Drug therapy for PKU reverses heart damage

After induced heart failure and five weeks of subsequent therapy, researchers found that BH4-treated mice showed “remarkable improvements,” according to Kass, when compared to placebo-treated animals. Ejection fraction measures of heart pumping function not only stabilized with BH4, but improved, from an average 87 percent before heart failure to roughly 48 percent at the start of therapy, then back to 59 percent at the end of study. Meanwhile, average pumping function in placebo-treated mice showed a perilous decline, from 87 percent to 48 percent, to 35 percent.

Heart weight, as measured by muscle mass, showed similar results. Pressure stress resulted in mice hearts growing from an average 100 milligrams to 290 milligrams before therapy, returning to an average 209 milligrams in the BH4-treated hearts, while placebo-treated hearts grew increasingly worse, to an average 330 milligrams.

Improvements with BH4 therapy were almost as dramatic in at least three other measurements of organ health, including heart wall thickness, muscle cell size and fibrosis, and lowered chemical production of dangerous free radicals.

“Hearts clearly got better from administering the drug, and our results offer proof of principle that damage to the left ventricle from hypertrophy can be stopped and reversed, providing a potential therapy for the lethal implications of prolonged high blood pressure,” says Moens, now a cardiologist at the University of Antwerp in Belgium.

Kass expects clinical trials to start within a year.

Though no harmful side effects have been observed with BH4 therapy, Kass says, at present, the drug comes with a significant cost drawback. Technologically complex to manufacture, it is currently priced at $375 per 100 milligrams, and individual treatments for PKU have been estimated to cost as much as $33,000 per year. (The drug is currently sold as sapropterin dihydrochlorid, or Kuvan, by its manufacturer, BioMarin Pharmaceuticals.)

Researchers say that even before symptoms of heart failure emerge, such as chronic fatigue and shortness of breath, the heart muscle contracts more strongly to counteract high blood pressure. As muscle action increases, the heart grows and its walls becomes thicker, taking up space inside the heart’s chambers normally reserved for blood. And despite harder muscle contractions, pumping function becomes increasingly weak as the heart can no longer push sufficient blood around the body to meet its energy needs.

According to the American Heart Association, more than 65 million American adults have high blood pressure, a major risk factor for developing larger-than-normal hearts. Experts say nearly a quarter of the adult population worldwide is estimated to have above- normal blood pressure. Hypertrophy increases by two to three times an adult’s risk of suffering cardiovascular disease, including heart failure and sudden cardiac death.