The Impact of Zinc Supplementation on Left Ventricular Function in Nonischemic Cardiomyopathy
Condition: Heart Failure; Cardiomyopathies
MeSH terms: Heart Failure; Cardiomyopathies
Intervention: Zinc Acetate
Intervention description: Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels ~10-12.
Intervention MeSH terms: Zinc
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 48.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: Heart Failure; Cardiomyopathy; Remodeling; Antioxidant; Zinc; Copper

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects (n=40) ≥21 years of age with chronic (≥1 year duration) nonischemic
             cardiomyopathy (NISCM), New York Heart Association (NYHA) functional class II-III
             symptoms on stable medical therapy (≥3 months of stable doses of β-blocker,
             angiotensin inhibitor or receptor blocker, and aldosterone inhibitor [if appropriate]
             therapies) with a documented left ventricular (LV) ejection fraction ≤40% and evidence
             of LV dilation will be eligible for study participation.

          -  The diagnosis of a nonischemic etiology for the cardiomyopathy must be supported by
             coronary angiography, stress echocardiography, or nuclear scintigraphy.

          -  To allow for a comparison of treatment effect in diabetic versus nondiabetic NISCM,
             half (n=20) of the subjects enrolled will be diabetic

        Exclusion Criteria:

          -  Subjects with HF that is deemed to be ischemic, congenital, valvular, or infiltrative
             in etiology, or chemotherapy/toxin-induced will not be eligible for enrollment.

          -  Other exclusion criteria include the presence of a life-threatening illness with a
             projected survival ≤6 months;

          -  recurrent ventricular arrhythmias; end-stage renal failure;

          -  ongoing infection;

          -  inability to follow-up;

          -  collagen vascular disease (lupus, sarcoid);

          -  enrollment in another investigational study;

          -  unstable or symptomatic peripheral artery disease;

          -  prior or active Zn supplementation;

          -  or ongoing alcohol abuse.