Nerve growth factor decreases death after heart attacks

Nerve growth factor (NGF) improved the functioning of damaged heart muscle in mice in a novel study – a finding that could yield a new human therapy, researchers reported in Circulation Research, a journal of the American Heart Association.

NGF is a small protein important for the survival of certain nerve cells. However, recent research shows that NGF is important to a variety of body processes beyond helping nerves.

The study is the first to explore the role of NGF on heart-cell health and healing instead of its influence on cardiac nerves.

"It is the latest investigation to indicate that growth factors affect more than just the body part for which they are named," said Costanza Emanueli, PhD, senior author of the study, a reader (associate professor) at the University of Bristol in England and a British Heart Foundation senior research fellow. "The most significant result was that NGF gene therapy improved post-heart attack survival."

The study focused on short-term results following surgery, rather than on NGF as a treatment for heart disease. Emanueli and her colleagues first established that NGF and TrkA – the cell-surface receptor to which the growth factor most readily binds – are present in both normal and damaged human heart muscle. They also found that damaged human hearts had higher NGF levels than normal ones.

Among the significant findings from the mouse experiments:

• Surgically induced heart attacks increased the levels of NGF and TrkA in the mice. In three days, NGF rose two-fold and TrkA increased 4.2-fold compared to levels in a control group of mice that underwent a sham operation.
• Lowering NGF levels reduced new blood vessel growth and left ventricular function, and increased programmed cell death.
• No deaths occurred in the sham-operation mice during the 14 days after surgery. But, among mice with induced heart attacks, 40 percent of those that received no NGF and 20 percent of those given the growth factor died within two weeks after surgery – a 50 percent reduction in mortality for the treated animals. "In a clinical trial, that reduction would be considered very good," Emanueli said.
• Raising heart NGF levels by gene therapy reduced programmed cell death, and increased blood vessel growth, cardiac blood flows and left ventricle function.
• Higher NGF also resulted in increased cardiac stem cells. But to the team’s surprise, more stem cells were not essential for obtaining the study’s positive results.
• A biological pathway known as Akt/Foxo-3a – which scientists earlier had identified as important in blood vessel growth and the survival of cardiovascular cells – regulates NGF’s beneficial effects.

"We may have identified a novel factor able to improve heart-attack-patient survival or delay heart failure after an attack," Emanueli said.

However, "it is important to perform further studies of the full biological function and therapeutic potential of NGF."

For example, before NGF can enter medical care, researchers need to:

• Determine the best method to put the growth factor into the heart. In the experiments reported in this study, researchers inserted NGF using an adenovirus modified so it would not reproduce in the body. But other viral vectors may be better, Emanueli said.
• Learn if NGF would result in adverse effects in the months and years after treatment.
• Assess whether NGF therapy in animals with hearts more similar to humans shows the same benefits as in mice.

(Source: American Heart Association: Circulation Research: April 2010)