Following my last article, we now have an idea that total cholesterol and LDL cholesterol give us an incomplete picture of future mortality and cardiovascular disease. In that article I mentioned more important markers such apolipoproteins and metabolic markers - specifically ApoB. So in this article I will be reviewing ApoB and apolipoproteins in more detail as risk factors for cardiovascular disease (CVD) and all-cause mortality (ACM).
TLDR
ApoB is important but so is A1 and ApoB/A1 ratio. Based on the literature, optimal ranges are:
ApoB: 1-1.3 g/L
ApoA1: 1.6 g/L (Men ~1.4; Women ~1.6)
ApoB/ApoA1: ~0.75
What are Lipoproteins?
Lipoproteins are a molecule that is a combination of fats/lipids (lipo) and proteins (in this case particularly apolipoproteins). In the context of cholesterol, we are talking about commonly discussed cholesterol molecules like Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL). The structure of these molecules allows them to travel in the blood stream while the proteins generally provide the ability to communicate with other cells via ligand/receptor function. If you want a crash course on lipoproteins I recommend watching Peter Attia’s episode on the topic.
There are other lipoproteins beyond just LDL and HDL which are potentially more atherogenic (causing atherosclerosis), which is why focusing on LDL alone has not been a core focus for many years. When we consume food, we package the fats and cholesterol into chylomicrons the largest of the family, which then get transported around the body for energy. Our liver also synthesizes cholesterol as VLDL (Very Large Density Lipoprotein), which then converts to IDL (Intermediate) and LDL as it transports fats and cholesterol around the body. VLDL, IDL and LDL all contain a specific apolipoprotein B-100 (or ApoB for short, whereas Chylomicrons contain ApoB-48). These are believed to be the more atherogenic lipoproteins and is why this area of research focuses on ApoB over LDL as a more sensitive risk marker. We also synthesize HDL which contains apolipoprotein A1 which transports cholesterol from the periphery back to the liver (reverse cholesterol transport). There is also another very important lipoprotein called Lipoprotein (a) – pronounced lipoprotein little a – but we’ll save that for another article along with remnant cholesterol.
ApoB
As mentioned, for quite some time now researchers and up-to-date clinicians have not focused on LDL as a risk marker for cardiovascular disease, but instead on ApoB. Even the European and Canadian Guidelines recommend ApoB over LDL [1]. One of the early large studies to show ApoB as a more sensitive marker was the AMORIS (Apolipoprotein-related MOrtality RISk) study [2]. They had a cohort of 175 553 Swedish men and women with a mean follow-up of 66·8 months and 64·4 months, respectively. They found that ApoB had the strongest risk in men and average overall (ApoB/A1 higher in women) (Figure 1).
Figure 1
You’ll notice in this table a reduced risk ratio for ApoA1 and ApoB/A1 as well. In fact, when we look at the full data breakdown (Figure 2) we see more significant declines in risk for ApoA1 and HDL (similar to what we discussed in our last article) which is often not talked about as much as ApoB.
Figure 2
This paper concluded that ApoB, ApoA1 and ApoB/A1 ratio are important risk factor for myocardial infarct, prioritising ApoB as more sensitive marker than LDL-C. They do however go on to show that “The numerically steepest increase in risk was obtained for the ratio apoB/apoA-I, which increased about 3·8-fold in men, when the risk for those in the highest quartiles was compared with those in the lowest quartiles”. Again, showing that the relative ratio is more important than just ApoB alone.
Many other studies including Mendelian Randomisations have also shown ApoB to be significantly correlated with CVD [3]. The research suggests ApoB to be a significant independent risk factor for CVD. However, we need to determine at what threshold and to what extent ApoB is a risk for not only CVD, but ACM as well because like LDL, there appears to be a J/U shaped relationship.
An important paper by published by Li et al. in 2022 [4] did just that by looking at ApoB and its relationship to CVD and ACM. They begin by stating that “few studies reported the association between baseline ApoB level on admission and long-term all-cause mortality” and discuss how previous research has shown, like LDL, that patients with low ApoB have a worse prognosis for mortality (in the context of CAD). When we look at the spline graphs (Figure 3) in A and B we see a very clear J shaped relationship where low and high ApoB have a higher risk of death. The interesting bit is that the risk is more significant with LOW ApoB. Even after adjusting for multiple variables, the risk remained - “After adjusting for age, gender, and comorbidity (model 2), there was no obvious difference in long-term all-cause mortality between patients with low ApoB” – albeit it was a lower risk. This seems to mimic what we see with LDL.
However, why this paper is interesting, is that when they adjusted for a measure of malnutrition in C and D (via CONUT and total bilirubin), the relationship becomes linear whereby the lower the ApoB the lower the risk and vice versa for higher. This would suggest that the lower your ApoB the better. What is confusing however, is that they previously state when the previously assessed independent markers correlations, “ApoB did not show a significant correlation with total bilirubin and no strong correlation between ApoB and nutritional status which was evaluated by CONUT score” which would initially suggest that mortality risk shouldn’t be affected by it – so I’m not sure what to make of that (if you have any thoughts leave a comment!).
Figure 3
It should also be noted that their classification of ‘low’ ApoB was <65 mg/dL which is quite low. We should also keep in mind that these were CAD patients who were a hospitalised population which are not indicative of a healthy population.
There have been many other recent papers looking at ApoB and mortality that we can review to formulate our position. Research by Meng-qi Yan et al. in 2023 [5] showed ApoB was linearly associated with increased risk of cardiovascular mortality and non-linearly associated with all-cause mortality in a U-shaped manner independently of other cardiovascular risk factors. This U shaped correlation matches the 2022 paper above as well as others. They noted that the ApoB with the lowest overall risk was around 108 mg/dL (well above the 65 in the previous study).
In 2024 Huang et al. [6] also looked at ACM and CVD mortality in those with hypertension. They found “In the US hypertensive population, serum Apo B levels were U-shaped [Figure 4] and correlated with ACM and CVM risk, with the lowest risk at 100 mg/dL.” In their study they showed that those who had low ApoB exhibited a 1.27-fold higher risk of ACM than the normal group in the unadjusted model and following full adjustments in Model 4, the low ApoB group maintained a 66% elevated risk of ACM. Interestingly, those in the high group had no increased risk as those in the normal group (Figure 5,6). Normal was classified as 55–140 mg/dL for Men and 55–125 mg/dL for Women – so it’s pretty amazing to see no increased risk in those with an ApoB over 125-140!
Figure 4
Figure 5
When we look at the breakdown in Figure 6 we can see that those in the high ApoB group did not reach any significance (P<0.05) for increased risk of ACM or CVD Mortality. And this was a decently large cohort from the NHANES database with a mean age of 57.8 years with those who developed cancer excluded. Model 4 also adjusted for glucose and lipid lowering medication and the association with low ApoB was still present with a HR of 1.66 (P<0.001)
Figure 6
Unlike the 2022 paper above, they did not assess or adjust for malnutrition, however, in those with BMI >30 the risk of low ApoB was still present (and higher than high ApoB!), which would in essence remove the confounding variable of malnutrition as we can assume someone with a BMI >30 is not malnourished.
Figure 7
Interestingly, an ApoB above 100 is often touted as high and yet in this study the high group did not have a significantly elevated risk for ACM and CVM. However, there is clearly a trend with increasing ApoB and increased risk across various studies lending itself the U/J shaped curve. So it seems based on this that an ApoB around 100-130 mg/dL is the ideal range for ACM and CVD – with a small caveat that there may be benefit with lower ApoB in those with current CAD/CVD per the 2022 paper. But overall, yet again, this research would not align with the common narrative around getting ApoB down below 60 or 50.
ApoA1
Like the familiar LDL and HDL pair, we shouldn’t view ApoB in a vacuum without considering ApoA1 as well. In fact, Florvall at el. in their 2006 paper [7] suggest “The strongest correlation described in the AMORIS study was that between increased risk of fatal myocardial infarction and the ApoB/ApoA1 ratio”. And unfortunately, much like LDL, ApoA1 does not get as much attention as ApoB, so let’s see how this marker relates to our discussion.
Looking at the Florvall paper, “The association between cardiovascular morbidity and/or mortality and ApoA1 was stronger than that for the other studied markers” with the highest area under the curve between ApoA1 and ischemic heart disease (IHD) mortality. We can see dose dependent response with higher quartiles of A1 having lower risk (Figure 8). Keep in mind this was in older (77 yo) Swedish men only and there were no significant differences in body mass index (BMI), blood pressure, hemoglobin A1c (HbA1c), glucose, insulin, triglycerides, and hsCRP between groups.
Figure 8
But that is an older paper, what about more recent evidence? Faaborg-Andersen et al. [8] looked at a larger cohort from the UK Biobank in 2023 assessing for CV and AC mortality, further broken down by gender. As with ApoB they also found a U-shaped relationship with A1 and mortality with low A1 being more significant (inverse J shape) (Figure 9). In their unadjusted analyses “participants with ApoA1 levels in the lowest decile between 0.42 and 1.22 g/L had the highest all-cause and cardiovascular mortality, while those with ApoA1 values between 1.67 and 1.75 g/L (8th decile, reference) had the lowest mortality”. After adjusting for various factors “those within the two lowest ApoA1 deciles (0.42– 1.32 g/L) had a significantly higher risk of all-cause and cardiovascular death compared with the reference decile” and “participants in the highest ApoA1 decile (1.91–2.50 g/L) were also at a 14% (CI 7–21%) higher risk of all-cause death and 21% (CI 7–37%) higher risk of cardiovascular mortality compared with those at lowest risk in the eighth ApoA1 decile”. When broken down by gender, the lowest risk was seen around 1.4 and 1.6 g/L for men and women respectively.
Figure 9
One of the concerns with low cholesterol, as we outlined in the previous article, is an association with a higher risk of cancer. Nishiyama et al. [9] assessed the risk of cancer in patients undergoing coronary surgery and treatment to lower cholesterol with incident cancer. They found that those with the lowest A1 had the highest incidence of cancer (Figure 10).
Figure 10
Although they state that improvements in CVD mortality have improved with better technology, surgery and medications, they further state “noncardiovascular death in patients after PCI is increasing”. For me this again points out the fact that we are not addressing root causes to optimal health, cardiovascular or otherwise.
So clearly ApoA1 is an important marker to consider in the context of mortality and its important to not become myopic with ApoB. ApoA1 seems to confer benefit due to the cholesterol shuttling preventing atherosclerosis and likely also due to its correlation with better metabolic health. It also possesses anti-thrombotic, anti-oxidant, anti-inflammatory, and endothelium-stabilizing properties that may benefit atherosclerosis.
ApoB/ApoA1 Ratio
Now that we know ApoB and ApoA1 are both important risk markers, it’s important to consider the ratio of them. Like LDL and HDL, we also have the ApoB/ApoA1 ratio which can give us a bit more information about the strength and importance of each marker as well as the interplay between them.
Ding et al. [10] looked at various markers in the AMORIS cohort to assess cholesterol markers and mortality stratified by age. What was good about this study is they looked for common phenotypes associated with the various markers and put them into clusters to assess risk (Figure 11). What they found is that those who had a lower A1, regardless of the markers like ApoB, had an increased risk of mortality (Cluster 2 and 3).
Figure 11
They further broke down each individual marker to assess risk and like much of the research above, also found a U/J shaped relationship - except for triglycerides which have a linear relationship, outlining the importance of this marker (which we’ll discuss more when we cover Remnant Cholesterol). They found the lowest risks for ApoB, A1 and B/A1 around 1.2, 1.6 and 0.7 respectively.
Figure 12
They also go on to state that “In all age groups, low ApoA-I (< 1.28 g/L) was associated with increased all-cause and cardiovascular mortality compared to the reference group (1.40–1.50 g/L). An elevated ApoB/ApoA-1 ratio was associated with higher all-cause mortality risk in ages up to 80 years and higher cardiovascular mortality risk in all ages”. Interestingly, the risk of ApoB seems to drop off after 60 years of age – “our findings suggest that, for people who survived to advanced ages, a high cholesterol, triglyceride, and apolipoprotein profile starts to lose some of its ability to confer a higher mortality” (Figure 13).
Figure 13
I do wish this study had added a 4th cluster to their analysis with people who had high lipids AND high A1 to see if the high A1 was protective in this state – hopefully more research to come on this phenotype with the lean mass hyper-responders.
The last paper to review is a 2024 meta-analysis from Zhang et al. [11] titled ‘Association of apolipoprotein levels with all-cause and cardiovascular mortality’. This is an interesting paper because of the findings related to ApoB. This is what they found – “The level of ApoA was negatively related to cardiovascular mortality. An increased ratio of ApoB/A1 was a risk factor for cardiovascular mortality and all-cause mortality. The level of ApoB was positively related to cardiovascular mortality, but the difference was not statistically significant”. This is very interesting given that much of the focus in cardiology seems to be about high ApoB and that alone… this is not to say there isn’t research showing improvements in cardiovascular mortality for secondary prevention, there certainly is. But it adds to the counter narrative that ApoB is not CAUSAL in atherosclerosis (again, necessary but not sufficient).
So clearly ApoA1 and the relative ratio between ApoB and A1 are important. This is likely because these are significantly modified based on metabolic health which we know is the biggest driver of disease. In fact, the best way to disrupt the balance between these is with metabolic syndrome and insulin resistance.
Summary
By now we should have a pretty good understanding on the significance of apolipoproteins and cardiovascular disease and all-cause mortality. These markers are certainly more sensitive than the traditional lipoproteins LDL and HDL, however they seem to follow a similar trend with a U-shaped curve. Much like LDL/HDL, it would appear the relative ratio of ApoB/A1 is more important than ApoB or A1 alone, although there seems to be mixed data on the significance of ApoB, at least in primary prevention. Even still, there are other more important and significant markers for CVD and ACM such as Lp(a), remnant cholesterol and particularly metabolic markers – which we’ll have to cover in a future article.
The key take away, as with most things, is to look at overall trends and not have the blinders on with specific markers. Understanding your ApoB and A1 adds to your overall picture of health but you should always consider the wider picture as well. Based on the more recent research covered here, this is what it seems are the ideal ranges for CVD and ACM to aim for when assessing your biomarkers (notwithstanding any previously diagnosed diseases):
ApoB: 1-1.3 g/L
ApoA1: 1.6 g/L (Men ~1.4; Women ~1.6)
ApoB/ApoA1: ~0.75
There are still gaps in our understanding around apolipoproteins and preventive cardiology overall. For example, much of the literature to date is looking at individuals who already have cardiovascular disease among other diseases or are looking at the general population which we know are mostly (>80%) metabolically unhealthy. Thus, we cannot deduce from this population what will be the case in a healthy and fit population. I think the research coming out around the lean mass hyper-responders will be a paradigm shift in cardiology as we learn more.
As usual, please leave any thoughts or comments or other literature you might be aware of that contradicts what I’ve outlined here. I’m not a cardiologist and this is not a comprehensive literature review, so I’m sure there are holes to be filled.
References
Aygun, S. & Tokgozoglu, L. Comparison of Current International Guidelines for the Management of Dyslipidemia. J Clin Med 11, (2022).
High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. The Lancet, 358(9298), 2026–2033 | 10.1016/s0140-6736(01)07098-2. https://sci-hub.se/10.1016/s0140-6736(01)07098-2.
Richardson Id, T. G. et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. (2020) doi:10.1371/journal.pmed.1003062.
Yoshida, H. et al. Paradoxical Association Between Baseline Apolipoprotein B and Prognosis in Coronary Artery Disease: A 36,460 Chinese Cohort Study. Frontiers in Cardiovascular Medicine | www.frontiersin.org 1, 822626 (2022).
Yan, M. qi et al. Association of apolipoprotein B with all-cause and cardiovascular mortality among adults: Results from the National Health and Nutrition Examination Surveys. American Journal of the Medical Sciences 366, 367–373 (2023).
Huang, Y., Chen, S., Pan, H., Yang, S. & Cheng, W. Relationship between serum apolipoprotein B and risk of all-cause and cardiovascular disease mortality in individuals with hypertension: a prospective cohort study. BMC Cardiovasc Disord 24, 1–12 (2024).
Florvall, G., Basu, S. & Larsson, A. Apolipoprotein A1 Is a Stronger Prognostic Marker Than Are HDL and LDL Cholesterol for Cardiovascular Disease and Mortality in Elderly Men. (2006).
Faaborg-Andersen, C. C. et al. U-shaped relationship between apolipoprotein A1 levels and mortality risk in men and women. Eur J Prev Cardiol 30, 293–304 (2023).
Nishiyama, H. et al. Low apolipoprotein A1 was associated with increased risk of cancer mortality in patients following percutaneous coronary intervention: A 10‐year follow‐up study. Int J Cancer 151, 1482 (2022).
Ding, M. et al. The association of apolipoproteins with later-life all-cause and cardiovascular mortality: a population-based study stratified by age. Scientific Reports | 11, 24440 (123AD).
Zhang, J. et al. Association of apolipoprotein levels with all-cause and cardiovascular mortality. Eur J Prev Cardiol 31, (2024).
Opmerkingen