Received: 16 April 2021 | Accepted: 25 June 2021

DOI: 10.1111/ijcp.14578

M E TA A N A LY S I S
Cardiovascular medicine

The association between apolipoprotein A-­1 plasma level and

premature coronary artery disease: A systematic review and
meta-­analysis

Mohammad Haji Aghajani1,2 | Arian Madani Neishaboori3 | Koohyar Ahmadzadeh3 |

Amirmohammad Toloui3 | Mahmoud Yousefifard3

1
Prevention of Cardiovascular Disease
Research Center, Shahid Beheshti University
of Medical Sciences, Tehran, Iran
2
Department of Cardiology, School of
Medicine, Shahid Beheshti University of
Medical Sciences, Tehran, Iran
3
Physiology Research Center, Iran University
of Medical Sciences, Tehran, Iran
Correspondence
Mahmoud Yousefifard and Amirmohammad
Toloui, Physiology Research Center, School
of Medicine, Iran University of Medical
Sciences, Shahid Hemmat Highway, Tehran
14496-­14535, Iran.
Email: yousefifard.m@iums.ac.ir (M. Y.);
toloui.amir@gmail.com (A. T.)
Funding information
This study was supported by Prevention of
Cardiovascular Disease Research Center,
Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
Abstract
Background: Apolipoprotein A-­1 (Apo A-­1) is a constituent of high-­density lipopro-
tein (HDL) and emerging evidences put forward a potential association between Apo
A-­1 plasma levels and premature coronary artery disease (pCAD). The aim of the
present study is to gather relative literature and perform a systematic review and
meta-­analysis regarding the association between serum ApoA-­1 levels and pCAD.
Methods: Medline (via PubMed), Scopus, Embase and Web of Science databases
were searched from the inception of databases until December 7, 2020. All articles
reporting the plasma levels of ApoA-­1 in patients with pCAD and the control group
were included. A meta-­analysis with pooled standardised mean difference (SMD) and
95% confidence interval (95% CI) was reported. Subgroup analyses were done based
on the observed heterogeneity in results.
Results: Seventeen case-­control studies were included. ApoA-­1 plasma level was
calculated to be lower in pCAD patients compared with the control group (SMD:
−0.67; 95% CI: −0.48 to −0.86; P < .001). The subgroup analysis and meta-­regression
showed that the variation in gender distribution, the development level of the target
population’s country and quality score of included studies were the main sources of
heterogeneity. It was observed that the relationship was only significant in the de-
veloped countries (P < .001). Also, the heterogeneity was reduced when the analysis
was limited to males (I2 = 57.2%) and females only (I2 = 26.0%).
Conclusion: In conclusion, there seems to be a significant association between the serum
levels of ApoA-­1 and pCAD. However, all of the included studies had a case-­control de-
sign and since there is no good quality and prospective cohort studies included, reliabil-
ity of the current evidence is debatable. Therefore, further well-­designed cohort studies
are required to assess the impact of serum ApoA-­1 reduction on pCAD onset.

1 | I NTRO D U C TI O N million in 1990 vs 573 million in 2019) with a disability-­a djusted

life years of 34.4 million in 2019, worldwide.1 Accordingly, shed-
Cardiovascular diseases (CVD) are the leading cause of death ding light on the pathophysiology and the contributing risk fac-
worldwide with nearly 18.6 million attributable deaths in 2019. The tors of coronary artery disease has been followed for many years
total prevalence of CVD has doubled during the last 30 years (271 till now. 2–­4

Int J Clin Pract. 2021;00:e14578. wileyonlinelibrary.com/journal/ijcp © 2021 John Wiley & Sons Ltd | 1 of 13
https://doi.org/10.1111/ijcp.14578
2 of 13 | HAJI AGHAJANI et al.
Some of the risk factors contributing to the development of CAD
are smoking, increasing age, diabetes, systemic hyperlipidemia and a
positive family history.5 Also, previous investigations have illustrated
that high density lipoprotein (HDL) deficiency or malformation in the
body plays an independent role in the development of CAD even
in young ages.6,7 Because of the importance of the occurrence of
CAD in younger individuals and its life-­long consequences, the term
premature coronary artery disease (pCAD) has been defined as the
incidence of CAD in men younger than 55 and women younger than
65 years of age.8,9
High density lipoproteins (HDLs) are particles mainly com-
posed of lipid and protein that regulate serum cholesterol levels.
HDL-­C holesterol (HDL-­C ) has been under evaluation for its po-
tential role in prediction of coronary artery disease.10 One of the
key constituents of HDL particles are apolipoproteins which are
11,12
important to HDL’s function and metabolism. Although the
level of HDL-­C in blood has been the subject for rigorous,13 apoli-
poprotein A-­1 (Apo A-­1) is arguably a better predictor of CAD.14,15
While Apo A-­1 level provides identical information as HDL-­C for
diagnosis, risk stratification and prognosis of CVD, the results are
mixed for pCAD.16–­20 There has been a tremendous number of
studies investigating the value of apolipoprotein A serum levels
in the development of pCAD; some studies conclude that serum
apolipoproteins A-­1 is clearly associated with the occurrence of
pCAD while others believe that this relationship could not be of
high value. 21–­23
Because of the lack of a definite conclusion, the aim of this study
is to gather relative literature and present a systematic review and
meta-­analysis regarding the association between apolipoprotein A-­1
(ApoA-­1) and pCAD.
2 | M E TH O D
2.1 | Study design
The present study is a systematic review and meta-­a nalysis re-
garding the association between plasma levels of Apolipoprotein
A-­1 and premature coronary artery disease (pCAD). Accordingly,
PICO was defined as follows: Patients (P): men younger than 55
and women younger than 65 years of age with documented cor-
9
onary artery disease ; Index test (I): measuring the plasma level
of ApoA-­1 in participants; Comparison (C): comparing the results
of the case group (patients with pCAD) with the control group
(healthy individuals without pCAD); Outcome (O): occurrence of
pCAD. Coronary artery disease was defined as having at least
50% occlusion in at least one coronary artery in angiography or
documented previous MI episode or having CABG were also de-
finitive of coronary artery disease.
For the purpose of this study, Medline (via PubMed), Scopus,
Embase and Web of Science databases were searched. The keywords
for our search were obtained from Mesh and Emtree vocabularies,
What’s known
• Apolipoprotein A-­1 (Apo A-­1) level is inversely associ-
ated with cardiovascular diseases (CVDs).
• While Apo A-­1 level provides identical information as
high density lipoprotein for diagnosis, risk stratification
and prognosis of coronary artery disease (CVD), the re-
sults are mixed for premature CAD.
• There has been a tremendous number of studies inves-
tigating the value of apolipoprotein A serum levels in
the development of premature coronary artery disease;
some studies conclude that serum apolipoproteins A-­1
is clearly associated with the occurrence of pCAD while
others believe that this relationship could not be of high
value.
What’s new
• The results of current study showed that there seems to
be a significant association between the serum levels of
ApoA-­1 and pCAD.
• However, since there are no good quality and prospec-
tive cohort studies in this issue, reliability of the current
evidence is debatable.
• Therefore, further well-­designed cohort studies are re-
quired to assess the impact of serum ApoA-­1 reduction
on pCAD onset.
reviewing similar articles’ relevant keywords and with the help of ex-
perts in the field; then, a search strategy was designed based on our
defined P and I, using the selected keywords. This search was per-
formed on articles from the inception of databases until December
7, 2020. The search strategy in Medline database is presented in
Appendix 1. In addition, a manual search was also performed in
Google and Google scholar databases’ websites to acquire any pre-
prints and possibly missing papers.
2.2 | Selection criteria
All observational studies reporting the plasma levels of ApoA-­1 in
patients with pCAD and levels in the control group were included. If
a non-­English article was considered relevant, a meticulous transla-
tion was achieved with the help of an expert in the field. Case re-
port articles, review articles, articles not reporting whether pCAD
or ApoA-­1 levels and their association or without a control group
were excluded. In addition, definition of pCAD only based on clini-
cal criteria, electrocardiographic studies and changes in laboratory
markers suggestive of CAD without performing a coronary artery
angiography were also excluded.
HAJI AGHAJANI et al.
2.3 | Data collection
Two reviewers independently screened the title and abstract of the
articles based on the population of interest (patients with pCAD) and
the test Index (reports of ApoA-­1 plasma level). After the first part of
screening, the articles reporting the occurrence of pCAD (Outcome)
along with a comparison of ApoA-­1 plasma levels in the case and
the control group were included based on our inclusion/exclusion
criteria. Finally, a summary of each included article was extracted
into a checklist. Variables recorded from the articles were: author,
year, country, study type and design, definition of pCAD, number of
males in the case and the control group, number of individuals in the
case and the control group, the age of the case and the control group
and Apo A-­1 concentration in the case and the control group. Any
disagreement on the steps through data gathering and extraction,
was discussed and resolved with the help of a third reviewer.
2.4 | Quality assessment
Two independent reviewers also performed the quality assessments
using the quality assessment tools of “National Heart, Lung, and
Blood Institute (NHLBI) quality assessment tools for case-­control
studies”24 Any disagreement in data collection or the quality assess-
ment of the articles was discussed and resolved with the help of a
third reviewer. The overall quality score was categorised into good
(low risk of bias), fair (some concern about the risk of bias) and poor
(high risk of bias). A study is considered good when all questions
were low risk. In addition, the study’s quality was poor if a fetal error
was present. Accordingly, we considered any flaws in questions 4, 5
and 6 of NHLBI quality assessment tools as a fetal error. Finally, the
study is considered to be fair when some concerns were present in
other questions.
2.5 | Statistical analysis
All analyses were performed using STATA 14.0 statistical program.
Data were recorded as mean and standard deviation (SD) in the case
and the control group, separately. Some studies reported median
and range or interquartile range. In this case we used Wan et al’s25
21
proposed method to calculate mean and SD. In an included study
the level of ApoA-­1 was divided into different subgroups and the
number of subjects was presented for each subgroup. Therefore, we
estimated the mean and SD of ApoA-­1 in this study by using the
mid value of ApoA-­1 multiplied by the number of patients in each
subgroup.
By using the “metan” command in the STATA program, a stan-
dardised mean difference (SMD) was calculated for each individual
study. Finally, a pooled SMD and 95% confidence interval (95% CI)
was reported. Heterogeneity among studies was assessed by using
the I2 test and subgroup analysis and meta-­
regression was per-
formed to assess the source of heterogeneity. I2 more than 50% was
| 3 of 13
considered a cut-­off for presence of important heterogeneity. 26 We
performed subgroup analysis based on patients’ gender, method of
pCAD diagnosis, development level of countries, publication year and
quality score of included studies. There is a gender based difference
in the lipid profile of individuals because of many physiologic rea-
sons. In addition, since there is a substantial difference in nutritional
status and other life-­style related habits between developed and de-
veloping countries, it was decided to stratify the analysis based on
countries’ development level. Moreover, in our included studies the
diagnosis of pCAD was done based on two different approaches: (i)
using angiography to detect pCAD to include patients in the study
and (ii) using patient records/registry data for a previous detection
of pCAD. This variation was assessed to evaluate its influence on
heterogeneity. In addition, we performed meta-­regression to assess
any possible association between the effect size and sample’s size,
mean age of subject in pCAD and non-­pCAD groups and publication
year of included studies and then a multivariate meta-­regression was
fitted to assess the independent sources of heterogenity. Finally, we
performed a sensitivity analysis by using leave-­one-­out approach to
find the influence of each individual study on pooled SMD of associ-
ation between ApoA-­1 and pCAD. Egger’s test and funnel plot were
used to assess the publication bias.
3 | R E S U LT S
3.1 | Study characteristics
The systematic search performed in online databases resulted
in 2849 articles. In total, 1280 duplicate articles were eliminated.
The initial screening process consisted of assessing articles by their
study groups and test indices. This process presented 117 potential
eligible articles. Then, the final screening process was performed
using the inclusion/exclusion criteria (the Outcome and Comparison)
which included 17 articles into the present systematic review and
meta-­analysis17–­21,27–­38 (Figure 1). The full-­text of one article was not
found after two reminders to the authors and the publishing journal.
All of the included studies had a case-­control design (Table 1).
Overall, 3220 patients in the case group and 5684 healthy con-
trols were enrolled in these included studies. Number of males in
the case and the control groups were 2422 and 3323 respectively.
One study had taken place in Brazil, one in Estonia, two in Greece,
one in India, two in Iran, one in Italy, one in Mexico, one in Turkey,
one in UK and six in USA. Detailed characteristics of the articles are
summarised in Table 1.
3.2 | Risk of bias assessment
Only one article applied sample size justification.39 Apart from four
studies, others chose the control groups from the same population
that gave rise to the patients.18,19,30,31 Random study sample collec-
tion from the target population, blinding of the assessors and the
4 of 13 | HAJI AGHAJANI et al.
FIGURE 1 PRISMA flow diagram of present meta-­analysis
use of concurrent controls were not applied in any of the studies.
Therefore, there were no good quality studies, while the quality of
13 articles was fair and 4 articles were poor. Table 2 presents the
details of the risk of bias assessment among included studies.
3.3 | Publication bias
Publication bias test was performed regarding the report of the case
and the control individuals’ plasma levels of ApoA-­1. As depicted on
Figure 2, there was no publication bias on this matter (P = .969).
3.4 | Meta-­analysis
The differences in plasma levels of ApoA-­1 between pCAD patients
and the control group were evaluated, and the results were shown
in Figure 3. It was concluded that ApoA-­1 plasma level was lower in
pCAD patients compared with the control group (SMD: −0.53; 95%
CI: −0.70 to −0.22; P < .001). Based on the I2 test analysis, a con-
siderable amount of heterogeneity was reported among the studied
articles (I2 = 89.2%, P < .001).
The subgroup analysis (Table 3) showed that the variation in
gender distribution was the main source of heterogeneity. From 19
separate analyses, seven analyses were performed on males, three
analyses were done on females and nine studies were performed
on the mixed population. The heterogeneity was reduced when
the analysis was limited to males (I2 = 57.2%) and females only (I2 =
26.0%) studies. The SMD of association between ApoA-­1 and pCAD
in studies with mixed population (SMD = −0.32; 95% CI: −0.57,
−0.06) was significantly lower than studies on male only (SMD:
−0.78; 95% CI: −0.92, −0.64) (odds ratio = 1.54; 95% CI: 1.05, 2.27;
P = .030).
Additionally, the country’s development level was another
possible source of heterogeneity. The countries in which the stud-
ies were performed, were divided into two major categories of
developed countries and developing countries. This classification
was made based on the statistics employed by World Economic
Situation and Prospects (WESP) prepared by the Development
Policy and Analysis Division (DPAD) of the Department of
Economic and Social Affairs of the United Nations Secretariat
(UN/DESA).40 Studies performed in developed countries (n = 13)
were more homogenous than the ones done in developing coun-
tries (n = 6) (I2: 57.1 vs 91.4%).
There was a significant association between ApoA-­1 and pCAD
in developed countries (SMD = −0.76; 95% CI: −0.88, −0.64; P <
.001), while the relationship was not significant in developing coun-
tries (SMD = −0.06; 95% CI: −0.38, 0.22; P = .599). Univariate meta-­
regression analysis showed that the SMD of relationship of ApoA-­1
and pCAD in developed countries was significantly higher than de-
veloping countries (odds ratio = 1.92; 1.46, 2.52; P < .001).
Also, the means of pCAD confirmation was not a considerable
source of heterogeneity. Although, the SMD was higher when pCAD
was proven with angiography (SMD = −0.60; 95% CI: −0.81, −0.38;
HAJI AGHAJANI et al. | 5 of 13

TA B L E 1 Characteristics of included studies

Sample size No. of male Agea in Age in

Author, year; country Study type Definition of pCAD (pCAD/control) (pCAD/control) pCAD controls
Aasvee, 2006; Estonia Case-­control MI at age ≤55 71/85 71/85 49.96 ± 6.88 48.13 ± 5.59
Azizi, 2002; Iran Case-­control >50% stenosis in a major 59/55 34/34 52.6 ± 6.4 52.4 ± 7.4
coronary artery in
angiography at age ≤55 for
men, ≤65 for women
Dahlen, 1998; USA Case-­control >75% blockage in coronary 47/55 0/0 50.8 ± 6.3 49.6 ± 7.9
artery and age ≤65
Elisaf, 1997; Greece Case-­control >70% blockage in coronary 108/104 86/83 50 ± 7 49.5 ± 7.5
artery and age ≤55 for men,
≤65 for women
Genest, 1991; USA Case-­control angiographically proven CAD 150/276 150/276 51 ± 7 49 ± 6
in age <60
Genest, 1991; USA Case-­control angiographically proven CAD 30/183 0/0 49 ± 6 49 ± 6
in age <60
Genest, 1992; USA Case-­control >50% stenosis in one major 321/901 321/901 50 ± 7 49 ± 6
coronary artery in age <60
Genest, 1991; USA Case-­control >50% stenosis in one major 145/136 145/136 51 ± 7 49 ± 11
coronary artery in age <60
Genest, 1992; USA Case-­control >50% stenosis in one major 87/901 87/901 51 ± 6 49 ± 6
coronary artery in age <60
Genest, 1992; USA Case-­control >50% stenosis in one major 15/1125 0/0 51 ± 3 49 ± 6
coronary artery in age <60
Heidari, 2001; Iran Case-­control >50% stenosis in one major 123/78 NR/NR NR ± NR NR ± NR
coronary artery in age ≤50
Kwiterovich, 1992; Case-­control >50% stenosis in one major 111/92 60/39 24-­60 24-­60
USA coronary artery in age ≤50
for men, ≤60 for women
Manocha, 2013; India Case-­control >50% stenosis in one major 204/161 183/95 44 (40-­46) 41 (36-­45)
coronary artery in age ≤45
Mansur, 2013; Brazil Case-­control angiographically documented 336/189 134/120 40.2 ± 5 40.7 ± 5.9
disease (>50% luminal
reduction) or a previous
myocardial infarction and
age <50
Pac, 2005; Turkey Case-­control Having coronary bypass 31/28 NR/NR 45.8 ± 3.6 20.4 ± 2.7
surgery before the age of 50
Parlavecchia, 1994; Case-­control angiographically documented 96/83 96/83 52 ± 7 50 ± 9
Italy CAD or a previous myocardial
infarction and age <55
Posades-­sanchez, Case-­control history of myocardial 1160/1106 941/456 54 ± 8 51 ± 9
2018; Mexico infarction, angioplasty,
revascularisation surgery or
coronary stenosis >50% or
angiography and age <55 for
men <65 for women
Rallidis, 2005; Greece Case-­control survival of first MI episode at 100/100 88/88 32 ± 3 32 ± 2
age <36
Vallance, 1995; UK Case-­control CABG in age <55 26/26 26/26 50.3 ± 6.5 51 ± 5.9

Abbreviations: CAD, coronary artery disease; CK-­MB, creatine kinase-­MB; ECG, electrocardiogram; MI, myocardial infarction.
a
Data are presented as mean ± standard deviation or median (range).

P < .001) than when it was confirmed based on a history of previous Publication year of the papers was another factor that was taken
MI or CABG (SMD = −0.41; 95% CI: −0.70, −0.12; P < .001), this into consideration for subgroup analysis. Although, publication year
difference was not statistically significant (odds ratio = 1.20; 95% was not a possible source of heterogeneity, it was found that there
CI: 0.80, 1.81; P = .358). was a significant association between ApoA-­1 and pCAD in studies
6 of 13 | HAJI AGHAJANI et al.

TA B L E 2 Quality assessment among included articles

Item Item Item Item Item Item Item Item Item Item Item Item
Study 1 2 3 4 5 6 7 8 9 10 11 12 Overall

Aasvee, 2006 Low Low High Low Low Low NA ND High Low High Low Fair
Azizi, 2002 Low Low High Low Low Low NA ND High Low High Low Fair
Dahlen, 1998 Low Low High Low Low Low NA ND High Low High Low Fair
Elisaf, 1997 Low Low High Low Low Low NA ND High Low High Low Fair
Genest, 1991 Low Low High High Low Low NA ND High Low High Low Poor
Genest, 1992 Low Low High High Low Low NA ND High Low High Low Poor
Genest, 1991 Low Low High High Low Low NA ND High Low High Low Poor
Genest, 1992 Low Low High High Low Low NA ND High Low High Low Poor
Heidari, 2001 Low Low High Low Low Low NA ND High Low High Low Fair
Kwiterovich, 1992 Low Low High Low Low Low NA ND High Low High Low Fair
Manocha, 2013 Low Low High Low Low Low NA ND High Low High Low Fair
Mansur, 2013 Low Low High Low Low Low NA ND High Low High Low Fair
Pac, 2005 Low Low High Low Low Low NA ND High Low High Low Fair
Parlavecchia, 1994 Low Low High Low Low Low NA ND High Low High Low Fair
Posades-­sanchez, Low Low High Low Low Low NA ND High Low High Low Fair
2018
Rallidis, 2005 Low Low High Low Low Low NA ND High Low High Low Fair
Vallance, 1995 Low Low High Low Low Low NA ND High Low High Low Fair

Abbreviations: High, high risk of bias; Low, low risk of bias; NA, not applicable; ND, not determined.
1. Was the research question or objective in this paper clearly stated and appropriate?
2. Was the study population clearly specified and defined?
3. Did the authors include a sample size justification?
4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)?
5. Were the definitions, inclusion and exclusion criteria, algorithms or processes used to identify or select cases and controls valid, reliable and
implemented consistently across all study participants?
6. Were the cases clearly defined and differentiated from controls?
7. If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those
eligible?
8. Was there use of concurrent controls?
9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a
participant as a case?
10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study
participants?
11. Were the assessors of exposure/risk blinded to the case or control status of participants?
12. Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account
for matching during study analysis?

published between 1990 and 1999 (SMD = −0.75; 95% CI: −0.89,
−0.62l; P < .001). Interestingly, not a significant association was ob-
served when analysis was limited to studies published from 2000
until 2009 (SMD = −0.25; 95% CI: −0.74, 0.24; P = .315) and 2010
until 2020 (SMD = −0.25; 95% CI: −0.62, 0.13; P = .198). In univariate
analysis, the observed SMD for association of ApoA-­1 and pCAD in
studies published from 2000 to 2009 (odds ratio = 1.60; 95% CI:
1.07, 2.39; P = .026) and 2010 to 2020 (odds ratio = 1.63; 95% CI:
1.04, 2.55; P = .034) was lower than older studies.
The quality score of included studies was a possible source of
heterogeneity. Heterogeneity in poor quality studies was lower than
fair quality studies (I2: 0.0% vs 87.3%). The reported association be-
tween ApoA-­1 and pCAD in poor quality studies (SMD = −0.86; 95%
CI: −0.95, −0.78) was higher than fair quality studies (SMD = −0.37;
95% CI: −0.57, −0.18) (odds ratio = 0.61; 95% CI: 0.43, 0.87; P = .009)
in univariate analysis.
Additional meta-­
regression analyses showed that the sample
size of included studies (coefficient = −0.0001; 95% CI: −0.0004 to
0.0002; P = .551) and mean age of patients in pCAD (coefficient =
−0.004; 95% CI: −0.044 to 0.036; P = .838) and non-­pCAD (coeffi-
cient = −0.0167; 95% CI: −0.0439 to 0.0105; P = .210) groups did not
substantially change the association of serum level of ApoA-­1 and
pCAD, which would show that the lower serum level of ApoA-­1 in
pCAD patients could be observed in all ages (Figure 4).
Table 4 shows result of univariate and multivariate meta-­
regression analyses to assess independent influential factors on
HAJI AGHAJANI et al.
F I G U R E 2 Funnel plot of assessment of publication bias among
included studies. There is no evidence of publication bias (P = .969)
F I G U R E 3 Forest plot for assessment of Apolipoprotein A-­1 and premature coronary artery disease. SMD, standardised mean difference;
CI, confidence interval
association of ApoA-­1 and pCAD. The findings depicted that the
country’s development level (odds ratio = 2.91; 95% CI: 1.71, 4.95;
P = .001) and quality score of included studies (odds ratio = 0.65;
95% CI: 0.45, 0.95; P = .029) were the only independent factors that
affect the association between ApoA-­1 and pCAD. The adjusted
| 7 of 13
R-­squared of the analysis was 77.3%, meaning that 77.3% of the het-
erogeneity among studies is related to difference in country’s devel-
opment level and the quality score of included studies.
3.5 | Sensitivity analysis
We performed a leave-­
one-­
out meta-­
analysis to investigate the
influence of each individual study on overall SMD of ApoA-­1 and
pCAD association (Figure 5). The analysis showed that by leaving
out any one the studies, the pooled SMD changed between −0.50
and −0.57 and there was still a significant association between the
serum level of ApoA-­1 and pCAD. Overall, excluding any individual
study from the meta-­analysis did not significantly change the overall
effect size.
4 | D I S CU S S I O N
The aim of this study was to review current literature and the
recently emerged evidences regarding the possible association
­
8 of 13 | HAJI AGHAJANI et al.

TA B L E 3 Subgroup analysis for

No. of
assessment of relationship of serum level
Subgroup analyses SMD (95% CI) P value I2 (P value)
of apolipoprotein A-­1 and pCAD
pCAD confirmation method
Documented previous MI 7 −0.41 (−0.70, −0.12) .005 89.6% (<.001)
or CABG
Angiography 12 −0.60 (−0.81, −0.38) <.001 87.6% (<.001)
Gender distribution
Male only 7 −0.78 (−0.92, −0.64) <.001 57.2% (.29)
Female only 3 −0.66 (−0.95, −0.37) <.001 26.0 (.259)
Mixed population 9 −0.32 (−0.57, −0.06) <.001 91.4% (<.001)
Country development
Developed 13 −0.76 (−0.88, −0.64) <.001 57.1% (.004)
Developing 6 −0.06 (−0.38, 0.22) .599 91.4% (<.001)
Publication year
1990-­1999 11 −075 (−0.89, −062) <.001 59.5% (.006)
2000-­2009 5 −0.25 (−0.74, 0.24) .315 90.3% (.001)
2010-­2020 3 −0.25 (−0.62, 0.13) .198 94.5% (<.001)
Overall quality score
Fair 13 −0.37 (−0.57, −0.18) <.001 87.3% (<.001)
Poor 6 −0.86 (−0.95, −0.78) <.001 0.0% (.438)

Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; MI, myocardial
infarction; pCAD, premature coronary artery disease; SMD, standardised mean difference.

between ApoA-­1 plasma level and pCAD. We determined that there
is a meaningful reduction of serum ApoA-­1 in pCAD patients than
healthy individuals; however, high levels of heterogeneity were
­observed among the results of the included studies.
In order to eliminate heterogeneity, we performed multiple
subgroup analyses (Table 3). One source of heterogeneity was the
gender distribution of the target population. Studies executed only
on a male or a female population had extremely less heterogene-
ity. The mentioned role of gender could be attributed to the dif-
ferences in the normal range of HDL in males and females, with
women having higher levels of HDL (and therefore serum ApoA),
and a higher cut-­off in normal range.41–­4 4 The hormonal effects of
estrogen and progesterone on HDL levels are well-­understood and
could be responsible for the matter.45 In addition, social habits may
be responsible for the differences in genders; as an example, smok-
ing, a far known independent risk factor of CAD is more prevalent
46,47
in men.
The developmental level of the country in which the study was
executed was also a source of heterogeneity. Fourteen studies chose
their studied population in a developed country, whereas nine ar-
ticles chose theirs in a developing one. Analyses showed that the
association between ApoA-­1 plasma levels in the pCAD and control
groups was significant, only in studies performed in developed coun-
tries. One could conclude that a better developmental level means a
better food supply and elimination of deficiencies, which could con-
tribute to blood lipid profile regulations.48 Moreover, the prevalence
of obesity and metabolic syndrome as risk factors of HDL deficiency
are higher in industrialised countries.49–­51 As a result of uncertainty
in the relationship between these concurrent mechanisms, the ef-
fects of different contributing factors need to be studied thoroughly
to determine the exact cause of different results between devel-
oped and developing countries.
Quality score of the included studies was another source of het-
erogeneity. Our results showed that pooled SMD for the association
of ApoA-­1 and pCAD is weaker in fair studies than poor ones. In ad-
dition, there were no good quality studies in our paper and all of the
included studies had a case-­control design. Therefore, the interpre-
tation of the results should be performed with caution. Accordingly,
we strongly recommend performing prospective cohort studies to
investigate possible role of ApoA-­1 in occurrence of pCAD.
Regarding the significance of our findings, it is clear that this
study shed light on the probable prognostic capacity of ApoA-­1
measurement in the development of pCAD. It is worth mentioning
that the occurrence of pCAD is one of the most important causes
of death in age below 55 in men and 65 in women. 52 With further
investigations we can better clarify the association between ApoA-­1
reduction in serum and pCAD occurrence and how long it will take
until the reduction in ApoA contributes to the incidence of pCAD.
By taking the results of this study into consideration and gathering
more evidences we could use a simple test to predict the occur-
rence of pCAD. It could be possible to manage the levels of ApoA-­1
through HDL increasing therapies to prevent or mitigate the out-
come of pCAD. Additionally, this potential biomarker of pCAD’s inci-
dence could be used in the follow-­up of our patients.
Further subgroup analyses in our study revealed no meaningful
negative impact of pCAD confirmation method on the final result.
HAJI AGHAJANI et al.
F I G U R E 4 Meta-­regression analysis for assessment of publication year (A), sample size (B) and mean age of included patients in non-­
pCAD (C) and pCAD (D) on association between serum level of ApoA-­1 and pCAD
Interestingly, the results were parallel in angiographically proven
pCAD patients and documented previous MI or CABG. This conclu-
sion may raise the reliability of ApoA-­1 plasma levels being a desir-
able prognostic factor for pCAD.
This systematic review and meta-­
analysis had its limitations.
The diagnostic approach that each study had established to con-
firm the occurrence of coronary artery disease was different. Seven
articles had accepted the self-­report of previous myocardial infarc-
tion or a history of CABG as the diagnosis and in 12 articles they
had performed coronary angiography to include the patients. Since
not all included studies had the same confounding factors analysed
(regardless of matching the case and the control group for age and
sex), we did not include comorbidities such as diabetes or hyperten-
sion or social habits such as smoking into our data. Also, the time
interval in which the ApoA-­1 was assessed after the onset of pCAD
was unclear; therefore, it was impossible for us to conclude when
meaningful differences in ApoA-­1 plasma levels are reliable after the
onset of pCAD. Since no study with a cohort design prospectively
enrolled patients, it is also unclear how long will it take for these
changes to contribute to the occurrence of pCAD. These show the
| 9 of 13
need for a more systematic approach to assess all confounding fac-
tors. Finally, although registering the protocol of systematic reviews
is optional, there was no prospectively registered protocol for this
meta-­analysis.
5 | CO N C LU S I O N
As a conclusion, there seems to be a significant association between
ApoA-­1 decrease in the bloodstream and the occurrence of pCAD.
However, all included studies had case-­control design. Since there
are no prospective cohort studies, level of current evidence is low.
Therefore, further well-­designed cohort studies are required to as-
sess the exact impact of ApoA-­1 reduction on pCAD onset.
DATA AVA I L A B I LIT Y S TATE M E NT
Individual data are available from the corresponding author on rea-
sonable request.
10 of 13 | HAJI AGHAJANI et al.

TA B L E 4 Meta-­regression analysis to assess independent associated factors on association of ApoA-­1 and pCAD

No. of Univariate Multivariate

Subgroup analyses odds ratio (95% CI) P value odds ratio (95% CI) P value

pCAD confirmation method

Documented previous MI or CABG 7 1 –­ –­
Angiography 12 1.20 (0.80, 1.81) .358 –­ –­
Gender distribution
Male only 7 1 1
Female only 3 1.10 (0.63, 1.94) .717 1.07 (0.71, 1.60) .724
Mixed population 9 1.54 (1.05, 2.27) .030 0.76 (0.50, 1.56) .180
Country’s development level
Developed 13 1 1
Developing 6 1.92 (1.46, 2.52) <.001 2.91 (1.71, 4.95) .001
Publication year
1990-­1999 11 1 1
2000-­2009 5 1.60 (1.07, 2.39) .026 0.81 (0.52, 1.26) .316
2010-­2020 3 1.63 (1.04, 2.55) .034 0.55 (0.30, 1.01) .053
Overall quality score
Fair 13 1 1
Poor 6 0.61 (0.43, 0.87) .009 0.65 (0.45, 0.95) .029

F I G U R E 5 Leave one out meta-­analysis to explore the influence of each study on the overall SMD of the association between ApoA-­1 and pCAD
HAJI AGHAJANI et al.
D I S C LO S U R E S
There is no conflict of interest.
ORCID
Arian Madani Neishaboori https://orcid.
org/0000-0002-1920-9299
Mahmoud Yousefifard https://orcid.org/0000-0001-5181-4985
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Haji Aghajani M, Madani Neishaboori
A, Ahmadzadeh K, Toloui A, Yousefifard M. The association
between apolipoprotein A-­1 plasma level and premature
coronary artery disease: A systematic review and meta-­
analysis. Int J Clin Pract. 2021;00:e14578. https://doi.
org/10.1111/ijcp.14578
APPENDIX 1
“Coronary Artery Disease” [mh] OR “Myocardial Infarction” [mh] OR
“Myocardial Ischemia” [mh] OR “Acute Coronary Syndrome” [mh] OR
“Coronary Stenosis” [mh] OR “ST Elevation Myocardial Infarction”
[mh] OR “Non-­
S T Elevated Myocardial Infarction” [mh] OR
Premature CAD[tiab] OR Premature coronary artery disease[tiab]
OR Coronary Artery Disease[tiab] OR Artery Disease, Coronary[tiab]
OR Artery Diseases, Coronary[tiab] OR Coronary Artery
Diseases[tiab] OR Disease, Coronary Artery[tiab] OR Diseases,
Coronary Artery[tiab] OR Coronary Arteriosclerosis[tiab] OR
Arterioscleroses, Coronary[tiab] OR Coronary Arterioscleroses[tiab]
OR Atherosclerosis, Coronary[tiab] OR Atheroscleroses,
Coronary[tiab] OR Coronary Atheroscleroses[tiab] OR Coronary
Atherosclerosis[tiab] OR Arteriosclerosis, Coronary[tiab] OR
Myocardial Infarction[tiab] OR Infarction, Myocardial[tiab] OR
Infarctions, Myocardial[tiab] OR Myocardial Infarctions[tiab] OR
Cardiovascular Stroke[tiab] OR Cardiovascular Strokes[tiab] OR
Stroke, Cardiovascular[tiab] OR Strokes, Cardiovascular[tiab] OR
Myocardial Infarct[tiab] OR Infarct, Myocardial[tiab] OR Infarcts,
Myocardial[tiab] OR Myocardial Infarcts[tiab] OR Heart Attack[tiab]
OR Heart Attacks[tiab] OR Myocardial Ischemia[tiab] OR Ischemia,
Myocardial[tiab] OR Ischemias, Myocardial[tiab] OR Myocardial
Ischemias[tiab] OR Ischemic Heart Disease[tiab] OR Heart Disease,
Ischemic[tiab] OR Disease, Ischemic Heart[tiab] OR Diseases,
Ischemic Heart[tiab] OR Heart Diseases, Ischemic[tiab] OR
Ischemic Heart Diseases[tiab] OR Acute Coronary Syndrome[tiab]
OR Acute Coronary Syndromes[tiab] OR Coronary Syndrome,
Acute[tiab] OR Coronary Syndromes, Acute[tiab] OR Syndrome,
Acute Coronary[tiab] OR Syndromes, Acute Coronary[tiab] OR
Premature heart attack[tiab] OR Coronary Stenosis[tiab] OR
Stenoses, Coronary[tiab] OR Stenosis, Coronary[tiab] OR Coronary
Artery Stenosis[tiab] OR Artery Stenoses, Coronary[tiab] OR Artery
Stenosis, Coronary[tiab] OR Coronary Artery Stenoses[tiab] OR
Stenoses, Coronary Artery[tiab] OR Stenosis, Coronary Artery[tiab]
OR Coronary Stenoses[tiab] OR ST Elevation Myocardial
Infarction[tiab] OR ST Segment Elevation Myocardial Infarction[tiab]
OR ST Elevated Myocardial Infarction[tiab] OR STEMI[tiab] OR
Non-­S T Elevated Myocardial Infarction[tiab] OR Non ST Elevated
Myocardial Infarction[tiab] OR NSTEMI[tiab] OR Non-­S T-­Elevation
Myocardial Infarction[tiab] OR Infarction, Non-­
S T-­
Elevation
Myocardial[tiab] OR Infarctions, Non-­S T-­Elevation Myocardial[tiab]
OR Myocardial Infarction, Non-­S T-­Elevation[tiab] OR Myocardial
Infarctions, Non-­S T-­Elevation[tiab] OR Non ST Elevation Myocardial
Infarction[tiab] OR Non-­S T-­Elevation Myocardial Infarctions[tiab]
AND Premature[tiab] OR early onset[tiab] AND “Apolipoproteins”
[mh] OR “Apolipoproteins A” [mh] OR “Apolipoprotein A-­1I” [mh] OR
“Apolipoprotein A-­1” [mh] OR “Apolipoprotein A-­V ” [mh] OR “apoli-
poprotein A-­1V” [Supplementary Concept] OR Apolipoproteins[tiab]
OR Apolipoprotein[tiab] OR Apolipoproteins A[tiab] OR Apo-­A[tiab]
OR ApoA[tiab] OR Apolipoprotein A-­
1I[tiab] OR Apolipoprotein
A II[tiab] OR Apo A-­1I[tiab] OR Apo A2[tiab] OR Apo AII[tiab] OR
ApoA-­
1I[tiab] OR Apolipoprotein A-­
2[tiab] OR Apolipoprotein A
2[tiab] OR Apolipoprotein A2[tiab] OR Apolipoprotein AII[tiab]
HAJI AGHAJANI et al.
OR Apo A-­
2[tiab] OR ApoA-­
2[tiab] OR Apolipoprotein A-­
1I
Isoproteins[tiab] OR Apolipoprotein A II Isoproteins[tiab] OR
Apo A-­1I Isoproteins[tiab] OR Apo A II Isoproteins[tiab] OR Pro-­
Apolipoprotein A-­
1I[tiab] OR Pro Apolipoprotein A II[tiab] OR
Proapolipoprotein A-­
1I[tiab] OR Proapolipoprotein A II[tiab] OR
Pro-­
Apo A-­
1I[tiab] OR Pro Apo A II[tiab] OR Apolipoprotein A-­
1[tiab] OR Apolipoprotein A I[tiab] OR Apo A-­
1[tiab] OR Apo
A1[tiab] OR Apolipoprotein AI[tiab] OR ApoA-­
1[tiab] OR ApoA-­
1[tiab] OR Apolipoprotein A-­1[tiab] OR Apolipoprotein A 1[tiab] OR
Apolipoprotein A1[tiab] OR Apo A-­1[tiab] OR Apo AI[tiab] OR Pro-­
Apolipoprotein A-­1[tiab] OR Pro Apolipoprotein A I[tiab] OR Pro-­
Apo A-­1[tiab] OR Pro Apo A I[tiab] OR Proapolipoprotein AI[tiab]
| 13 of 13
OR Apolipoprotein AI Propeptide[tiab] OR Apolipoprotein A-­
1
Isoproteins[tiab] OR Apolipoprotein A I Isoproteins[tiab] OR Apo
A-­1 Isoproteins[tiab] OR Apo A I Isoproteins[tiab] OR Apolipoprotein
A-­
1 Isoprotein-­
2[tiab] OR Apolipoprotein A I Isoprotein 2[tiab]
OR Apolipoprotein A-­1 Isoprotein-­4[tiab] OR Apolipoprotein A I
Isoprotein 4[tiab] OR Apolipoprotein A-­V[tiab] OR Apolipoprotein A
V[tiab] OR APOA5 Protein[tiab] OR ApoA-­V Protein[tiab] OR ApoA
V Protein[tiab] OR Apo A-­V Protein[tiab] OR Apo A V Protein[tiab]
OR Apolipoprotein A5[tiab] OR Apo A5 Protein[tiab] OR apolipo-
protein A-­1V[tiab] OR apolipoprotein A4[tiab] OR apolipoprotein
AIV[tiab] OR apo A-­1V[tiab] OR APOA4 protein, human[tiab] OR
apolipoprotein A-­1V, human[tiab]