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

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.

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.