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. 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
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.
Altered regulation of the transition-metal copper (Cu) may lead to an overproduction of
reactive oxygen species (ROS) with subsequent development of a nonischemic cardiomyopathy
(NISCM). Myocardial Cu levels are elevated in NISCM, and Cu levels are highest in the
"diabetic cardiomyopathy." In humans, zinc (Zn) is an essential component of proteins
critical for regulating myocardial cytoskeleton turnover and cellular proliferation. Zn also
serves as an antioxidant and indirect regulator of redox-active Cu. By upregulating the
chelator metallothionein, Zn reduces the levels of free Cu implicated in oxidative myocardial
Transgenic over-expression of the antioxidant metallothionein has been shown to reduce
ROS-induced myocardial damage. In diabetic cardiomyopathy, Cu chelation improves left
ventricular (LV) diastolic relaxation abnormalities. However, it is unknown if Zn
supplementation could alter the progression of LV systolic dysfunction through Cu depletion
and ROS reduction. The aim of this pilot study is to assess the impact of a novel
intervention, Zn supplementation, on myocardial remodeling by examining changes in serum
levels of the types I (PINP) and III (PIIINP) collagen N-terminal propeptides. The primary
study hypothesis is that Zn supplementation will have a favorable impact on the
pathophysiology of NISCM by either repleting a Zn deficiency/insufficiency or by reducing
myocardial damage and adverse remodeling in the setting of redox-active Cu excess.
Stable outpatients (n=40) with chronic NISCM (ejection fraction ≤40%) will receive daily oral
Zn-acetate (50 mg po tid) for 10 months. Serum PINP, PIIINP, and markers of inflammation
(CRP, sedimentation rate, myeloperoxidase) and oxidative stress (8-isoprostane, superoxide
dismutase) will be obtained at baseline and following 10 months of Zn supplementation.
Changes in collagen turnover will then be correlated with changes noted in LV systolic and
diastolic function by echocardiography. Finally, we will examine for a differential treatment
effect of Zn therapy in a diabetic subset (n=20) with NISCM compared with the nondiabetics.
- 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
- 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.