only does the drug neuregulin trigger heart cell regeneration and improve overall heart function in newborn mice, but its effects are most potent for humans within the first six months of life.
Earlier is better
Polizzotti and his team began by studying three groups of mice. One group received a neuregulin injection at birth and then once a day for 34 days. Another group received its first injection five days after birth and then again every day for 34 days. The third, a control group, received daily injections of a neutral protein (bovine serum albumin, or BSA) for the same length of time.
The mice given neuregulin from birth were found to have a sustained increase in heart function, as observed by both echocardiogram and MRI. Polizzoti also noticed that these mice had more connectivity among the damaged heart muscle cells, or cardiomyocytes, which means they were able to work together more efficiently. That’s important because heart cells need to “talk” with one another to create a consistent heart rhythm. If one area of tissue becomes isolated, it can lead to a life-threatening arrhythmia.
Polizzotti explains that early administration of neuregulin aids heart health in several ways: 1) it is “cardio-protective,” meaning it prevents heart muscle cells from dying due to the injury; 2) it stimulates the regeneration (proliferation) of cardiomyocytes, and (3) it improves the hearts ability to pump blood to the rest of the body.
“We saved about 136,000 cardiomyocytes with early administration of neuregulin,” says Polizzotti. Additionally, the stimulated proliferation resulted in the formation of 224,000 new heart cells. “We estimate that thirty-eight percent of the additional cardiomyocytes were present due to cardioprotection, while sixty-two percent were the result of regeneration.”
Improving the injury model
The study also introduces a new disease model for testing neuregulin’s effects.
While there were a couple of well-established injury models in mice for studying damaged hearts, Polizzotti had to think outside the box to model the specific kind of damage caused by CHD.
He developed a cryo-injury model that closely recreates the structure and function of a heart with CHD. By pressing a metal probe dipped in liquid nitrogen onto an area of a mouse’s heart, he caused the heart to scar and to pump less blood per contraction. The latter was evidenced by a decreased ejection fraction, which measures the volume of blood pumped through the left ventricle each time it contracts. Both scarring and a lower-than-normal ejection fraction are common to many types of CHD.
Of mice and men
After the mouse trial, Polizzotti and colleagues turned to human heart muscle cells taken from children during surgery for tetralogy of Fallot. The researchers cultured these cells for three days with either neuregulin or a harmless serum. Their results mirrored those from the mouse study: neuregulin stimulated cell cycling and proliferation in the diseased myocardium of infants less than 6 months old.
Polizzotti plans to take this research farther by testing neuregulin in mouse models and human heart cells from patients with other types of CHD. His first choice would be any condition that affects the contractility unit of the heart, such as dilated cardiomyopathy.
“Neuregulin therapy likely stimulates a variety of molecular mechanisms and signaling pathways that may improve cardiac function and structure in patients suffering from different forms of CHD,” says Polizzotti. “I am interested in seeing if these results translate to those patient populations.”
He is also exploring ways to simulate the passage of time in a controlled experiment to observe neuregulin’s long-term effects. If this work holds up, neuregulin could become an early, sustainable intervention for pediatric heart failure patients.