Drug therapy for PKU reverses heart damage

Studies with BH4 in mice show promise

A pricy drug used to treat a rare but well-known genetic disorder may hold wider promise as a treatment for millions of Americans with potentially lethal enlarged hearts, due mainly to high blood pressure, a study from Johns Hopkins shows.

The common denominator in both phenylketonuria (PKU) and cardiac hypertrophy is the chemical tetrahydrobiopterin (BH4). In PKU, this enzyme coworker helps break down the molecule phenylalanine whose buildup is toxic to the brain. In the heart, BH4 helps build the chemical nitric oxide, which is needed for normal heart function and neutralizing toxic chemicals, called oxygen free radicals.

Doctors have used BH4 and diets that exclude phenylalanine for almost a decade to treat PKU, a so-called inborn error of metabolism that if left untreated causes irreversible brain damage. It affects an estimated 15,000 newborns in the United States each year.

Building on what has been known about BH4’s activities, the Hopkins team, working with mice, found that treatment with BH4 stabilizes the pumping function of failing, enlarged hearts and dramatically shrinks the muscle size in a relatively short timeframe of just over a month. The team’s findings appear in the May 20 edition of the journal Circulation.

“Our results show for the first time the pivotal role played by BH4 in stopping and reversing the weakening and damage done – even in severe cases – to the heart muscle as a result of hypertension and subsequent hypertrophy,” says study senior investigator David Kass, M.D., a professor at the Johns Hopkins University School of Medicine and its Heart Institute. “This key evidence may help us develop new therapies that stop and reverse hypertrophy, preventing the disease from leading to end-stage heart failure and keeping affected individuals from needing heart-assist pumps or a treatment of last resort, the heart transplant.”

Specifically, Kass and Belgian scientist, An Moens, M.D., a postdoctoral cardiology research fellow at Hopkins, fed a daily dose of 5 milligrams of BH4 per 25 grams of body weight to 31 mice whose hearts had been subjected to prolonged experimental hypertension created by constricting their aortas for four weeks.

Before and after treatment, heart function was monitored by several key tests, such as echocardiogram and magnetic resonance imaging, as well as catheters placed within the heart. This was supplemented by post-treatment tissue analysis. Results from this group were compared to another group of 25 mice, also subjected to high blood pressure, who were given placebo instead of BH4 during the same timeframe.