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

NCT ID: NCT00696410

Last Updated: 2017-11-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-06-30
• Study Completion Date: 2011-06-30

Brief 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.

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.

Conditions

Heart Failure; Cardiomyopathies

Keywords

Heart Failure; Cardiomyopathy; Remodeling; Antioxidant; Zinc; Copper

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CHF patients Given Zinc Acetate

Patients with CHF received zinc acetate 50 mg po TID. This is a pre-post study

Group Type: EXPERIMENTAL

Zinc Acetate

Intervention Type: DRUG

Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels \~10-12.

Healthy controls

Health controls; no zinc acetate administered.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Zinc Acetate

Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels \~10-12.

Intervention Type: DRUG

Other Intervention Names

Galzin (zinc acetata, Teva Pharmaceuticals)

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.
• 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.

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

Jennifer Cowger , MD, MS

Assistant Professor, study Coinvestigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Keith D Aaronson, MD, MS

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Jennifer A Cowger, MD, MS

Role: STUDY_CHAIR

University of Michigan

Locations

University of Michigan Health System

Ann Arbor, Michigan, United States

Countries

United States

Other Identifiers

NIHT32-HL007853

Identifier Type: -

Identifier Source: secondary_id

HUM0001911

Identifier Type: -

Identifier Source: org_study_id