The Impact of Zinc Supplementation on Left Ventricular Function in Nonischemic Cardiomyopathy
Information source: University of Michigan
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Heart Failure; Cardiomyopathies
Intervention: Zinc Acetate (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: University of Michigan Official(s) and/or principal investigator(s): Keith D Aaronson, MD, MS, Principal Investigator, Affiliation: University of Michigan Jennifer A Cowger, MD, MS, Study Chair, Affiliation: University of Michigan
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.
Clinical Details
Official title: Pilot Study to Assess the Impact of Zinc Supplementation on Left Ventricular Remodeling, Function, and Oxidative Stress in Nonischemic Cardiomyopathy
Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Change from baseline in markers of cardiac collagen turnover (PINP and PIIINP)
Secondary outcome: Change from baseline in measures of oxidation (superoxide dismutase, isoprostane), inflammation (CRP, myeloperoxidase), left ventricular function (systolic and diastolic).
Detailed description:
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 damage.
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.
Eligibility
Minimum age: 21 Years.
Maximum age: N/A.
Gender(s): Both.
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.
Locations and Contacts
University of Michigan Health System, Ann Arbor, Michigan 48109, United States
Additional Information
Starting date: June 2008
Last updated: December 17, 2012
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