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

Pilot Study to Assess the Impact of Zinc Supplementation on Left Ventricular Remodeling, Function, and Oxidative Stress 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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Cardiomyopathies
• Intervention / Treatment: Drug: Zinc Acetate

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.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: CHF patients Given Zinc Acetate; Patients with CHF received zinc acetate 50 mg po TID. This is a pre-post study	Drug: Zinc Acetate; Zinc acetate 50 mg po TID for 10 months. Dose will be titrated to achieve ceruloplasmin levels ~10-12.; Other Names: Galzin (zinc acetata, Teva Pharmaceuticals)
NO_INTERVENTION: Healthy controls; Health controls; no zinc acetate administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Markers of Cardiac Collagen Turnover (PINP) in Patients With Systolic Heart Failure and Compared With Healthy Controls.	The intervention group (patients with systolic heart failure) was given Zinc Acetate 50 mg po three times daily for 10 months. The change from baseline in markers of cardiac collagen turnover (PINP) in patients with systolic heart failure after 10 months of zinc acetate was measured and compared with a single measure from healthy controls.	Baseline (time 0) and after 10 months of Zinc Acetate.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Serum Isoprostane in Patients With Systolic Heart Failure	Change from baseline in serum isoprostane 10 months after Zn Acetate in patients with systolic heart failure and compared with a single measure in healthy subjects	Baseline (time 0) and 10 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PIIINP From Baseline After 10 Months of Zinc Acetate in Systolic Heart Failure and Compared With a Single Measure in Healthy Controls	Change in PIIINP from baseline after 10 months of Zinc Acetate in patients with systolic heart failure and compared with a single measure in healthy controls	Baseline (time 0) and 10 months
Change From Baseline in Serum Superoxide Dismutase	Change from baseline in serum superoxide dismutase after 10 months of zinc acetate in patients with systolic heart failure and compared with a single measure in healthy controls	Baseline (time 0) and 10 months
Change From Baseline in Serum Measures of of Myeloperoxidase (MPO) After 10 Months of Zinc Acetate Treatment	Change from baseline in serum myeloperoxidase (MPO) after 10 months of zinc acetate treatment in patients with systolic heart failure and compared with a single measure from healthy controls	Baseline (time 0) and 10 months

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institutes of Health (NIH)
• Investigators: Principal Investigator: Keith D Aaronson, MD, MS, University of Michigan; Study Chair: Jennifer A Cowger, MD, MS, University of Michigan

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (ACTUAL): June 1, 2011
• Study Completion (ACTUAL): June 1, 2011

Study Registration Dates

• First Submitted: June 9, 2008
• First Submitted That Met QC Criteria: June 9, 2008
• First Posted (ESTIMATE): June 12, 2008

Study Record Updates

• Last Update Posted (ACTUAL): November 6, 2017
• Last Update Submitted That Met QC Criteria: October 5, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Heart Failure; Cardiomyopathy; Zinc; Antioxidant; Remodeling; Copper
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Cardiomyopathies; Physiological Effects of Drugs; Trace Elements; Micronutrients; Zinc
• Other Study ID Numbers: HUM0001911; NIHT32-HL007853