Indian Heart Journal 76 (2024) S121–S129

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Indian Heart Journal

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Review Article

Apolipoprotein B - An ideal biomarker for atherosclerosis?

Kavita Singh a, b, Dorairaj Prabhakaran c, d, e, *
a
Public Health Foundation of India, Gurugram, Haryana, India
b
Heidelberg Institute of Global Health, Heidelberg University, Germany
c
Public Health Foundation India, Gurugram, Haryana, India
d
Centre for Chronic Disease Control, New Delhi, India
e
London School of Hygiene & Tropical Medicine, United Kingdom

A R T I C L E I N F O A B S T R A C T

Keywords: This review article describes the pathophysiological mechanisms linking Apolipoprotein B (Apo-B) and athero­
Apo-lipoprotein B sclerosis, summarizes the existing evidence on Apo B as a predictor of atherosclerotic cardiovascular disease and
Atherosclerosis recommendations of (inter)national treatment guidelines regarding Apo B in dyslipidemia management. A single
India
Apo B molecule is present in every particle of very low-density lipoprotein, intermediate density lipoprotein, low
Dyslipidaemia
Biomarker
density lipoprotein, and lipoprotein(a). This unique single Apo B per particle ratio makes plasma Apo B con­
centration a direct measure of the number of circulating atherogenic lipoproteins. This review of global evidence
on Apo B as a biomarker for atherosclerosis confirms that Apo B is a single atherogenic lipid marker present in all
lipids sub-fractions except HDL-C, and thus, Apo B integrates and extends the information from triglycerides and
cholesterol, which could simplify and improve care for atherosclerotic cardiovascular disease.

1. Introduction 1.1. Pathophysiological mechanisms linking Apo-B and atherosclerosis

A clear understanding of the physiology of plasma lipid transport and
role of apolipoprotein B (Apo-B) in the pathophysiology of atheroscle­
rosis reveals how the care for dyslipidemia can be simplified and
improved if Apo-B replaces the other four atherogenic lipoproteins (total
cholesterol, triglycerides, LDL cholesterol, and non-HDL cholesterol).
Apo B is a critical structural protein of the atherogenic lipoproteins with
two major isoforms: apoB48 and apoB100. ApoB48 is found in chylo­
microns and chylomicron remnants with one apoB48 molecule per
chylomicron particle. Likewise, a single apoB100 molecule is contained
per particle of VLDL, intermediate density lipoprotein, LDL, and lipo­
protein(a). In this article, we describe the pathophysiological mecha­
nisms linking Apo-B and atherosclerosis and evidence of Apo B as a
predictor of atherosclerotic cardiovascular disease (AsCVD) events from
epidemiological and genetic studies. Further, we report the high-level
recommendations of the treatment guidelines regarding the role of
Apo B and the rationale for choosing Apo B as an ideal biomarker for
atherosclerosis in Indians.
Apolipoproteins bind to lipids and transport them throughout the
body. Lipoproteins rely on apolipoproteins for structural integrity and to
protect the hydrophobic lipids at their core. Most lipoproteins contain
cholesterol or triglycerides and transport lipids throughout the body for
cell uptake. Chylomicrons are lipoprotein particles that transport dietary
lipids from the digestive tract to the liver via the bloodstream. In the
liver, these dietary lipids are repackaged and combined with apo B-100
to form triglyceride-rich VLDL. Additionally, the lipoprotein lipase
enzyme removes triglycerides from VLDL to produce intermediate-
density lipoproteins first, followed by LDL. Each VLDL particle con­
tains one molecule of apo B which is retained as VLDL loses triglycerides
and shrinks to become the higher-cholesterol-containing LDL. Apo B is
recognized by receptors found on the surface of many of the body’s cells.
These receptors promote cholesterol uptake into cells. The cholesterol
that LDL and Apo B transport are vital for cell membrane integrity, sex
hormone production, and steroid production. Excess LDL, on the other
hand, can cause fatty deposits (plaques) in artery walls, as well as
hardening and scarring of the blood vessels, resulting in atherosclerosis
and the downstream consequences of coronary heart disease, carotid
disease, and peripheral vascular disease.

* Corresponding author. Public Health Foundation India, Centre for Chronic Disease Control, New Delhi, India.
E-mail address: dprabhakaran@ccdcindia.org (D. Prabhakaran).

https://doi.org/10.1016/j.ihj.2023.12.001
Received 31 October 2023; Accepted 2 December 2023
Available online 8 April 2024
0019-4832/© 2023 Cardiological Society of India. Published by Elsevier, a division of RELX India, Pvt. Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
K. Singh and D. Prabhakaran
Fig. 1. Central illustration linking Apo B lipoproteins as atherogenic particles in LDL-C and triglycerides.
Obesity which is integrally linked to coronary heart disease and
diabetes plays a major role in lipid metabolism. It reduces the clearance
of cholesterol and triglyceride-rich lipoproteins. By abnormal glucose
metabolism and impaired insulin action it worsens plasma levels of
VLDL, cholesterol and triglyceride-rich remnant Apo-B lipoproteins, and
maladaptive inflammation.1–3 Increased levels of triglyceride-rich apo-B
lipoproteins are linked to an increased risk of AsCVD (see Fig. 1 – central
illustration and Fig. 2 – progression and regression of atherosclerotic
plaques mediated by Apo-B).
1.2. Evidence for Apo-B as a predictor of atherosclerosis
1.2.1. Epidemiological studies
Aside from age, gender, family history of heart disease, and ethnicity,
common modifiable risk factors for ASCVD include high blood choles­
terol, hypertension, diabetes, prediabetes, overweight and obesity,
smoking, excessive alcohol use, physical inactivity, and stress.4,5 The
INTERHEART study, which included 12,461 AMI cases and 14,637 age-
and sex-matched controls, found that apolipoproteins (Apo-B and
Apo-A1) were better predictors of AMI than total cholesterol, LDL
cholesterol, and non-HDL cholesterol.6) The INTERHEART findings were
also consistent with those of other cohort studies, such as the
Apolipoprotein-related MOrtality RISk Study (AMORIS).7,8).
In a rapid review of PubMed and Google scholar search of relevant
articles on Apo B and ASCVD published between 2015 and 2023, we
extracted (unpublished) and analysed data of 34 published studies (8
cross-sectional, 10 case–control, 14 cohorts, and 2 systematic reviews
and meta-analysis) that evaluated Apo-B as a biomarker for athero­
sclerosis (Table 1). Almost all the studies show a positive association
between Apo-B levels and atherosclerosis except a 2021 cross-sectional
study from India involving 87 patients on statins therapy found no sig­
nificant association between Apo-B levels and future risk of coronary
heart disease events. Also, a 2019 systematic review9 found that both
statins and non-statin therapies (PCSK9 inhibitor and ezetimibe)
reduced cardiovascular risk per decrease in Apo B. However, in­
terventions such as fibrates, niacin, omega-3 fatty acids, which reduced
Apo B independently of LDL-C was, not significantly associated with
cardiovascular benefit. However, in the majority of other studies (n =
32) reviewed, the Apo B/Apo A1 ratio was found to have better
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Indian Heart Journal 76 (2024) S121–S129
predictive value than classical lipid parameters among patients with
ASCVD9) (Table 1).
1.2.2. Genetic studies
According to genetic studies, high levels of Apo-B correspond to high
levels of LDL-C and non-HDL-C and are associated with an increased risk
of CVD. Elevations may be caused by a high-fat diet and/or a decrease in
LDL clearance from the blood. Some Apo B (and LDL-C) elevations are
caused by mutations in the APOB gene, which causes it to produce Apo B
that is not as easily recognised by LDL receptors. Other mutations are in
the liver cell’s LDL receptor system, which recognises apo B-100. These
genetic changes impede LDL-C clearance from the blood, resulting in
LDL-C accumulation in plasma, increasing the risk of heart disease. In­
dividuals with genetically lower LDL-C or apo B lipoproteins, on the
other hand, have a lower lifetime risk of ASCVD, even when other risk
factors are present.43,44,18 Similarly, in animal models, atherosclerosis
develops only when plasma apo B levels are elevated in the presence of
other risk factors (tobacco smoke, hypertension, or immune
dysregulation).45
1.3. Recommendations of guidelines on the role of Apo-B
A comparison of international and national guidelines for the use of
Apo B in diagnosing and managing dyslipidaemia suggests that Apo B is
currently recommended for testing in case of familial hypercholester­
olemia and to estimate the ASCVD risk in the younger population reli­
ably. However, National Institutes of Clinical Excellence (NICE) 2017
lipid guidelines recommend non-HDL cholesterol as a better CVD risk
indicator than LDL –C or Apo B.46 Importantly, the NICE cholesterol
guideline is currently being updated and will be available by 2023. The
American Heart Association/American College of Cardiology
(AHA/ACC) 2018 guidelines for cholesterol now recognize Apo-B as a
strong indicator of atherogenicity than LDL-C alone.
However, Apo B measurement carries an extra expense, and its
measurement in some laboratories may not be reliable. A relative indi­
cation for Apo B measurement is in when triglyceride is ≥ 200 mg/dl.
Also, persistent elevation of Apo-B can be considered a risk-enhancing
factor. Measurement of Apo B is particularly useful in determining
whether hypertriglyceridemia is an atherogenic condition.47,48 The
K. Singh and D. Prabhakaran
Fig. 2. Schematic representation of the pathophysiological mechanisms showing the progression and regression of atherosclerotic plaques mediated by the apoli­
poprotein B particles. Abbreviations: low density lipoprotein cholesterol, IDL = intermediate density lipoprotein, VLDL = very low-density lipoprotein, Lp(a) =
lipoprotein a, Apo B = apolipoprotein cholesterol.
European Society of Cardiology (ESC 2019) guidelines emphasize that
Apo B is the preferred measurement to estimate ASCVD risk because Apo
B provides an accurate estimate of the total concentration of atherogenic
particles under all circumstances. Further, to slow the progression of
atherosclerosis, 2019 ESC guidelines recommend a healthy lifestyle to
maintain low levels of Apo B-containing lipoproteins throughout life,
coupled with statins and other lipid lowering treatment to lower LDL-C
and other Apo B-containing lipoproteins, for both the primary and sec­
ondary prevention of ASCVD events.49,50 In patients with VLDL-C levels
and elevated triglycerides, measurement of both Apo B and non-HDL-C
is recommended as part of a routine lipid panel for ASCVD risk evalu­
ation51 (Table 2).
1.4. Apo-B an ideal biomarker for atherosclerosis in Indians?
As summarized in the section above, a single Apo B per particle ratio
makes plasma Apo B concentration a direct measure of the number of
circulating atherogenic lipoproteins. While LDL-C, the major
cholesterol-carrying serum lipoprotein, is the primary target for man­
aging and preventing ASCVD, there is now strong evidence that Apo B is
a more accurate indicator of cardiovascular risk than either total
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Indian Heart Journal 76 (2024) S121–S129
cholesterol or LDL-C.
Literature suggests that Indians have high levels of small dense LDL.
Though when measured, the total cholesterol or LDL cholesterol is lower
than the Caucasian or other populations, the apo B levels will be higher
given that Apo B is a single atherogenic lipid marker present in all lipids
sub-fractions except HDL-C and hence have high atherogenicity. Apo B
thus integrated and extends the information from triglycerides and
cholesterol. This forms the rationale for suggesting Apo B as the primary
measure for dyslipidaemia management among Indians. This hypothesis
is further supported by a recent analysis involving data of 4244 adults
from Delhi, India, and 11,778 from the United States compared the
lipids and Apo B among Asian Indians and Americans.55 This study
found that total cholesterol, non-HDL-C, and LDL-C were significantly
higher among Americans, whereas plasma triglycerides, and Apo B were
significantly higher among Indians. The mean LDL-C (mg/dl) was 112 vs
105 and Apo B (mg/dl) 89 vs 95 in Americans and Indians, respectively
(Fig. 3). This study suggests that Apo B integrates and extend the in­
formation from the other four biomarkers of dyslipidaemia. Therefore,
Apo B measurement could simplify and improve the management of
dyslipidaemia.
However, before widely recommending Apo-B in the Indian
K. Singh and D. Prabhakaran Indian Heart Journal 76 (2024) S121–S129

Table 1
Epidemiological studies evaluating Apo-B as a biomarker for atherosclerosis (2015–2021).
Author, Year Location Study design Patient population Research question Comparator Total Main results
(Country) sample

Modi R, India Cross- Coronary heart To assess the Apo B/Apo A NA 4232 Apo B/Apo A ratio and CAD
201710 sectional disease ratio with coronary artery were found to be significantly
study disease in patients with associated in patients with
normal lipid profile. normal LDL and among
patients with dyslipidemia.
Akande JO, Nigeria Cross- Stroke To determine plasma levels NA 100 Significant positive
201911 sectional of total cholesterol, HDL-c, association between ApoA1,
study LDL-c, triglyceride, Apo A-1, Apo B/ApoA1 ratio, total
and Apo B in patients with cholesterol, HDL-c, and LDL-c
stroke. was found in stroke patients.
Zhang H, China Cross- Heart failure and To determine the association HF without renal 336 Triglyceride, LDL-C, HDL-C,
201912 sectional renal dysfunction between lipid profile and dysfunction apo A1 and apo B were
study renal dysfunction in the significantly associated with
heart failure patients renal dysfunction in
hospitalized heart failure
patients.
Cao J, 201913 USA Cross- Coronary heart To investigate whether Not mentioned 4623 Apo B was associated with
sectional disease discordance between apo B CAC among adults ≥45 years.
study and LDL-C or non-HDL-C
levels was associated with
subclinical ASCVD
measured by coronary
artery calcium.
Yaseen RI, Not Cross- Coronary heart To measure apo B/apo A-1 NA 90 Apo B/Apo A1 ratio highly
202114 mentioned sectional disease ratio in patients with ACS significant in patients with
study and assess its relationship ACS and ApoB found to be
with the severity of CAD independent risk predictor for
CAD severity.
Badrinath AK, India Cross- Coronary heart To study non-HDL, apo-B, NA 87 Non-HDL or TC/HDL or LDL/
202115 sectional disease TC/HDL, TG/HDL, LDL/ HDL ratios were found be
study HDL ratios, and hs-CRP in better biomarkers for future
patients under statin CHD risk prediction. Levels of
therapy; and to correlate hs-CRP, apo-B, and TG/HDL
them with their LDL; and to ratio were not statistically
identify which biomarker is significant in assessing the
better at detecting CHD risk. future CHD events.
Malek R, Bangladesh Case-control Stroke (early onset- To evaluate the association Late onset stroke - Age 100 High Apo B concentration
201516 study age 45 years) of Apo B, Apo A1 and lipid >50 years found with early onset stroke
profile with early onset as compared to late onset
stroke stroke.
Chowdhury Bangladesh Case-control Coronary heart To determine the blood Age and sex matched 100 Significant alteration of
AK, 201517 study disease, levels of apolipoproteins in with no serum Apo A-I level, and Apo
documented by patients with coronary electrocardiographic or B/Apo A-I ratio was found
coronary artery disease (CAD). CAG evidence of CAD among CAD patients.
angiogram (CAG)
Rada FH, Iraq Case-control Coronary heart To analyze the association of Healthy controls, aged 45 110 Angina pectoris was
201618 study disease, aged 55 serum lipids and ± 4 years associated with increased
years lipoproteins in patients with serum levels of Lp(a) more
angina pectoris. than serum levels of
apolipoprotein-B.
Bansal SK, India Case-control Coronary heart To find the lipid parameters Age and sex matched 60 Lp (a), ApoA-1, small dense
201619 study disease which correlate better with healthy persons without LDL, Apo B were better
premature CAD CAD discriminator of premature
CAD.
AL-Tu’ma FJ, Iraq Case-control Coronary heart To find association between Matched with age and 90 Significant association
201720 study disease AMI and vitamin D3, Apo body mass index between vitamin D3, Apo B,
A1, Apo B, and Apo B/Apo Apo A1 levels, Apo B/Apo A1
A1 ratio and other risk ratio was found with AMI.
factors (age, body mass
index and smoking).
Sathe CA, India Case-control CVD To evaluate whether the Apo Traditional lipid 30 Apo B/Apo A1 ratio was
201721 study B/Apo A1 ratio is a better measurements found to be better predictive
predictor of the occurrence value than classical lipid
of future CVD events parameters in cardiovascular
compared to traditional risk assessment.
lipid measurements.
Patel LB, India Case-control Coronary heart To evaluate and compare Age and sex matched 90 Total Cholesterol vs. HDL-C
201922 study disease the efficacy of Apo B and healthy subjects and LDL-C vs. HDL-C were
Apo A-I level with LDL-C helpful in assessing risk of
and HDL-C level as risk CHD while raised Apo B to
factors of coronary heart Apo A-I ratio was found to be
disease. risk factor for CHD.
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K. Singh and D. Prabhakaran Indian Heart Journal 76 (2024) S121–S129

Table 1 (continued )
Author, Year Location Study design Patient population Research question Comparator Total Main results
(Country) sample

Pencina MJ, USA Cohort study Coronary heart To determine the additional NA 2966 Risk assessment of CHD
201523 disease value of Apo B beyond LDL- events over and beyond LDL-
C or non-HDL-C as a C or non-HDL-C improved
predictor of coronary heart with Apo B.
disease.
Saputri D, Indonesia Cohort study Coronary heart To investigate whether apo without MACE 182 Elevated apo B/apo A-1 ratio
201524 disease B/apo A-1 ratio has a was a predictor of MACE in
predictive role in ACS patients.
hospitalized ACS patients
for major adverse cardiac
events (MACE).
Wilkins JT, USA Cohort study Atherosclerotic To quantify the associations NA 2794 Apo B found to be an
201625 cardiovascular between Apo B and the important marker in young
disease discordance between Apo B adults for CVD risk factors.
and LDL-C or non-HDL-C in
young adults and measured
coronary artery calcium in
midlife.
Prajapati JS, India Cohort study Coronary heart To evaluate and compare People without CHD. 295 Apo B/A-I found to have
201626 disease the diagnostic efficacy of higher diagnostic efficacy for
LDL-C/HDL-C ratio to Apo CHD and could be effectively
B/Apo A-I ratio in coronary used in clinical practice.
heart disease patients.
Ljungberg J, Sweden Cohort study Coronary heart To examine the impact of Lp Not mentioned 336 Lp(a) and Apo B/A1 ratio
201727 disease (a) and Apo B in subgroups were positively associated
of patients with aortic with aortic stenosis in
stenosis. patients with CAD
Steffen BT, USA Cohort study Coronary heart To determine whether Healthy individuals 2228 Apo-B and small LDL-c
201728 disease elevated Apo B measures are provide atherosclerosis risk
associated with carotid information that is not
atherosclerosis and plaque revealed by typical CV risk
progression independent of factors.
cardiovascular risk factors
Ohwada T, Japan Cohort study Coronary heart To determine the High Apo-B groups 115 Elevated Apo-B level was
201929 disease relationship between plaque associated with coronary
composition and LDL-c, artery lesions which suggests
HDL-c, Apo-B, and Apo-A1 Apo-B as a biomarker of
unstable plaque.
Bajaj A, 201930 USA Cohort study Coronary heart To evaluate the associations Not mentioned 3811 Higher VLDL-C and Apo-B
disease of lipid and Apo B levels levels, as well as lower HDL-C
with risk for atherosclerotic and Apo-A1 levels, were
CVD associated with increased risk
for ASCVD.
Mowafy KA, Egypt Cohort study Coronary heart To examine whether high Type 2 DM with no CVD. 60 Serum level of Lp (a) and
202031) disease and levels of Lp (a) and Apo-B serum level of Apo-B showed
diabetes have a significant risk and higher significant prediction
prognostic value in type 2 for occurrence of CVD.
diabetic patients with CVD.
Ghodsi S, Not Cohort study Coronary heart To determine the potential NA 2259 Compared to non-HDLC and
202132 mentioned disease prognostic utility of LDL-C, Apo B appears to be a
calculated Apo-B in a cohort simple tool for prediction of
of patients with STEMI cardiovascular events in
undergoing primary PCI. STEMI patients.
Sandhu PK, Multiple Systematic CVD To assess the use of non- NA 9 studies Apo B and apo B/apo I ratio
201633 countries Review traditional lipid biomarkers can improve the risk
(Cohort including apo B, apo A-I, apo prediction for cardiovascular
Study) B/A-I ratio, and non-HDL-C events.
in improving CVD risk
prediction
Khan SU, Multiple Systematic Atherosclerotic To explore whether NA 3,32,912 Statin and non-statin
20199 countries Reviews and cardiovascular lowering Apo B is associated therapies (PCSK9 inhibitor
Meta- disease with decrease in mortality and ezetimibe) reduced
Analysis and major adverse cardiovascular risk per
cardiovascular events decrease in Apo B.
(MACEs) and whether these Interventions (fibrates,
potential clinical effects niacin, omega-3 fatty acids)
vary by different lipid- which reduce Apo B
lowering strategies. independently of LDL-c was
not associated with
cardiovascular benefit.
Muheeb G, India Case-Control ST-segment To determine the levels of age and gender matched 110 Lipid biomarkers such as Apo
202234 elevation biomarkers such as Lp (a), controls A1, Apo B and PON1 and
myocardial Apo A1, Apo B, PON-1 and their genetic polymorphism
infarction (STEMI) Lp-PLA2 in young patients are associated with the
with STEMI and study the
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K. Singh and D. Prabhakaran
Table 1 (continued )
Author, Year Location Study design Patient population Research question
(Country)
distributions of respective
gene polymorphism in the
Apo A1 (75G/A) and the
PON1 (Q192R) gene in the
young STEMI group.
Karagiannidis Greece Cohort Coronary artery To investigate potential
E, 202235 disease correlations between
metabolic fingerprints and
prospective major adverse
cardiovascular or
cerebrovascular events
(MACE) or baseline CAD
complexity.
Deepa PK, India Case-Control Coronary artery To explore the relationship
202236 disease between plasma levels of
PCSK9, Apo B, and HbA1C
in patients with coronary
artery disease (CAD) with
Diabetes Mellitus
Mustafa B, Pakistan Cross- Acute MI To estimate the ApoB blood
202237 sectional levels and its usefulness and
to analyze the total
cholesterol TC, non-HDL
cholesterol, triglycerides,
HDLc, LDL/HDL and LDLc
ratios in AMI patients.
Shrestha D, Nepal Cross- Acute MI To estimate the blood level
202238 sectional of ApoB and determine its
usefulness alongside
analysis of TC, TG, HDL,
LDLc, non-HDL cholesterol,
LDL/HDL ratio in AMI
patients
Chen X, 202239 China Cohort Ischemic stroke To analyze the correlation
between Lpa, APO-A, APO-
B, and middle cerebral
artery (MCA) stenosis in CIS
patients, aiming to provide a
new research direction for
clinical prevention and
treatment of Ischemic stroke
(CIS).
Mei Y, 202240 China Case-Control Patients with To evaluate and compare
coronary artery the ApoB/ApoA1 ratio and
disease and type 2 GDF-15 concentrations in
diabetes mellitus T2DM patients with or
without CAD and examine
their ability to predict CAD.
Yao T, 202241 Not Cohort Coronary To determine if elevated
mentioned atherosclerotic levels of apoB is superior to
heart disease LDL-C in assessing residual
risk of coronary
atherosclerotic heart disease
and severity of coronary
atherosclerosis in
participants with statin
treatment.
Nomura SO, US Cohort Coronary heart To compare small dense
202342 disease low-density lipoprotein
cholesterol (sdLDL-C) with
apolipoprotein B (apo B),
and LDL-c in predicting CHD
risk in generally healthy
adults with normal fasting
glucose (NFG).
Abbreviations: TC- total cholesterol; TG-triglycerides; LDL-C- low density lipoprotein cholesterol; Lp(a) = lipoprotein a; HDL-C- high density lipoprotein cholesterol;
Apo-A- Apolipoprotein A; Apo-B- Apolipoprotein B; AS = aortic stenosis; CAG-coronary angiogram; CAD-coronary artery disease; CVD-cardiovascular disease; CHD-
coronary heart disease; MACE-major adverse cardiac events; CAC- coronary artery calcium; PCI- percutaneous coronary intervention; STEMI- ST-elevation myocardial
infraction; CRP- C-reactive protein; NA = not applicable; NFG = normal fasting glucose.
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Indian Heart Journal 76 (2024) S121–S129
Comparator Total Main results
sample
susceptibility for STEMI in
young individuals.
NA 316 Higher levels of apoB,
acylcarnitine ratio C4/C18:2,
and HsTnT were associated
with higher risk for the
primary composite outcome
of MACCE, repeat unplanned
revascularization and
cardiac-disease related
hospitalizations.
age and gender matched 124 Both plasma levels of PCSK9
healthy individuals and Apo B and HbA1C were
significantly higher in
patients with CAD and DM as
compared with those with
CAD without DM.
Healthy Controls 81 Moderate correlation
between Apo B and non-HDL-
C and HDL-C were observed
in the AMI patients.
Healthy Controls 73 Significantly higher level of
Apo was found in Acute MI
with moderate correlation
with non-HDL-C and HDL-C,
necessitating its usage as a
complementary marker to
conventional lipid profile.
Individuals without 186 Levels of Lpa, APO-A, and
middle cerebral artery APO-B in the peripheral blood
(MCA) stenosis of CIS patients have a certain
correlation with the degree of
MCA stenosis. When the
levels of Lpa and APO-B
increase and the level of APO-
A decreases, the risk of MCA
stenosis occurs.
Coronary Artery disease 502 Circulating GDF-15 levels and
serum ApoB/ApoA1 ratio
vary in CAD group and T2DM
group. ApoB/ApoA1 and
GDF-15 may be helpful for
predicting the occurrence of
CAD in patients with T2DM.
NA 131 Elevated apoB are superior in
assessing the residual risk of
coronary atherosclerotic
heart disease and severity of
coronary atherosclerosis in
participants with statin
treatment.
NA 3258 Apo B, LDL-P and sdLDL-C are
all significantly associated
with CHD risk in
normoglycemic, non-diabetic
individuals. Overall, sdLDL-C
is comparable to apo B and
LDL-P in prediction of CHD
risk among generally healthy
adults with NFG
K. Singh and D. Prabhakaran Indian Heart Journal 76 (2024) S121–S129

Table 2
Comparison of guidelines on the role of Apo B in dyslipidaemia management and prevention of atherosclerosis.
2018-AHA/ACC guideline 2019-ESC guideline

Dyslipidemia ⁃ A relative indication for Apo B measurement would be ⁃ Apo-B analysis is recommended for risk assessment, particularly in people with high
diagnosis triglyceride ≥200 mg/dl. TG, DM, obesity or metabolic syndrome, or VLDL-C.
⁃ Apo-B measurement carries extra expense, and its ⁃ Apo-B can be used as an alternative to LDL-C, if available, as the primary measure­
measurement in some laboratories may not be reliable.52 ment for screening, diagnosis, and management.
⁃ Measurement of apo-B may be useful in determining whether ⁃ Apo-B may be preferred over non-HDL-C in people with high TG, diabetes, obesity, or
hypertriglyceridemia is an atherogenic condition.53,54 VLDL-C.
Dyslipidemia ⁃ High correlation between apo B and non-HDL-C.52 ⁃ Because Apo B provides an accurate estimate of the total concentration of atherogenic
management ⁃ Like non-HDLC, apo-B is a stronger indicator of atherogenicity particles under all circumstances, it is the preferred measurement to further refine the
than LDL-C alone. estimate of ASCVD risk that is modifiable by lipid-lowering therapy.
⁃ Persistent elevation of apo-B can be considered a risk-
enhancing factor.
Target Apo B <65 mg/dl- very high risk
<80 mg/dl- high risk
<100 mg/DL- moderate CV risk
Target LDL-C Acceptable- <110 mg/dl <70 mg/dl- high risk
Borderline- 110–129 mg/dl <100 mg/DL- moderate risk
Abnormal- ≥130 mg/dl <116 mg/dl- low-CV risk
Target HDL-C Acceptable- <45 mg/dl <30 mg/dl
Borderline- 40–45 mg/dl
Abnormal- <40 mg/dl
Target non-HDL-C Acceptable- <120 mg/dl <85 mg/dl- high risk
Borderline- 120–144 mg/dl <100 mg/DL- moderate risk
Abnormal- ≥145 mg/dl <130 mg/dl- low-CV risk

Abbreviations: *TC- total cholesterol; TG-triglycerides; LDL-C- low density lipoprotein cholesterol; HDL-C- high density lipoprotein cholesterol; APO-A- Apolipo­
protein A; APO-B- Apolipoprotein B; VLDL = very low-density lipoprotein, AsCVD-atherosclerotic cardiovascular disease; CV = cardiovascular.

Fig. 3. Comparison of Apo-B and LDL-c (mean values across age-group) in Indians vs Americans. Abbreviations:LDL-C = low density lipoprotein cholesterol, Apo B
= apolipoprotein cholesterol, US=United States.

population, we need longitudinal data from Indian cohorts, mechanistic
studies including multi-omics, Mendelian randomization and artificial-
intelligence-based studies along with standardized quality control and
cost of Apo B measurements in primary care centres, or potential
implementation of Apo-B measurements using point of care devices.
Further, there are concerns related to Apo-B measurement being non-
standardized. However, LDL-C value is also not directly measured
worldwide. The majority of the laboratories in low-middle-income
countries (LMICs) use the Friedewald formula for LDL-C estimation,
which is not valid if the triglyceride is > 400 mg/dl. Thus, direct mea­
surement of LDL-C is not only expensive but for its calculation requires
to perform other lipid fractions such as total cholesterol, triglycerides,
and HDL-C.
2. Conclusion
This review of global evidence on Apo-B as a potential biomarker for
atherosclerosis suggest that Apo B is a single atherogenic lipid marker
present in all lipids sub-fractions except HDL-C. The conventional lipid
panel is complex and can be contradictory. However, Apo B integrates
and extends the information from triglycerides and cholesterol, which
could simplify and improve care for ASCVD. Compelling evidence from
systematic reviews, Mendelian randomization studies, and artificial
intelligence-based analysis performed in the western countries further
validate the value of Apo B as a superior marker for atherosclerosis.
Routine clinical care around the world could be simplified and improved
by substituting Apo B for the conventional lipid panel to monitor the
adequacy of lipid-lowering therapy, particularly in the low resource
settings, where the burden of atherosclerosis has risen faster than the
resources available to treat and prevent it.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.

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K. Singh and D. Prabhakaran Indian Heart Journal 76 (2024) S121–S129

References [Internet]. ACI (Acta Cardiologia Indonesiana); 2017 Jan 9 [cited 2021 Jul 28];1(2).
Available from: https://jurnal.ugm.ac.id/jaci/article/view/17799.
25. Wilkins JT, Li RC, Sniderman A, Chan C, Lloyd-Jones DM. Discordance between
1. Ohukainen P, Kuusisto S, Kettunen J, et al. Data-driven multivariate population
apolipoprotein B and LDL-cholesterol in young adults predicts coronary artery
subgrouping via lipoprotein phenotypes versus apolipoprotein B in the risk
calcification: the CARDIA study. J Am Coll Cardiol. 2016;67(2):193–201.
assessment of coronary heart disease. Atherosclerosis. 2020;294:10–15.
26. Prajapati J, Deshmukh JK, Patel KH, et al. Apolipoprotein B/apolipoprotein A-I ratio
2. Richardson TG, Sanderson E, Palmer TM, et al. Evaluating the relationship between
a better diagnostic marker of coronary heart disease than conventional LDL/HDL
circulating lipoprotein lipids and apolipoproteins with risk of coronary heart
ratio. Natl J Lab Med. 2016;5(3). http://njlm.net/citation_mgr.asp?issn=&year=2
disease: a multivariable Mendelian randomisation analysis. PLoS Med. 2020;17(3),
016&month=July&volume=5&issue=3&page=&id=130.
e1003062.
27. Ljungberg J, Holmgren A, Bergdahl IA, et al. Lipoprotein(a) and the apolipoprotein
3. Jorgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjaerg-
B/A1 ratio independently associate with surgery for aortic stenosis only in patients
Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant
with concomitant coronary artery disease. J Am Heart Assoc. 2017;6(12).
cholesterol as causal risk factors for myocardial infarction. Eur Heart J. 2013;34(24):
28. Steffen BT, Guan W, Remaley AT, et al. Apolipoprotein B is associated with carotid
1826–1833.
atherosclerosis progression independent of individual cholesterol measures in a 9-
4. Walli-Attaei M, Joseph P, Rosengren A, et al. Variations between women and men in
year prospective study of Multi-Ethnic Study of Atherosclerosis participants. J Clin
risk factors, treatments, cardiovascular disease incidence, and death in 27 high-
Lipidol. 2017;11(5):1181–11891 e1.
income, middle-income, and low-income countries (PURE): a prospective cohort
29. Ohwada T, Sakamoto T, Kanno Y, et al. Apolipoprotein B correlates with intra-
study. Lancet. 2020;396(10244):97–109.
plaque necrotic core volume in stable coronary artery disease. PLoS One. 2019 Feb
5. Uspst Force, Krist AH, Davidson KW, et al. Behavioral counseling interventions to
19;14(2), e0212539.
promote a healthy diet and physical activity for cardiovascular disease prevention in
30. Bajaj A, Xie D, Cedillo-Couvert E, et al. Lipids, apolipoproteins, and risk of
adults with cardiovascular risk factors: US preventive services task force
atherosclerotic cardiovascular disease in persons with CKD. Am J Kidney Dis. 2019
recommendation statement. JAMA. 2020;324(20):2069–2075.
Jun;73(6):827–836.
6. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors
31. Mowafy KAE-A, Mosaad A Soliman MD, Shahir Kamal George MD, Zaghloul H.
associated with myocardial infarction in 52 countries (the INTERHEART study):
Prognostic Value of Serum Lipoprotein (A) and Apo Lipoprotein-B in Diabetics with
case-control study. Lancet. 2004;364(9438):937–952.
Myocardial Infarction and Chronic Limb Threatening Ischemia; 2020 Apr 24 [cited 2021
7. Mariosa D, Hammar N, Malmstrom H, et al. Blood biomarkers of carbohydrate, lipid,
Jul 28]; Available from: https://zenodo.org/record/3812601.
and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: a more
32. Ghodsi S, Mohebi M, Sadre-Bafghi S-A, et al. Prognostic implications of calculated
than 20-year follow-up of the Swedish AMORIS cohort. Ann Neurol. 2017;81(5):
Apo-lipoprotein B in patients with ST-segment elevation myocardial infarction
718–728.
undergoing primary percutaneous coronary intervention: outcome is tied to lower
8. Walldius G, de Faire U, Alfredsson L, et al. Long-term risk of a major cardiovascular
cut-points. Clin Cardiol. 2021;44(6):824–832.
event by apoB, apoA-1, and the apoB/apoA-1 ratio-Experience from the Swedish
33. Sandhu PK, Musaad SM, Remaley AT, et al. Lipoprotein biomarkers and risk of
AMORIS cohort: a cohort study. PLoS Med. 2021;18(12), e1003853.
cardiovascular disease: a laboratory medicine best practices (LMBP) systematic
9. Ho HV, Sievenpiper JL, Zurbau A, et al. A systematic review and meta-analysis of
review. J Appl Lab Med. 2016;1(2):214–229.
randomized controlled trials of the effect of barley beta-glucan on LDL-C, non-HDL-C
34. Muheeb G, Gupta MD, Kunal S, et al. Novel lipid biomarkers and associated gene
and apoB for cardiovascular disease risk reduction(i-iv). Eur J Clin Nutr. 2016;70
polymorphism in young ST-segment elevation myocardial infarction. Indian Heart J.
(11):1239–1245.
2023 Jan-Feb;75(1):68–72. https://doi.org/10.1016/j.ihj.2022.11.014.
10. Modi R, Kothiwale VA, Patted S, Halkati PC. APO B/APO AI ratio with coronary
35. Karagiannidis E, Moysidis DV, Papazoglou AS, et al. Prognostic significance of
artery disease with normal lipid profile in the Indian population. J Assoc Phys India.
metabolomic biomarkers in patients with diabetes mellitus and coronary artery
2017 Oct;65(12):22–27.
disease. Cardiovasc Diabetol. 2022;21(1):70.
11. Akande JO, Salawu AA, Atiba AS, Oke EO, Akande RO, Oparinde DP, et al. Plasma
36. P K D, G S R K, C R R. Association of pro protein convertase subtilisin/kexin 9, apo B
levels of total cholesterol, high-density lipoprotein-cholesterol, low-density
and HbA1c in coronary artery disease with and without diabetes mellitus: life
lipoprotein-cholesterol, triglyceride, Apo A-1, and Apo B in patients with Stroke in
sciences-biochemistry. Int J Life Sci Pharm Res. 2022;12(2):L93–L100.
Ogbomoso, Southwestern Nigeria. J Appl Biol Biotechnoly. 7(3):29–35.
37. Mustafa B, Anwar M, Nazim M, Khokhar A. Apolipoprotein B and lipid profile
12. Zhang H, Shi S, Zhao XJ, et al. Association between the lipid profile and renal
among patients diagnosed with acute myocardial infarction Pakistan. Biomed J.
dysfunction in the heart failure patients. Kidney Blood Press Res. 2019;44(1):52–61.
2022;5(7).
13. Cao J, Nomura SO, Steffen BT, et al. Apolipoprotein B discordance with low-density
38. Shrestha D, Yadav BK, Gajurel RM, et al. Apolipoprotein B and lipid profile among
lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to
patients diagnosed with acute myocardial infarction. Nepal Heart J. 2022;19(1):
coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
35–38.
J Clin Lipidol. 2020;14(1):109–121 e5.
39. Chen X, Lu X, Li W, Zhang H, Wang T. Correlation between lpa, APO-A, APO-B, and
14. Yaseen RI, El-Leboudy MH, El-Deeb HM. The relation between ApoB/ApoA-1 ratio
stenosis of middle cerebral artery in patients with cerebral ischemic stroke. Emerg
and the severity of coronary artery disease in patients with acute coronary
Med Int. 2022;2022, 6403645.
syndrome. Egypt Heart J. 2021;73(1):24.
40. Mei Y, Zhao Z, Lyu Y, Li Y. Circulating growth differentiation factor 15 levels and
15. Badrinath A, Nagarajan K, Anand P, Babu S, Asmathulla S, Inaamul Hassan M.
apolipoprotein B to apolipoprotein A1 ratio in coronary artery disease patients with
Coronary risk prediction by the correlation of total cholesterol/high-density
type 2 diabetes mellitus. Lipids Health Dis. 2022;21(1):59.
lipoprotein, triglyceride/high-density lipoprotein, low-density lipoprotein/high-
41. Yao T, Lu W, Ke J, et al. Residual risk of coronary atherosclerotic heart disease and
density lipoprotein ratios, non-high-density lipoprotein, apolipoprotein-B, and high-
severity of coronary atherosclerosis assessed by ApoB and LDL-C in participants with
sensitivity C-reactive protein with low-density lipoprotein in Indian patients under
statin treatment: a retrospective cohort study. Front Endocrinol. 2022;13, 865863.
statin therapy. 2019;7(2):63–67.
42. Nomura SO, Karger AB, Garg P, et al. Small dense low-density lipoprotein
16. Malek RHM, Shaha PR, Hossain MS, Ahmed A, Akhter M. Association of apo B, apo
cholesterol compared to other lipoprotein biomarkers for predicting coronary heart
A1 and lipid profile with early onset stroke. J Bangladesh Soc Physiol. 2015;10(2):
disease among individuals with normal fasting glucose: the Multi-Ethnic Study of
51–55.
Atherosclerosis. Am J Prev Cardiol. 2023;13, 100436.
17. Chowdhury AK, Shafique AM, Rahman ZF. Apolipoprotein A-I and B levels in
43. Wulff AB, Nordestgaard BG, Tybjaerg-Hansen A. APOC3 loss-of-function mutations,
Bangladeshi patients with coronary artery disease. Ibrahim Med Coll J. 2016;9(1):
remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk:
31–33.
mediation- and meta-analyses of 137 895 individuals. Arterioscler Thromb Vasc Biol.
18. Association FR. Of lipid fractions levels with cardiovascular disease. Asian J
2018;38(3):660–668.
Pharmaceut Clin Res. 2015;Mar;1(10):180–182.
44. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause
19. Bansal SKAS, Daga MK. Conventional and advanced lipid parameters in premature
atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and
coronary artery disease patients in India. J Clin Diagn Res. 2015;Nov(11):BC09–11.
clinical studies. A consensus statement from the European Atherosclerosis Society
20. Al-Tu’ma FJMZ, Al-Sarraf HH. Role of vitamin D3 level and Apo-B/Apo-A1 ratio in
Consensus Panel. Eur Heart J. 2017;38(32):2459–2472.
patients with unstable angina in Kerbala province, Iraq. J Contemp Med Sci. 2017;
45. Williams KJ, Tabas I, Fisher EA. How an artery heals. Circ Res. 2015;117(11):
Jun 26;(10):224–228.
909–913.
21. Sathe CA, Chogle SA, Bharadwaj D. Apo B/apo A1 ratio: a risk marker in patients
46. Lipid Modification: Cardiovascular Risk Assessment and the Modification of Blood Lipids
with cardiovascular disease. Int J Res Med. 2017;6(2):20–23.
for the Primary and Secondary Prevention of Cardiovascular Disease. 2014. London.
22. Patel LB, Raghavani PH. Comparison of apolipoprotein levels with conventional
47. Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/
Lipid profile parameters in patients with coronary heart disease. IJCBR. 2019 Dec
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood
28;6(4):514–517.
cholesterol: a report of the American College of Cardiology/American heart
23. Pencina MJ, D’Agostino RB, Zdrojewski T, et al. Apolipoprotein B improves risk
association task force on clinical practice guidelines. Circulation. 2018;139(25):
assessment of future coronary heart disease in the Framingham Heart Study beyond
e1082–e1143, 2019.
LDL-C and non-HDL-C. Eur J Prev Cardiol. 2015;22(10):1321–1327.
48. Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/
24. Saputri D, Hariawan H, Irawan B. High Apo B/Apo A-1 Serum Ratio as a Predictor of
ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood
In-Hospital Major Adverse Cardiovascular Events in Acute Coronary Syndrome Patients
cholesterol: a report of the American College of Cardiology/American heart

S128
K. Singh and D. Prabhakaran
association task force on clinical practice guidelines. J Am Coll Cardiol. 2018;73(24):
e285–e350, 2019.
49. Landmesser U, Chapman MJ, Stock JK, et al. Update of ESC/EAS Task Force on
practical clinical guidance for proprotein convertase subtilisin/kexin type 9
inhibition in patients with atherosclerotic cardiovascular disease or in familial
hypercholesterolaemia. Eur Heart J. 2017;39(14):1131–1143, 2018.
50. Nordestgaard BG, Langlois MR, Langsted A, et al. Quantifying atherogenic
lipoproteins for lipid-lowering strategies: consensus-based recommendations from
EAS and EFLM. Atherosclerosis. 2020;294:46–61.
51. Puri R, Mehta V, Duell PB, et al. Proposed low-density lipoprotein cholesterol goals
for secondary prevention and familial hypercholesterolemia in India with focus on
PCSK9 inhibitor monoclonal antibodies: expert consensus statement from Lipid
Association of India. J Clin Lipidol. 2020;14(2):e1–e13.
S129
Indian Heart Journal 76 (2024) S121–S129
52. Grundy SM, Vega GL, Tomassini JE, Tershakovec AM. Comparisons of
apolipoprotein B levels estimated by immunoassay, nuclear magnetic resonance,
vertical auto profile, and non-high-density lipoprotein cholesterol in subjects with
hypertriglyceridemia (SAFARI Trial). Am J Cardiol. 2011;108(1):40–46.
53. Sniderman AD, Tremblay A, De Graaf J, Couture P. Phenotypes of
hypertriglyceridemia caused by excess very-low-density lipoprotein. J Clin Lipidol.
2012;6(5):427–433.
54. Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB. Plasma
lipoproteins in familial combined hyperlipidemia and monogenic familial
hypertriglyceridemia. J Lipid Res. 1983;24(2):147–155.
55. Singh K, Thanassoulis G, Dufresne L, et al. A comparison of lipids and apoB in Asian
Indians and Americans. Glob Heart. 2021;16(1):7.