Plasma concentration of apolipoprotein B (apoB) reflects the number of the entire spectrum of atherogenic lipoprotein particles in the circulation. Since apoB reliably detects the total number of circulating atherogenic particles irrespective of their cholesterol content, knowledge of apoB concentration aids in avoiding some pitfalls associated with the traditional lipid metrics low-density lipoprotein (LDL)-cholesterol and non-high-density lipoprotein (HDL)-cholesterol. Thus, when small cholesterol-depleted dense LDL particles are generated in the circulation of patients with obesity, type 2 diabetes and related conditions characterized by insulin resistance, significant increases in the apoB concentration ensue, while the LDL cholesterol concentration may remain normal or only modestly elevated. Consequently, the excess risk associated with this type of dyslipidaemia may easily remain unrecognized, unless apoB concentration is measured and the result correctly interpreted. Evidence of the superiority of apoB over LDL-cholesterol and non-HDL-cholesterol concentrations in the evaluation of coronary heart disease risk is continuously gaining in strength, with the newest evidence coming from a study on the Framingham Offspring Cohort and reported in the present issue of the European Journal of Preventive Cardiology. Yet, implementation of apoB measurement into clinical practice is advancing sluggishly. Further efforts are necessary for apoB to become integrated as a valid additional determinant of coronary heart disease (CHD) risk stratification and goal for statin treatment in the ever-growing population of patients with insulin resistance-induced dyslipidaemias.
Atherosclerosis, the underlying cause of CHD, results from the infiltration of apoB-containing lipoprotein particles into the coronary artery wall.1 Under normal physiological conditions in a fasting state, the vast majority of apoB-containing lipoproteins in the circulation are LDL particles, a small fraction of them belonging to the group of triglyceride-rich lipoproteins (very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL)).2 Since each apoB-containing particle contains a single apoB-molecule, measuring the plasma concentration of apoB provides direct information about the number of all apoB-containing lipoprotein particles in the circulation. Besides apoB-particles, also apolipoprotein A-I-containing lipoproteins are present in the circulation, that is, the HDL fraction of lipoproteins. In terms of cholesterol, plasma total cholesterol is then the sum of cholesterol in apoB particles (LDL-cholesterol (LDL-C), lipoprotein(a)-cholesterol (Lp(a)-C), VLDL-cholesterol (VLDL-C) and IDL-cholesterol (IDL-C)) and in apoA-I particles (HDL-cholesterol (HDL-C)).2,3 Then, by subtracting HDL-C from total cholesterol, a calculated value, the ‘non-HDL-C’, can be obtained as a single index of cholesterol in all apoB-containing atherogenic lipoproteins. Thus, it is not surprising that the global measure of the ‘bad cholesterol’, that is, the non-HDL-C, is a better predictor of CHD risk than LDL-C, which is merely a single, although the major, component of the non-HDL-C.
LDL particles, like the triglyceride-rich lipoproteins, are heterogeneous in size. The large buoyant LDL particles contain more cholesterol and the small dense LDL particles contain less cholesterol per particle, that is, per one molecule of apoB.4 Such variation in the LDL-C/apoB ratio among patients enables the use of either LDL-C or apoB as a variable in CHD risk estimation (Figure 1). Importantly, however, an increase in the concentration of apoB may reveal emergence of small cholesterol-depleted LDL particles, which is not reflected in the concentration LDL-C, and yet the risk of CHD is increased. Moreover, an increased apoB concentration may reflect elevated numbers of triglyceride-rich particles, the other group of apoB-containing lipoproteins besides LDL.
Graphical presentation of the importance of low-density lipoprotein (LDL) particle number as a determinant of coronary heart disease risk. Two clinical cases are shown in which the plasma concentration of LDL cholesterol (LDL-C) is identical (both 3.5 mmol/l, which corresponds to 135 mg/dl). Yet, the risk of coronary heart disease (CHD) associated with this LDL-C concentration is smaller when LDL particles are large and buoyant (‘cholesterol (C) enriched’; left) than when they are small and dense (‘cholesterol depleted’; right). This difference in particle size relates directly to the number of LDL particles at a given LDL-C concentration. Since each particle contains a single molecule of apoB-100 (in the body of text, simply apolipoprotein B (apoB)), the particle number is reflected by the concentration of apoB-100, which is higher for the small particles than for the large particles. Patients with insulin resistance associated with obesity, type 2 diabetes or other metabolic disorders sharing this pathophysiology may have low, normal or only mildly elevated LDL-C, yet their apoB concentration is high, reflecting the presence of increased numbers of small dense LDL particles.
The type of atherogenic dyslipidaemia associated with obesity, type 2 diabetes, metabolic syndrome and other conditions of insulin resistance includes hypertriglyceridaemia, low HDL-C and mildly elevated LDL-C with an increased number of small dense LDL particles.5 In terms of the quantity of apoB-containing lipoprotein particles, such dyslipidaemia is characterized by an increased number of both small dense cholesterol-depleted LDL-particles and triglyceride-rich lipoprotein particles. While an increase in the number of the triglyceride-rich particles can be suspected from the increase in plasma triglyceride concentration, there is no direct lipid metric to arouse suspicion of an increased number of the small cholesterol-depleted LDL particles. Consequently, it is easy to understand that apoB is superior not only to LDL-C, but also to the measure of cholesterol in all apoB-containing lipoproteins (the non-HDL-C) in determining the CHD risk in patients with atherogenic dyslipidaemia.6
Two large studies have focused on unravelling the ability of apoB to determine CHD risk more effectively than is achieved by the traditional lipid metrics: the prospective AMORIS (175,553 individuals derived from the Swedish screening programmes) and the cross-sectional INTERHEART (worldwide 12,120 control subjects and 9345 patients with acute myocardial infarction), and both revealed that determination of apoB improves the assessment of CHD risk.7,8 In the prospective AMORIS study, apoB was more precise than LDL-C, and in the INTERHEART study it was superior to both LDL-C and non-HDL-C in predicting myocardial infarction. Moreover, in the NHANES III survey (7594 US adults from a multi-ethnic US population), the concentration of apoB was better than the routine clinical lipid measurements in predicting CHD mortality.9 The findings on the superiority of the use of apoB in risk estimation of fatal or nonfatal ischaemic cardiovascular events described in the above-listed studies were confirmed in a large meta-analysis which included altogether 12 independent reports, including 233,455 subjects and 22,950 events.10
In this issue of the journal, Pencina and coworkers asked whether apoB would be superior to LDL-C and non-HDL-C in predicting new-onset CHD over a maximum of 20 years’ follow-up among 1569 female and 1397 male Framingham Offspring participants aged 40 to 75 years.11 The primary analysis estimated hazard ratios of the difference between observed and expected apoB, designated ‘discordant apoB’, as a predictor of new-onset CHD. The expected apoB concentration at a given LDL-C concentration was a calculated value corresponding to the presence of LDL particles containing normal amounts of cholesterol.6 Given that apoB, LDL-C and non-HDL-C are highly interrelated, the authors avoided the use of conventional statistical approaches, which have yielded inconsistent or inconclusive results.12,13 Rather, they utilized a sophisticated combination of multivariate-adjusted Cox regression models and C-statistics to assess the impact on discrimination, once the differences between the observed and expected apoB had been included in the model. Also, integrated discrimination improvement (IDI) was used. Using such a comprehensive and powerful statistical approach, the authors found that apoB offered an additional predictive value beyond LDL-C and non-HDL-C level after adjustment for standard risk factors, and even when LDL-C, HDL-C and non-HDL-C were included in the statistical analysis. The main finding of the analysis was that study subjects in the top tertile of discordant apoB included more men, they were older, more obese, diabetic and hypertensive, and, accordingly, in this group the prevalence of metabolic syndrome was the highest. Thus, particularly in these subjects the CHD risk did relate more closely to the number of apoB lipoprotein particles than to the mass of cholesterol within them. This important observation validates and extends previous analyses, the vast majority of which have shown that the number of atherogenic particles, whether estimated by measuring plasma apoB concentration or counting LDL particle numbers by nuclear magnetic resonance (NMR), are superior to LDL-C as indices of cardiovascular risk,14–16 and that apoB is associated with an increased risk for metabolic syndrome.17
Regarding the implementation of apoB measurement to the existing armamentarium of the traditional lipid-based measurements, the following points merit consideration. The latest European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines recommend that, in addition to the traditional plasma lipid measurements, apoB can be used to assess total cardiovascular risk.18 However, the guidelines also remind that most risk estimation systems are based on total cholesterol and LDL-C, and that clinical benefit from using other measures including apoB, non-HDL-C or various ratios has not been well proven in risk prediction. Moreover, the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline considered the contribution of apoB in risk assessment for a first atherosclerotic cardiovascular disease event uncertain, and so refrained from giving a recommendation – either for or against it.19 In this context, the present paper by Pencina and coworkers11 is important, as it adds to the slowly, but steadily, growing number of well-performed studies which prove an improved risk assessment value for apoB beyond LDL-C and also non-HDL-C. Based on the available reports on the special value of apoB measurements in patients with atherogenic dyslipidaemias, it is to be hoped that the next updates of guidelines will introduce this knowledge when guiding clinicians in optimization of risk assessment in this particular patient group.
Since apoB is powerful in predicting future CHD, one has to ask whether it could, or even should, supersede the inferior lipid-based metrics in the evaluation of CHD risk in certain well-specified patient groups. The answer is obviously ‘no’: in the foreseeable future, apoB, either alone or in combination with apoA-I, cannot be regarded as an adequate substitute for the traditional well-known lipid metrics, which include the enzymatically measured values of total cholesterol, triglycerides and HDL-C, and the calculated value of LDL-C (based on the use of the Friedewald formula), and possibly also including the calculated value of the relative newcomer, the non-HDL-C. Thus, even at its best, apoB measurement can only serve as an additional piece of information, when adapted to the well-defined relevant subgroups of patients. The add-on value of apoB measurement also applies to the estimation of the benefit of statin therapy, since, at a given dose of statin, the reduction of apoB concentration is often smaller than that of LDL-C or non-HDL-C.20 Accordingly, at least in high-risk patients with diabetic dyslipidaemia, apoB concentration appears to be not only a better risk marker but also a better treatment goal than LDL-C or non-HDL-C.21,22 Yet, it has been also doubted whether clinical management of a statin-treated diabetic patient with a residual risk caused by increased numbers of small dense LDL particles would change, provided the treating physician were aware of, besides LDL-C concentration, also the concentrations of apoB and non-HDL-cholesterol.23
In conclusion, increased numbers of atherogenic apoB-containing lipoprotein particles commonly associate with relatively normal or even low LDL-C levels in obesity, type 2 diabetes and metabolic syndrome, that is, conditions characterized by insulin resistance. Accordingly, implementation of apoB would improve risk assessment of future CVD in these disorders. Nevertheless, a major disadvantage of apoB is its absence from algorithms for calculation of the global cardiovascular risk. Regarding implementation of a novel metric, that is, apoB concentration, as a treatment target, the recent abolition of a traditional metric, that is, the LDL-C concentration, as treatment target in the ACC/AHA guidelines24–26 can be regarded as a misfortune. Ultimately, however, translation of the evidence from even the most successful prospective clinical studies into practice will be based on a careful assessment of the benefits and the costs of measuring this valuable non-lipid biomarker of CHD risk, particularly when evaluated in the context of the calculated non-HDL-C. At any rate, implementation of a new non-lipid metric as part of individualized patient care in the busy daily clinical praxis will be a real challenge to the general practitioner who is facing the many medical challenges arising from the ever growing global epidemic of obesity and the related cardiometabolic disorders.
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