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The newspaper of The Johns Hopkins University May 19, 2008 | Vol. 37 No. 35
Drug Therapy for Genetic Disorder Reverses Heart Damage

Studies show promising treatment for potentially lethal condition

By David March
Johns Hopkins Medicine

A pricey 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, or PKU, and cardiac hypertrophy is the chemical tetrahydrobiopterin, known as BH4. In PKU, this enzyme co-worker 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 traditionally used diets excluding phenylalanine to treat PKU, a so-called inborn error of metabolism that can lead to irreversible brain damage; but more recently, they have also begun to treat the disease with BH4. An estimated 13,000 Americans are living with PKU, and each year more than 300 newborns are diagnosed with the disease.

Building on what has been known about BH4's activities, the Johns 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," said study senior investigator David Kass, a professor at the 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, a postdoctoral cardiology research fellow at Johns 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 those from another group of 25 mice, also subjected to high blood pressure, who were given placebo instead of BH4 during the same timeframe.

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 and 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," said 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 said, at present the drug comes with a significant cost drawback. Technologically complex to manufacture, it is currently priced at $29 per 100 milligrams, and average individual treatments for PKU have been estimated to cost as much as $57,000 per year. (The drug is currently sold as sapropterin dihydrochlorid, or Kuvan, by its manufacturer, BioMarin Pharmaceuticals.)

Researchers say that even before the emergence of symptoms of heart failure, 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 become 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.

For nearly two decades, Kass and his team have studied the nitric oxide pathway for clues to its overall role in causing heart failure in the belief that improving its function or lowering its production of oxygen free radicals could prevent or reverse the course of disease.

The Johns Hopkins team says that BH4, whose tissue levels are degraded in stressed hearts from hypertrophy and the muscle's weakened state, works by recoupling the enzyme nitric oxide synthase.

Researchers say that this is the only form of the enzyme that functions normally, making more nitric oxide rather than free radicals. Testing of another potent antioxidant, Tempol, did not counter the effects of hypertrophy like BH4 and failed to recouple nitric oxide synthase. "This tells us that BH4's targeted action is key to its benefits," Kass said.

Researchers next plan to look at combined therapies that could improve upon the effectiveness of BH4. Add-on drugs include vitamin C or folic acid, both of which are known to interact with the so- called enzyme cofactor, and researchers plan to monitor closely the effects of combined therapy on heart function, size and weight.

In related work, Kass and his team have studied Viagra as a possible treatment for hypertrophy in its early stages. However, Kass points out that the Viagra-based research focuses on a different route, the phosphodiesterase-5 chemical pathway, and how it is involved in the process of heart failure. But, he said, BH4 is known to have some effect on this chemical pathway, so "there could be some combination from these two therapies" that he also plans to study.

Funding for the study of BH4 was provided by the National Institutes of Health and Peter Belfer Laboratory Foundation, with additional support from the American Heart Association, Belgian American Educational Foundations and University of Antwerp, Belgium.

In addition to Kass and Moens, Johns Hopkins researchers involved in this study were Eiki Takimoto, Carlo Tocchetti, Khalid Chakir, Djahida Bedja, Gianfranco Cormaci, Elizabeth Ketner, Maulik Majmudar, Kathleen Gabrielson, Marc Halushka, Shyam Biswal, Nazareno Paolocci and Hunter Champion. Kass is also the Abraham and Virginia Weiss Professor of Cardiology at Johns Hopkins.


Related Web sites

Johns Hopkins Heart Institute


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