Hypothesis: role for ammonia neutralization in the prevention and reversal of heart failure

Ammonia plays a central role in the life and death of all living organisms and has been studied for over 100 yr. Ammonia is necessary for growth and development, but it is toxic in excess, and, as a result, differing methods of ammonia neutralization have evolved. After physiological and pathological stress to the heart, tissue ammonia levels rise. Local ammonia neutralization may be inadequate, and excess ammonia may exert its toxic effects. Phenylbutyrate (PBA), which is Federal Drug Administration approved for the treatment of elevated blood ammonia in urea cycle disorders, provides an accessory pathway for ammonia excretion. Recently, PBA has also been found to prevent specific cardiomyopathies. The central theme presents the hypothesis that stress to the myocardium from a variety of environmental sources causes injury, cell death, necrosis, and ammonia production. Ammonia, if not neutralized, exerts downstream toxic effects. Here, data are presented showing that neutralization with PBA alone and PBA combined with angiotensin-converting enzyme inhibition prevent and reverse pathophysiology associated with specific cardiomyopathies. NEW & NOTEWORTHY Ammonia produced after myocardial injury is hypothesized to be an upstream stress contributing to the pathophysiology of heart failure, effects that may be attenuated by a documented ammonia-reducing treatment. Reversal of heart failure can be achieved using an angiotensin-converting enzyme inhibitor combined with an ammonia-reducing treatment.