Apolipoprotein B - An ideal biomarker for atherosclerosis?

Abstract

This review article describes the pathophysiological mechanisms linking Apolipoprotein B (Apo-B) and atherosclerosis, summarizes the existing evidence on Apo B as a predictor of atherosclerotic cardiovascular disease and recommendations of (inter)national treatment guidelines regarding Apo B in dyslipidemia management. A single Apo B molecule is present in every particle of very low-density lipoprotein, intermediate density lipoprotein, low density lipoprotein, and lipoprotein(a). This unique single Apo B per particle ratio makes plasma Apo B concentration 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

A clear understanding of the physiology of plasma lipid transport and role of apolipoprotein B (Apo-B) in the pathophysiology of atherosclerosis 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 chylomicrons 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 lipoprotein(a). In this article, we describe the pathophysiological mechanisms 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.

1.1. Pathophysiological mechanisms linking Apo-B and atherosclerosis

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 contains 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.

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, 2, 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).

Fig. 1.

Central illustration linking Apo B lipoproteins as atherogenic particles in LDL-C and triglycerides.

Fig. 2.

Schematic representation of the pathophysiological mechanisms showing the progression and regression of atherosclerotic plaques mediated by the apolipoprotein B particles. Abbreviations: low density lipoprotein cholesterol, IDL = intermediate density lipoprotein, VLDL = very low-density lipoprotein, Lp(a) = lipoprotein a, Apo B = apolipoprotein cholesterol.

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 cholesterol, 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 atherosclerosis (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 significant 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, interventions 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 predictive value than classical lipid parameters among patients with ASCVD⁹⁾ (Table 1).

Table 1.

Epidemiological studies evaluating Apo-B as a biomarker for atherosclerosis (2015–2021).

Author, Year	Location (Country)	Study design	Patient population	Research question	Comparator	Total sample	Main results
Modi R, 201710	India	Cross-sectional study	Coronary heart disease	To assess the Apo B/Apo A ratio with coronary artery disease in patients with normal lipid profile.	NA	4232	Apo B/Apo A ratio and CAD were found to be significantly associated in patients with normal LDL and among patients with dyslipidemia.
Akande JO, 201911	Nigeria	Cross-sectional study	Stroke	To determine plasma levels of total cholesterol, HDL-c, LDL-c, triglyceride, Apo A-1, and Apo B in patients with stroke.	NA	100	Significant positive association between ApoA1, Apo B/ApoA1 ratio, total cholesterol, HDL-c, and LDL-c was found in stroke patients.
Zhang H, 201912	China	Cross-sectional study	Heart failure and renal dysfunction	To determine the association between lipid profile and renal dysfunction in the heart failure patients	HF without renal dysfunction	336	Triglyceride, LDL-C, HDL-C, apo A1 and apo B were significantly associated with renal dysfunction in hospitalized heart failure patients.
Cao J, 201913	USA	Cross-sectional study	Coronary heart disease	To investigate whether discordance between apo B and LDL-C or non-HDL-C levels was associated with subclinical ASCVD measured by coronary artery calcium.	Not mentioned	4623	Apo B was associated with CAC among adults ≥45 years.
Yaseen RI, 202114	Not mentioned	Cross-sectional study	Coronary heart disease	To measure apo B/apo A-1 ratio in patients with ACS and assess its relationship with the severity of CAD	NA	90	Apo B/Apo A1 ratio highly significant in patients with ACS and ApoB found to be independent risk predictor for CAD severity.
Badrinath AK, 202115	India	Cross-sectional study	Coronary heart disease	To study non-HDL, apo-B, TC/HDL, TG/HDL, LDL/HDL ratios, and hs-CRP in patients under statin therapy; and to correlate them with their LDL; and to identify which biomarker is better at detecting CHD risk.	NA	87	Non-HDL or TC/HDL or LDL/HDL ratios were found be better biomarkers for future CHD risk prediction. Levels of hs-CRP, apo-B, and TG/HDL ratio were not statistically significant in assessing the future CHD events.
Malek R, 201516	Bangladesh	Case-control study	Stroke (early onset- age 45 years)	To evaluate the association of Apo B, Apo A1 and lipid profile with early onset stroke	Late onset stroke - Age >50 years	100	High Apo B concentration found with early onset stroke as compared to late onset stroke.
Chowdhury AK, 201517	Bangladesh	Case-control study	Coronary heart disease, documented by coronary angiogram (CAG)	To determine the blood levels of apolipoproteins in patients with coronary artery disease (CAD).	Age and sex matched with no electrocardiographic or CAG evidence of CAD	100	Significant alteration of serum Apo A-I level, and Apo B/Apo A-I ratio was found among CAD patients.
Rada FH, 201618	Iraq	Case-control study	Coronary heart disease, aged 55 years	To analyze the association of serum lipids and lipoproteins in patients with angina pectoris.	Healthy controls, aged 45 ± 4 years	110	Angina pectoris was associated with increased serum levels of Lp(a) more than serum levels of apolipoprotein-B.
Bansal SK, 201619	India	Case-control study	Coronary heart disease	To find the lipid parameters which correlate better with premature CAD	Age and sex matched healthy persons without CAD	60	Lp (a), ApoA-1, small dense LDL, Apo B were better discriminator of premature CAD.
AL-Tu'ma FJ, 201720	Iraq	Case-control study	Coronary heart disease	To find association between AMI and vitamin D3, Apo A1, Apo B, and Apo B/Apo A1 ratio and other risk factors (age, body mass index and smoking).	Matched with age and body mass index	90	Significant association between vitamin D3, Apo B, Apo A1 levels, Apo B/Apo A1 ratio was found with AMI.
Sathe CA, 201721	India	Case-control study	CVD	To evaluate whether the Apo B/Apo A1 ratio is a better predictor of the occurrence of future CVD events compared to traditional lipid measurements.	Traditional lipid measurements	30	Apo B/Apo A1 ratio was found to be better predictive value than classical lipid parameters in cardiovascular risk assessment.
Patel LB, 201922	India	Case-control study	Coronary heart disease	To evaluate and compare the efficacy of Apo B and Apo A-I level with LDL-C and HDL-C level as risk factors of coronary heart disease.	Age and sex matched healthy subjects	90	Total Cholesterol vs. HDL-C and LDL-C vs. HDL-C were helpful in assessing risk of CHD while raised Apo B to Apo A-I ratio was found to be risk factor for CHD.
Pencina MJ, 201523	USA	Cohort study	Coronary heart disease	To determine the additional value of Apo B beyond LDL-C or non-HDL-C as a predictor of coronary heart disease.	NA	2966	Risk assessment of CHD events over and beyond LDL-C or non-HDL-C improved with Apo B.
Saputri D, 201524	Indonesia	Cohort study	Coronary heart disease	To investigate whether apo B/apo A-1 ratio has a predictive role in hospitalized ACS patients for major adverse cardiac events (MACE).	without MACE	182	Elevated apo B/apo A-1 ratio was a predictor of MACE in ACS patients.
Wilkins JT, 201625	USA	Cohort study	Atherosclerotic cardiovascular disease	To quantify the associations between Apo B and the discordance between Apo B and LDL-C or non-HDL-C in young adults and measured coronary artery calcium in midlife.	NA	2794	Apo B found to be an important marker in young adults for CVD risk factors.
Prajapati JS, 201626	India	Cohort study	Coronary heart disease	To evaluate and compare the diagnostic efficacy of LDL-C/HDL-C ratio to Apo B/Apo A-I ratio in coronary heart disease patients.	People without CHD.	295	Apo B/A-I found to have higher diagnostic efficacy for CHD and could be effectively used in clinical practice.
Ljungberg J, 201727	Sweden	Cohort study	Coronary heart disease	To examine the impact of Lp(a) and Apo B in subgroups of patients with aortic stenosis.	Not mentioned	336	Lp(a) and Apo B/A1 ratio were positively associated with aortic stenosis in patients with CAD
Steffen BT, 201728	USA	Cohort study	Coronary heart disease	To determine whether elevated Apo B measures are associated with carotid atherosclerosis and plaque progression independent of cardiovascular risk factors	Healthy individuals	2228	Apo-B and small LDL-c provide atherosclerosis risk information that is not revealed by typical CV risk factors.
Ohwada T, 201929	Japan	Cohort study	Coronary heart disease	To determine the relationship between plaque composition and LDL-c, HDL-c, Apo-B, and Apo-A1	High Apo-B groups	115	Elevated Apo-B level was associated with coronary artery lesions which suggests Apo-B as a biomarker of unstable plaque.
Bajaj A, 201930	USA	Cohort study	Coronary heart disease	To evaluate the associations of lipid and Apo B levels with risk for atherosclerotic CVD	Not mentioned	3811	Higher VLDL-C and Apo-B levels, as well as lower HDL-C and Apo-A1 levels, were associated with increased risk for ASCVD.
Mowafy KA, 202031)	Egypt	Cohort study	Coronary heart disease and diabetes	To examine whether high levels of Lp (a) and Apo-B have a significant risk and prognostic value in type 2 diabetic patients with CVD.	Type 2 DM with no CVD.	60	Serum level of Lp (a) and serum level of Apo-B showed higher significant prediction for occurrence of CVD.
Ghodsi S, 202132	Not mentioned	Cohort study	Coronary heart disease	To determine the potential prognostic utility of calculated Apo-B in a cohort of patients with STEMI undergoing primary PCI.	NA	2259	Compared to non-HDLC and LDL-C, Apo B appears to be a simple tool for prediction of cardiovascular events in STEMI patients.
Sandhu PK, 201633	Multiple countries	Systematic Review (Cohort Study)	CVD	To assess the use of non-traditional lipid biomarkers including apo B, apo A-I, apo B/A-I ratio, and non-HDL-C in improving CVD risk prediction	NA	9 studies	Apo B and apo B/apo I ratio can improve the risk prediction for cardiovascular events.
Khan SU, 20199	Multiple countries	Systematic Reviews and Meta-Analysis	Atherosclerotic cardiovascular disease	To explore whether lowering Apo B is associated with decrease in mortality and major adverse cardiovascular events (MACEs) and whether these potential clinical effects vary by different lipid-lowering strategies.	NA	3,32,912	Statin and non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced cardiovascular risk per decrease in Apo B. Interventions (fibrates, niacin, omega-3 fatty acids) which reduce Apo B independently of LDL-c was not associated with cardiovascular benefit.
Muheeb G, 202234	India	Case-Control	ST-segment elevation myocardial infarction (STEMI)	To determine the levels of biomarkers such as Lp (a), Apo A1, Apo B, PON-1 and Lp-PLA2 in young patients with STEMI and study the distributions of respective gene polymorphism in the Apo A1 (75G/A) and the PON1 (Q192R) gene in the young STEMI group.	age and gender matched controls	110	Lipid biomarkers such as Apo A1, Apo B and PON1 and their genetic polymorphism are associated with the susceptibility for STEMI in young individuals.
Karagiannidis E, 202235	Greece	Cohort	Coronary artery disease	To investigate potential correlations between metabolic fingerprints and prospective major adverse cardiovascular or cerebrovascular events (MACE) or baseline CAD complexity.	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.
Deepa PK, 202236	India	Case-Control	Coronary artery disease	To explore the relationship between plasma levels of PCSK9, Apo B, and HbA1C in patients with coronary artery disease (CAD) with Diabetes Mellitus	age and gender matched healthy individuals	124	Both plasma levels of PCSK9 and Apo B and HbA1C were significantly higher in patients with CAD and DM as compared with those with CAD without DM.
Mustafa B, 202237	Pakistan	Cross-sectional	Acute MI	To estimate the ApoB blood levels and its usefulness and to analyze the total cholesterol TC, non-HDL cholesterol, triglycerides, HDLc, LDL/HDL and LDLc ratios in AMI patients.	Healthy Controls	81	Moderate correlation between Apo B and non-HDL-C and HDL-C were observed in the AMI patients.
Shrestha D, 202238	Nepal	Cross-sectional	Acute MI	To estimate the blood level of ApoB and determine its usefulness alongside analysis of TC, TG, HDL, LDLc, non-HDL cholesterol, LDL/HDL ratio in 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.
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).	Individuals without middle cerebral artery (MCA) stenosis	186	Levels of Lpa, APO-A, and APO-B in the peripheral blood 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.
Mei Y, 202240	China	Case-Control	Patients with coronary artery disease and type 2 diabetes mellitus	To evaluate and compare the ApoB/ApoA1 ratio and GDF-15 concentrations in T2DM patients with or without CAD and examine their ability to predict CAD.	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.
Yao T, 202241	Not mentioned	Cohort	Coronary atherosclerotic heart disease	To determine if elevated levels of apoB is superior to LDL-C in assessing residual risk of coronary atherosclerotic heart disease and severity of coronary atherosclerosis in participants with statin treatment.	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.
Nomura SO, 202342	US	Cohort	Coronary heart disease	To compare small dense 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).	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

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.

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. Individuals 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 hypercholesterolemia and to estimate the ASCVD risk in the younger population reliably. 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 indication 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 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 secondary 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 evaluation⁵¹ (Table 2).

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

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 managing and preventing ASCVD, there is now strong evidence that Apo B is a more accurate indicator of cardiovascular risk than either total 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 information from the other four biomarkers of dyslipidaemia. Therefore, Apo B measurement could simplify and improve the management of dyslipidaemia.

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.

However, before widely recommending Apo-B in the Indian 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 measurement 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.