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150
Jalali M, Symonds ME, Zare M, Sohrabi Z
J Health Sci Surveillance Sys April 2022; Vol 10; No 2
Reference Range of Serum Zinc Concentration
in Patients with Heart Failure: A Systematic
Review and Meta-analysis of Cross-Sectional
Studies in the 21st Century
Mohammad Jalali1,2, MSc;
Michael E Symonds3, MD;
Morteza Zare2, MSc;
Zahra Sohrabi2, PhD
1Student Research Committee,
Shiraz University of Medical Sciences,
Shiraz, Iran
2Nutrition Research Center, School of
Nutrition and Food Sciences, Shiraz
University of Medical Sciences, Shiraz,
Iran
3The Early Life Research Unit,
Academic Division of Child Health,
Obstetrics and Gynaecology, and
Nottingham Digestive Disease Centre
and Biomedical Research Centre, The
School of Medicine, The University of
Nottingham, Nottingham, NG7 2UH,
United Kingdom
Correspondence:
Zahra Sohrabi, PhD;
Nutrition Research Center, School of
Nutrition and Food Sciences,
Shiraz University of Medical Sciences,
Razi Ave, Post Code: 71536-75541,
Shiraz, Iran
Tel : +98 9177113086
Fax: +98 71 37257288
Email: Sohrabi@sums.ac.ir
zahra_2043@yahoo.com
Received: 3 January 2022
Revised: 15 February 2022
Accepted: 18 March 2022
Review ARticle
Abstract
Background: Heart failure (HF) is a clinical disorder and Zinc is
an important cofactor in regulating oxidative status. The present
study aimed to determine the mean concentration of serum zinc
in patients with HF.
Methods: PubMed, Embase, Scopus, and Web of Science were
used in the present systematic review and meta-analysis to nd
relevant cross-sectional studies up to 1st January 2020. A random-
eects model was used to pool the eect size (ES) and 95%
condence intervals (CI). In addition, meta-regression analysis
was performed to nd the sources of statistical heterogeneity
among the studies.
Results: Our meta-analysis of 1358 HF patients indicated that
their mean serum zinc concentration was 66.24 µg/dl (95% CI:
59.16, 73.33). In sub-analysis, the mean concentration was 75.04
µg/dl and 52.90 µg/dl in patients <65 years and >65 years old,
respectively. Subgroup analysis by geographical region showed
that mean serum zinc was 70.70 µg/dl, 69.08 µg/dl and 60.91 µg/
dl in HF patients from Europe, America, and Asia, respectively.
Meta-regression analysis indicated a reduction of 1.42 µg/dl in
serum zinc per each year of aging.
Conclusion: In summary, our meta-analysis indicates that
serum zinc concentrations have a narrow range in HF patients
worldwide that declines with age and varies with geographical
region. Additionally, serum zinc concentrations are lower in HF
patients, specically in the elderly.
Please cite this article as: Jalali M, Symonds ME, Zare M, Sohrabi Z. Reference
Range of Serum Zinc Concentration in Patients with Heart Failure: A Systematic
Review and Meta -analysis of Cross-Sectional Studies in the 21st Centur y. J
Health Sci Surveillance Sys. 2022;10(2):150-157.
Keywords: Cardiovascular diseases, Heart failure, Trace elements,
Zinc
Introduction
Heart failure (HF) is one of the leading causes of
mortality globally and patients affected by heart
failure have a poor prognosis, especially the elderly.1
Micronutrients have essential roles in protecting the
body from various diseases, including cardiovascular
system diseases. Zinc is an important micronutrient as
it has a role in maintaining cell growth and function
as well as regulating gene expression.2 Moreover, Zinc
has cardio-protective effects through regulating the
differentiation and regeneration of cardiac muscles and
cardiac conductance. Furthermore, zinc has an essential
role in maintaining antioxidant status in enzymes
such as superoxide dismutase and regulates many
metalloproteases, including angiotensin-converting
enzyme.3 In addition, it can have protective effects against
acute stress and recovery after heart transplantation,4
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Zinc and heart failure
J Health Sci Surveillance Sys April 2022; Vol 10; No 2
whereas zinc deficiency induces cellular damage.5, 6
Several factors can result in zinc deciency,
including alcoholism, gastrointestinal disorders, and
aging.7, 8 Plasma zinc decrease with age and both
intra- and extracellular concentrations are associated
with cardiovascular health.9, 10 It has been suggested
that Zinc can be cardio-protective against ischemia/
reperfusion injury of the myocardium.7, 11 Zinc
deciency could contribute to cardiovascular disease
due to either low dietary intakes, low absorption,
increased excretion, or some medications used in HF
patients.12 Many studies have assessed serum zinc
concentration in patients with HF, reporting either
lower serum zinc concentrations13, 14 or no dierence
compared to healthy populations.15-17 However, no
study has dened the mean concentration of serum
zinc in HF patients and its association with age or
geographical location. Therefore, we have conducted a
comprehensive meta-analysis of the current literature
to nd a serum zinc concentration reference range in
contemporary HF patients.
Methods
The Preferred Reporting Items for Systematic reviews
and Meta-Analyses (PRISM A) indicate the process of
study selection.18
Literature Search
A systematic electronic search was undertaken by
two independent authors (MJ and MZ) using several
online databases, including PubMed, Scopus, Embase,
and Web of Science, for all available publications
between 1
st
January 2000 to 1
st
January 2020. Authors
searched Cross-sectional studies investigating serum
zinc in patients with HF. Our search terms were
designed as follows: (“Zinc”[Title/Abstract] OR
“Zink”[Title/Abstract]) AND (“Heart Failure”[Title/
Abstract] OR “HF”[Title/Abstract] OR “CVD” [Title/
Abstract] OR “Cardiac*”[Title/Abstract] OR “Arterial
Fibrillation”[Title/Abstract] OR “Cardio*”[Title/
Abstract] OR “AHF”[Title/Abstract] OR “CHF”[Title/
Abstract]) AND (“Observational” [Title/Abstract]
OR “Cross sectional” [Title/Abstract] OR “Cross-
sectional” [Title/Abstract]). The wild-term “*” was
used to increase the sensitivity of the search. Our
search was augmented through a hand scan of a
list of references for included studies and relevant
reviews. EndNote X9 was used to simplify the
screening process. A discussion between the named
authors solved doubts. The corresponding author was
consulted if any inconsistencies arose.
Eligibility Criteria
Studies were included if they met the following
terms: (1) cross-sectional, (2) published in or after
2000, (3) assessed serum zinc concentration in patients
with HF, (4) reported mean serum zinc and at least
one of the standard error (SE) or standards deviation
(SD) or 95% condence intervals (CI) for mean serum
zinc concentration and (5) had human participants.
Exclusion criteria were: (1) reporting unusable or / and
unconvertable data for serum zinc or / and SE or / and
SD or / and 95% CI, (2) a review article, editorials,
patents, conference abstracts, comments, and thesis
and (3) non-English language. The inclusion and
exclusion criteria were evaluated by two independent
reviewers (MJ and MZ), and the corresponding author
resolved any disagreements.
Data collection and Quality Appraisal
Two independent reviewers (MJ and MZ)
abstracted all eligible references and extracted the
following data: rst author’s last name, publication
year, country, sample size, type of HF, age of
participants, serum zinc concentration in µg/dl,
SD, SE, lower-limit of 95% CI, upper-limit of 95%
CI, and quality of studies. The quality assessment
of all included studies was appraised using the
Joanna Briggs Institute (JBI) checklist.19 If data
were presented as a graph, WebPlotDigitizer (htt ps://
automeris.io/WebPlotDigitizer/) was executed to
extract data. Discussion between MJ and MZ resolved
any doubt. The corresponding author was asked to
solve disagreements, if any.
Statistical Analysis
A random-eects model was used to assess the
pooled eect size (ES) and 95% CI, where only SD
for mean was published, SE were calculated using the
following formula: (SD/√n). 95% CI was calculated
using (Eect±(1.96×SE). I2 statistics (>50%) and
P-value (<0.05) for chi-square were checked to assess
the between-studies statistical heterogeneity. In the
presence of heterogeneity among studies, a random-
eects meta-regression was undertaken to evaluate its
potential sources. Subgroup analysis was performed
by region (Europe, America, and Asia) and mean
age (less than 65 years old vs. more than 65 years
old). Sensitivity analysis was planned to verify the
robustness of the ES estimates by excluding each
study at a time. Stata computer software v13 was used
to analyze all data. A P value<0.05 was assumed as
statistically signicant.
Results
Systematic Review
Literature Search
Figure 1 shows The PRISMA diagram used to
demonstrate the study selection process. Initially, 1674
records were retrieved, of which 738 references were
excluded as they were duplicate ndings. Then, 936
papers were selected for the title and abstract screening,
152
Jalali M, Symonds ME, Zare M, Sohrabi Z
J Health Sci Surveillance Sys April 2022; Vol 10; No 2
and 924 were omitted. At the next step, 12 full-text
articles were assessed for eligibility, and nally, 9
full-text papers comprising 16 separate cross-sectional
studies were included in the meta-analysis.
1, 3, 14 , 16, 17, 20 -24
Demographic Characteristics
Table 1 outlines the demographic characteristics
of all included studies between 2001 – 2018. Three
studies were conducted in Ira n,
14, 16 , 17
two in Turkey,
21,
23
one in the USA,
22
France,
20
Greece,
3
and Japan.
1
They included 998 participants with decompensated
HF, 81 with acute HF, 68 with idiopathic dilated
cardiomyopathy, 65 with chronic HF, 58 with ischemic
cardiomyopathy, 40 with HF plus atrial brillation,
Figure 1: Flowchart of the data selection process
Table 1: Demographic characteristics of the included studies
First author Yea r Country Sample size Age HF ty pe
de Lorgeril et al.20 2 001 France 21 27 – 76 Chronic HF
Topuzoglu21 20 03 Tu rke y 24 18 – 75 Idiopathic dilated cardiomyopathy
Arroyo et al. 1 22 2006 USA 10 52 Compensated HF
Arroyo et al. 2 22 2006 USA 15 56 Decompensated HF
Arroyo et al. 3 22 2006 USA 15 50 Decompensated HF
Kosar et al. 1 23 2006 Tu rke y 26 62 Idiopathic dilated cardiomyopathy
Kosar et al. 2 23 2006 Tu rke y 28 62 Ischemic cardiomyopathy
Salehi et al. 16 2008 Iran 18 49.06 Idiopathic Dilated Cardiomyopathy
Shokrzadeh et al.17 2009 Iran 30 57.17 Ischemic cardiomyopathy
Ghaemian et al. 1 14 2 011 Iran 40 66.7 HF with arterial brillation
Ghaemian et al. 2 14 2 011 Iran 38 70.1 HF without arterial brillation
Alexanian et al. 1 32 014 Greece 81 69.22 Acute HF
Alexanian et al. 2 32 014 Greece 44 67.5 Chronic HF
Yoshihisa et al. 1 12018 Japan 323 62.4 Decompensated HF
Yoshihisa et al. 2 12018 Japan 322 65.9 Decompensated HF
Yoshihisa et al. 3 12018 Japan 323 71.4 Decompensated HF
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Zinc and heart failure
J Health Sci Surveillance Sys April 2022; Vol 10; No 2
38 with HF without atrial brillation, and 10 with
compensated HF with an age range of 18 – 71 years.
Meta-analyses
The pooled eect of the 16 datasets showed that
mean ser um zinc concentration was 66.24 µg/dl (95%
CI: 59.16, 73.33) in HF patients (Figure 2). It was 75.04
µg/dl (95% CI: 64.64, 85.43) and 52.90 µg/dl (95%
CI: 59.16, 64.16) in patients younger than 65 and
older than 65 years old, respectively (Figure 3A). In
addition, after sub-groupi ng for dierent geographical
regions, serum zinc levels were 70.70 µg/dl (95% CI:
59.31, 82.09), 69.08 µg/dl (95% CI: 63.33, 74.82), and
60.91 µg/dl (95% CI: 49.48, 72.35) in HF patients of
Europe, America and Asia, respectively (Figure 3B).
Meta-regression
Meta-regression analysis by mean age indicated
that serum zinc concentration decreased 1.42 µg/
dl (95% CI: -4.73, -0.96, P=0.03) for each year, and
mean age was assessed as the source of between-study
statistical heterogeneity (Figure 4).
Sensitivity Analysis
Sensitivity analysis showed that mean serum zinc
concentration was not aected by removing each
study one at a time (Figure 5).
Discussion
Our meta-analysis showed that mean serum zinc
concentration in HF patients was 66.24 µg/dl and had a
narrower range than in healthy adults (70-120 ug/dl),25
confirming zinc deficiency was prevalent. This findings
agreed w ith other studies.13, 14 Pro-in flam matory cyt okines
including interleukin-1 (IL-1), interleukin-6 (IL-6), and
tumor necrosis factor-alpha (TNF-α) are increased in
HF patients,26 and these can increase metallothioneins
(MTs) which bind Zinc in plasma and tissues. Lower
bioavailability of Zinc may, therefore, occur.27
Figure 2: Overall ES with 95 % CI of mean serum zinc concentration
Figure 3: Subgroup analysis of mean age (less than or more than 65 years old) (A) and geographical regions (Europe, America, and
Asia) ( B)
154
Jalali M, Symonds ME, Zare M, Sohrabi Z
J Health Sci Surveillance Sys April 2022; Vol 10; No 2
Other adaptations also occur in HF patients, including
raised catecholamines and parathyroid hormone (PTH),
which induce calcium accumulation. These may then
elevate intracellular zinc concentrations in HF patients.3,
28 HF patients also tend to have a lower dietary intake
due to a reduced appetite, nausea, vomiting, and sense
of fullness at the beginning of their meals,29-31 with
lower absorption rates and higher loss from the gut.
32
Furthermore, the use of diuretics raises urinary zinc
excretion12 and activates the renin-angiotensin system.33
Other comorbiditiesinclude diabetes mellitus and
hypertension, whichfurther impair zinc homeostasis,
especially in older patients.34, 35
Zinc is present in the antioxidant enzyme,
superoxide dismutase, and any decrease in zinc
concentration can cause oxidative stress, which is
an important cause of HF.13 The zinc concentration
decreases with age
8, 36
and persists in HF patients. Any
eects may be exacerbated by a decreased Zn/Cu
ratio with aging37 and hospitalization,38 which results
in oxidative stress and atherosclerosis,
39
together with
the elevated inammatory status and poor nutritional
status.13, 40
After subgrouping studies by geographical
locations, mean serum zinc was higher in Europeans,
followed by the Americans and Asians (70.70 µg/
dl, 69.08 µg/dl, and 60.91 µg/dl, respectively). This
nding aligns with a recent study by Yu et al.13 On a
population-wide basis, zinc deciency is most common
in some areas of Asia, especially Iran41 (included in
the current study). A reduced bioavailability causes
this issue due to lower animal protein intakes and
higher phytate consumption,41 which is also the case
for Japan, especially the elderly.36 However, high-
income countries, including those in Europe and the
USA, are less likely to experience zinc deciency.41
Another important point that should be considered
in future studies is that there might be a circadian
variation in serum zinc measurement (high in the
morning and low in the afternoon).42 Conclusion
Figure 4: Meta-regression a nalysis by mean age (year) of patients
Figure 5: Result of the sensitivity analysis
155
Zinc and heart failure
J Health Sci Surveillance Sys April 2022; Vol 10; No 2
This is the rst systematic review and meta-
analysis to dene the mean serum zinc concentration
in HF patients to the best of our knowledge. This study
enjoyed a sucient number of studies and assessed
dierent age groups and geographical locations .
However, one limitation is the lack of control groups,
as we only assessed cross-sectional studies, so we
cannot determine any causal relationships. Another
limitation is that serum zinc concentration may not
be an appropriate marker for body zinc status, and
zinc serum depletion can occur regardless of body
stores. It seems that there might be a vicious cycle
between serum zinc concentration and HF, as one
can cause the other and vice versa. In addition, it is
suggested to conduct more studies to better dene the
mean concentration of Zinc in healthy and unhealthy
populations in dierent geographical areas to clarify
the relationship between zinc concentration and
disease progression.
Therefore, standardizing the time of zinc
assessment in the serum may be benecial. A
reference range of serum zinc concentration in HF
patients could be adopted, which diers from normal
or healthy groups.
In summary, serum zinc concentrations are lower
in HF patients and have a narrow range, specically
in the elderly. A decrease in zinc concentration while
the age increase may increase the prevalence of HF
in older patients. Lower Zinc might be more prevalent
in some regions such as Asia, especially in Iran,
suggesting dietary modications in these areas.
Author Contribution
MJ contributed to the study concept and design. MJ, MZ,
and ZS contributed to literature search, data collection,
and analysis. MJ, ZS, and MES contributed to drafting
and reviewing the final manuscript. All authors read and
approved the final manuscript.
Funding
This work was prepared without any specific funding.
Acknowledgments
We thank all the participants of the study.
Ethics approval and consent to participate: Not
applicable.
Conflicts of interest: None declared.
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