The Impact of Zinc Supplementation on Left Ventricular Function in Nonischemic Cardiomyopathy

Heart failure affects over 5.3 million Americans and, while other cardiovascular diseases have enjoyed a reduction in mortality rates over the last decade, the mortality from heart failure continues to rise[1]. Thus, identifying novel therapies that can reduce heart failure development and/or progression are warranted. Unifying to most cardiomyopathic processes is an impaired handling of reactive oxygen species (ROS)[2-4]. Reactive oxygen species are generated as byproducts of inflammation and oxidative stress that occur in the setting of normal myocardial aerobic metabolism. Metallothionein, glutathione reductase, and superoxide dismutase are major antioxidants in the myocardium that help combat oxidative stress and prevent myocardial damage. In certain clinical settings, including cardiac ischemia, diabetes, and heavy metal excess (copper, iron), myocardial oxidative stress levels are greatly increased. When pro-oxidant levels exceed myocardial antioxidant capabilities, ROS-induced membrane, protein, and DNA inactivation can lead to the development of cardiac dysfunction. One means of preventing the development or progression of cardiomyopathy is to reduce oxidative stress through up-regulation of intramyocardial antioxidants. Murine studies of cardiomyopathy have shown that oral administration of zinc acetate may succeed as an indirect myocardial anti-oxidant because zinc sufficiently up-regulates the intramyocardial production of superoxide dismutase (a zinc-dependant anti-oxidant enzyme) and metallothionein (a "super antioxidant") [5-8]. Zinc also directly reduces prooxidant Cu levels by reducing gastrointestinal zinc absorption. However, to date, no studies have examined the impact of zinc acetate supplementation in subjects with cardiomyopathy and systolic failure on antioxidant capacity and remodeling. The hypothesis of this pilot study is that administration of oral zinc acetate to humans with cardiomyopathy will lead to an up-regulation of myocardial anti-oxidant capabilities,leading to a favorable reduction in oxidative stress. This study will provide preliminary data to support a randomized, placebo-controlled trial of zinc therapy in heart failure as a means of improving or preventing the progression of systolic dysfunction in subjects with mild-moderate heart failure.