Drug therapy for PKU reverses heart damage

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 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 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,” says Kass.

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 for 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 says, BH4 is known to have some effect on this chemical pathway, so “there could be some combination from these two therapies,” which he also plans to study.

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

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

Additional assistance with biochemical analysis was provided by James Mitchell, Ph.D., from the National Cancer Institute, a member of the National Institutes of Health; Miles Wolin, Ph.D., from the New York University School of Medicine; and Keith Channon, M.D., Ph.D., and Nicholas Alp, M.D., Ph.D., both from Oxford University, in the United Kingdom.

For additional information, go to:
http://www.hopkinsheart.org/
http://circ.ahajournals.org/