Effects of angiotensin-converting enzyme inhibitors (ACEi) on zinc metabolism in patients with heart failure

doi:10.1016/j.jtemb.2007.09.018

Journal of Trace Elements in Medicine and Biology

Volume 21, Supplement 1, 11 December 2007, Pages 53-55

https://doi.org/10.1016/j.jtemb.2007.09.018 Get rights and content

Abstract

The aim of this study is to investigate the effects of angiotensin-converting enzyme (ACE) inhibitors and furosemide on zinc metabolism by assessing serum zinc and urine levels in hospitalized subjects. We recruited 11 patients with heart failure from the Internal Medicine Department; these patients had been hospitalized less than 72 h before. Heart failure was defined using clinical and radiological signs. Serum zinc concentrations were measured using an air/acetylene flame atomic absorption spectrophotometer. Urine zinc levels were analyzed by inductively coupled plasma mass spectrometry (ICP-MS).

Data were obtained from the 11 patients and 24 healthy controls matched for age and sex. Results indicate higher urine zinc levels and lower concentrations of zinc in serum in heart failure patients vs matched controls (p<0.05).

This study suggests that treating heart failure patients with ACE inhibitors may result in zinc deficiency.

Introduction

Heart failure (HF) is a clinical syndrome with a high mortality rate even in western countries. It develops most frequently as a consequence of arrythmias, valvular disease and coronariopathy. It is recognized clinically by a constellation of symptoms and signs produced by complex circulatory and neurohormonal responses to cardiac dysfunction [1].

Angiotensin-converting-enzyme inhibitors (ACE_i), together with diuretics (furosemide), have been in widespread use in the last two decades, due to a better outcome in symptoms and prognosis in systolic left ventricular dysfunction and chronic HF [2]. ACE_i have been associated with sustained excessive renal zinc excretion and low serum zinc levels [3], [4]. In HF, a single oral dose of furosemide resulted in no change in serum zinc levels and 24-hour urine zinc excretion [5]. Moreover, if combined with captopril (ACE_i), there was little less urinary zinc excretion than in the group treated with captopril alone [6]. Captopril has a sulphydryl group (SH) and it has been hypothesized that the ability of the SH to bind to bivalent metals could induce urinary zinc losses [7].

Zinc is an essential trace element required for essential catalytic functions of many enzymes (at least 300 are known at present). It plays an important role in the structure of proteins and cell membranes [8], regulating gene expression by acting as a transcription factor and it could play a role in apoptosis [9]. Zinc has also been found to influence hormone release and nerve impulse transmission.

In this study we compare the urine and serum zinc levels in a HF group, which has begun treatment with ACE_i in the previous hours, with those of a healthy control group.

Section snippets

Subjects

We recruited 11 patients with HF (73% female, 27% male) within the age range 58–91 years (mean age 78 years) from the Internal Medicine Department. Left ventricular ejection fraction (LVEF) of 40 or less was considered HF due to systolic dysfunction. We also considered the following parameters: body mass index (BMI), hypertension, diabetes mellitus (DM), dislipemia, atrial fibrillation and NYHA classification. The inclusion criteria were age of more than 25 years, radiological signs of HF

Results

As shown in the figures, significant differences were observed between cases and controls for serum and urine zinc concentrations. Serum zinc levels were lower in the HF group (67.27 vs 87.32) (p=0.001) (Fig. 1) and the urine zinc excretion was significantly higher in the treated group (2.24 vs 0.21) (p<0.001) (Fig. 2).

Discussion and conclusion

No study has examined zinc metabolism in a large population with HF. A few small studies have done so, with varying results. And very few studies have explored the effects of drugs commonly used in HF treatment on zinc metabolism. Previous studies have indicated a serum zinc depletion and high zinc urinary excretion in patients chronically treated with ACE_i [10]. We have observed a high urinary zinc excretion and low serum zinc levels in patients hospitalized because of HF, and in those who

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Cited by (19)

Zinc Deficiency and Heart Failure: A Systematic Review of the Current Literature
2020, Journal of Cardiac Failure
Citation Excerpt :
Plasma zinc levels have been reported in multiple observational studies of patients with HF. Particularly in studies of idiopathic dilated cardiomyopathy, serum zinc levels have been found to be low, although results have been mixed in other etiologies of cardiomyopathy (Table 2).12,14,17–28 In the general US population, the prevalence of zinc deficiency is between 1% and 4%.29
Zinc is an essential micronutrient that impacts the cardiovascular system through modulation of oxidative stress. It is unknown whether zinc levels are affected in heart failure (HF), and whether the association, if present, is causal. A systematic search for publications that report coexisting zinc deficiency in patients with HF was performed to provide an overview of the pathophysiological and epidemiological aspects of this association (last search April 2019). Review of the literature suggests multiple potential pathophysiologic causes for zinc deficiency in HF as a result of impaired micronutrient consumption, hyper-inflammatory state, upregulation of the renin-angiotensin-aldosterone axis, diminished absorption, and hyperzincuria from HF medications. In a longitudinal study of patients with HF in the setting of intestinal malabsorption, there was partial cardiomyocyte and left ventricular ejection fraction recovery with intravenous selenium and zinc supplementation. Two randomized double-blind control trials evaluating micronutrient and macronutrient supplementation including zinc in patients with HF found improvement in echocardiographic findings compared with placebo. Two recently completed studies evaluated the role for zinc supplementation in 2 different HF populations: a trial of zinc supplementation in patients with non-ischemic HF, and a trial of micronutrient supplementation (including B vitamins, vitamin D, and zinc) in veterans with systolic dysfunction; the results of which are still pending. Several pathobiological pathways to link zinc deficiency with the development and deterioration of HF are presented. Preliminary clinical data are supportive of such an association and future studies should further investigate the effects of zinc supplementation on outcomes in patients with HF.
Effect of hypotensive therapy combined with modified diet or zinc supplementation on biochemical parameters and mineral status in hypertensive patients
2018, Journal of Trace Elements in Medicine and Biology
Citation Excerpt :
A high number of trials have provided data on the disorders of trace elements metabolism resulting from hypotensive therapy [1–4]. Treatment with angiotensin-converting enzyme inhibitors (ACE-Is) and some diuretics leads to deficits of zinc, magnesium, and potassium [5]. Disturbances in macroelement and microelement status can additionally be a reason for unfavorable changes in the metabolism of carbohydrates and lipids, and may affect enzyme activity of enzymes such as superoxide dismutase (SOD), catalase (CAT), and carbonic anhydrase (CA) [6].
Hypotensive therapy leads to a number of trace elements metabolism disturbances. Zinc balance is frequently affected by antihypertensive treatment.
To evaluate the effect of a hypotensive treatment, modified diet and zinc supplementation on mineral status and selected biochemical parameters in newly diagnosed hypertensive patients on monotherapy.
In the first stage, arterial hypertension in ninety-eight human subjects was diagnosed. In the second stage, antihypertensive monopharmacotherapy was implemented. In the third stage, patients were randomized into three groups and continued antihypertensive monotherapy: group D received an optimal-mineral-content diet, group S received zinc supplementation, and group C had no changes in diet or zinc supplementation. Iron, zinc, and copper concentrations in serum, erythrocytes, urine, and hair were determined. Lipids, glucose, ceruloplasmin, ferritin, albumin, C-reactive protein (CRP), tumor necrosis factor α (TNF-α), nitric oxide (NO), superoxide dismutase (SOD) and catalase (CAT) were assayed in serum.
Antihypertensive monotherapy decreased zinc concentration in serum and erythrocytes and increased the level of zinc in urine, decreased CAT and SOD activity, TNF-α concentration in serum, and increased the level of NO in the serum. Zinc supply led to an increase in zinc concentration in serum, erythrocytes, and hair (in group S only). In the groups with higher zinc intake, decreased glucose concentration in the serum was observed. Significant correlation was seen between the zinc and glucose serum concentrations.
Hypotensive drugs disturb zinc status in newly diagnosed hypertensive patients. Antihypertensive monotherapy combined with increased zinc supply in the diet or supplementation favorably modify zinc homeostasis and regulate glucose status without blood pressure affecting in patients with hypertension.
The Relationship Between Serum Zinc Levels, Cardiac Markers and the Risk of Acute Myocardial Infarction by Zinc Quartiles
2018, Heart Lung and Circulation
Citation Excerpt :
Therefore, whether zinc supplementation has a positive effect on high-risk patients remains in doubt and should be confirmed by further study. There were some possible limitations to our study, including that we did not entirely except medications used in patients’ treatment that lead to zinc deficiency, such as angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and the diuretic furosemide [29–31]. Second, we only describe a study in patients who were admitted to a hospital cardiology department and didn't include a set of serum zinc measurements from healthy participants as a negative control.
Zinc is one of the most important microelements in the body and zinc homeostasis plays a critical role in maintaining cellular structure and function. Zinc dyshomeostasis can lead to many diseases, such as cardiovascular disease. Our aim was to investigate whether there is a relationship between zinc and cardiac markers, and the risk of acute myocardial infarction (AMI) by zinc quartiles.
We enrolled a total of 529 patients and measured their serum zinc levels and cardiac markers. We performed further studies after dividing subjects into four groups according to their concentrations of zinc by quartile to clarify the relationship between zinc levels and risk of increased acute myocardial infarction prevalence rate.
We observed that there was a significant inverse linear relationship between zinc and Lg(creatine kinase) (p = 0.011), Lg(creatine kinase-MB) (p = 0.002) and Lg(cardiac troponin T) (p = 0.045). In addition, the acute myocardial infarction prevalence rates were 28.8%, 24.8%, 20.5%, and 18.2% by patients with zinc quartiles, respectively. Multivariate logistic regression analysis showed that the odds ratio between the lowest and highest zinc quartile groups was 1.92 (1.019–3.604) (p < 0.05).
The present study revealed a relationship between serum zinc levels in that zinc levels were significantly inversely correlated with serum creatine kinase (CK), creatine kinase-MB (CKMB) and cardiac troponin T (cTnT) levels. Furthermore, we found that the prevalence rate of acute myocardial infarction decreased with increasing zinc quartiles.
Combined spectroscopic and molecular docking techniques to study interaction of Zn (II) DiAmsar with serum albumins
2014, Journal of Luminescence
Citation Excerpt :
Zinc is not stored in the body and excess intakes result in reduced absorption and increased excretion [25]. Zinc deficiency contributes to degenerative changes associated with aging such as immune senescence, cognitive dysfunction, and chronic inflammation [26–29]. The potential application of zinc (II) diamine-sarcophagine (Zn (II) DiAmsar) complexes in the treatment of diabetic mellitus has been reported [30].
Zinc (II) diamine-sarcophagine (Zn (II) DiAmsar) as a water soluble hexadentate ligand was synthesized and characterized by nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR) and UV–visible (UV–vis) spectroscopy. The bindings of Zn (II) DiAmsar with human serum albumin (HSA) and bovine serum albumin (BSA) were investigated under the simulative physiological conditions. To study this binding, the fluorescence spectra in combination with FT-IR, UV–vis, cyclic voltammetry (CV), and molecular docking techniques were used in the present work. The results indicate that Zn (II) DiAmsar quenched effectively the intrinsic fluorescence of HSA and BSA via a static quenching process. The fluorescence quenching data was also used to determine binding sites and binding constants at different temperatures. The calculated thermodynamic parameters (∆G°, ∆H°, and ∆S°) suggest that the binding process occurs spontaneously by involving hydrogen bond and van der Waals interactions. The distance between HSA (or BSA) as a donor and Zn (II) DiAmsar as an acceptor was obtained according to fluorescence resonance energy transfer (FRET). In addition, the docking results revealed the possible binding sites and assess the microenvironment around the bounded Zn (II) DiAmsar.
Zinc and cardiovascular disease
2010, Nutrition
Citation Excerpt :
Thiazide diuretics, which are widely used for volume reduction and hypertension, cause zincuria and decrease the tissue zinc concentration [46]. Other medications used in congestive heart failure treatment that lead to zinc deficiency include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and the diuretic furosemide [71,72,73]. More data and a better understating of the causal relation between zinc deficiency and heart failure will help in the development of new therapeutic modalities for this disease.
Zinc is a vital element in maintaining the normal structure and physiology of cells. The fact that it has an important role in states of cardiovascular diseases has been studied and described by several research groups. It appears to have protective effects in coronary artery disease and cardiomyopathy. Intracellular zinc plays a critical role in the redox signaling pathway, whereby certain triggers such as ischemia and infarction lead to release of zinc from proteins and cause myocardial damage. In such states, replenishing with zinc has been shown to improve cardiac function and prevent further damage. Thus, the area of zinc homeostasis is emerging in cardiovascular disease research. The goal of this report is to review the current knowledge and suggest further avenues of research.
Antihypertensive effect of Cu and Mg enriched modified poultry egg<sup>Ψ</sup> on Zn-induced hypertension in Wistar rat
2010, Journal of Trace Elements in Medicine and Biology
Excessive bioavailability of Zn either due to genetic predisposition or its high concentration in diet has been linked to increase in the prevalence of hypertension (HT) implicating the resultant deficiencies of Cu and Mg as its cause in some populations. To combat their nutritional deficiencies, a modified poultry egg (ME^Ψ) was designed containing higher amounts of Cu, Mg and other antioxidants (vitamin E and linolenic acid) in their optimized concentrations. Prior to its human clinical trials, its efficacy was tested in Zn induced HT Wistar rat model in the present study.
In one set, the rats were fed on equicaloric semi-synthetic basal diet containing 20 mg Zn/kg diet (control diet-I, control group-I), Zn-induced-hypertensive-diets-II and III (Zn-HT-diet-II and Zn-HT-diet-III) containing 40 and 80 mg Zn/kg diet (groups-II and III) for 180 days. In another set, the rats were initially fed Zn-HT-diet-II and Zn-HT-diet-III for 90 days and then shifted to ME^Ψ mixed Zn-HT-diet-II and III designated as groups-IIME and IIIME fed for another 90 days completing 180 days of feeding.
The results revealed that increase in systolic pressure (SP) and heart rates (HR) were Zn concentration dependent and coincided well with higher serum Zn, Cu, Mg, aldosterone, cortisol, dyslipidemia and higher Zn, and low Cu and Mg concentrations in liver of groups-II and III rats. On feeding ME^Ψ mixed diets, a significant reduction in SP and HR were linked with decrease in serum Zn, Cu, Mg, aldosterone, cortisol and blood lipid profile along with fall in Zn and rise in Cu and Mg concentrations in liver of groups-IIME and IIIME approaching closer to control group-I.
This study makes the basis for human clinical trials of ME^Ψ on HT patients who exhibit high Zn, Cu and Mg in their blood serum.

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THIRD INTERNATIONAL FESTEM SYMPOSIUMEffects of angiotensin-converting enzyme inhibitors (ACEi) on zinc metabolism in patients with heart failure

Abstract

Introduction

Section snippets

Subjects

Results

Discussion and conclusion

Metabolism

J Nutr

J Nutr

The epidemiology of heart failure

Eur Heart J

ABC of heart failure. Management, diuretics, ACE inhibitors and nitrates

Br Med J

THIRD INTERNATIONAL FESTEM SYMPOSIUM
Effects of angiotensin-converting enzyme inhibitors (ACE_i) on zinc metabolism in patients with heart failure