Author + information
- Allan D. Sniderman, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Allan D. Sniderman, Mike Rosenbloom Laboratory for Cardiovascular Research, Room H7.22, McGill University Health Centre, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1 Canada.
There are large lessons to learn from the Cardiovascular Risk Study in Young Finns, published in this issue of the Journal (1). Two reiterate what we already knew but have largely ignored—first, whether we are paying attention or not, atherosclerosis is well underway by the third and fourth decades of our lives and, second, this disease is directly traceable to the atherogenic imbalance in the plasma lipoproteins that is identifiable by puberty. As important as these lessons are, Juonala et al. (1), break much fresh ground.
They found that the plasma apolipoprotein (apo) B and the apoB/apoA-I ratio at age 12 to 18 years were directly related to carotid artery intima-media thickness (IMT) at age 24 to 39 years, whereas apoA-I was indirectly related to carotid IMT. Moreover, these relations were not altered when adult levels of the apolipoproteins and non-lipid risk factors were taken into account. In addition, the same relations were noted, although in samples from an even earlier age, between the levels of the apoB, apoB/apoA-I ratio and impaired flow-mediated vasodilatation (FMD). Also of interest was the lack of any significant gender interaction between the association of the apolipoproteins and either carotid IMT or FMD.
That the plasma lipoproteins matter in atherogenesis and that atherogenesis starts early should be easy for all to accept. The challenge lies in what follows. Juonala et al. (1) demonstrate convincingly that apoB is superior to both low-density lipoprotein (LDL) cholesterol and non–high-density lipoprotein (HDL) cholesterol as an estimate of the atherogenic lipoproteins, that apoA-I is superior to HDL cholesterol as a marker of the antiatherogenic lipoproteins, and that the apoB/apoA-I ratio was significantly better than either the LDL/HDL cholesterol or the non–HDL/HDL cholesterol ratio as overall estimates of the lipoprotein-related vascular disease (1). Not only were the standardized beta coefficients of the apolipoproteins substantially greater than their cholesterol counterparts, but significant differences in favor of the apoB/apoA-I ratio were also evident by the c-statistic.
Perhaps no other issue in lipidology has been as contentious as the debate as to whether cholesterol or apolipoproteins are better markers of risk. All major guideline groups had already embraced cholesterol, and prior commitment and the perceived need for continuity are potent arguments for the status quo. However as the number of studies comparing apoB with LDL cholesterol has mounted, the comparison has become one-sided. Except in the oldest subjects where LDL by any measure is not predictive (2), in all other groups, whether those with symptomatic disease or those without, in men or women, those receiving therapy or those not treated, apoB has come out on top against LDL cholesterol (Online Appendix, supplementary references 1 to 23).
Understandably, it is not easy for most clinicians to fully appreciate just how clear the difference in predictive power is. Hazard ratios, c-statistics, and p values do not translate into simple, intuitively transparent, quantitative comparisons. In this instance, a picture is worth more than any number of words, and perhaps the best comes from Framingham. Figure 1 compares the predictive power of LDL particle number (LDL P) versus LDL cholesterol in the Framingham Offspring Study (3). Apolipoprotein B measures all the atherogenic particles, of which more than 90% are LDL particles (4). The apoB and LDL P are therefore equivalent markers. Figure 1 demonstrates that when both LDL cholesterol and LDL P are high, so is risk, and when both are low, so is risk. The battle is decided when they differ. When LDL P is high but LDL cholesterol is low, risk is high. When LDL P is high but LDL cholesterol is low, risk is high. The outcome could not be clearer: it is the number of atherogenic particles rather than the cholesterol they contain that we should measure.
On the basis of our knowledge of the biology of atherosclerosis, this should not be surprising. Atherosclerosis is what happens after apoB lipoprotein particles are trapped within the arterial wall. Moreover, the number of apoB particles in plasma determines the likelihood of an apoB particle entering and being trapped within the arterial wall (4). Take away the apoB particles and you take away atherosclerosis. Conversely, because LDL particles contain variable amounts of cholesterol, LDL cholesterol might seriously underestimate or overestimate apoB particle number leading to either under-treatment or to over-treatment and therefore to failure to prevent events that were preventable or to excessive cost and risk with therapy that was not necessary. Although much attention has been paid as to whether smaller cholesterol-depleted LDL particles are more—or less—atherogenic than their larger cholesterol-enriched counterparts, the majority of recent studies indicate that all LDL particles are atherogenic and that if one is worse than the other, it is a distinction without a difference (5–7).
Non-HDL cholesterol is closer to apoB and LDL P in predictive power. Indeed, they finish in a statistical tie in several studies (Online Appendix, supplementary references 24–28), but apoB winds up ahead in even more (Online Appendix, supplementary references 29–38) including the present study (1). Moreover, statin therapy lowers LDL cholesterol and non-HDL cholesterol more than apoB or LDL P (8). These are amongst the reasons that the American Diabetes Association and the American College of Cardiology have issued a joint consensus statement recommending that apoB be the final test of the adequacy of LDL-lowering therapy (9).
In contrast, the outcome of the contest between apoA-I versus HDL cholesterol remains unclear. Some studies such as the AMORIS (Apolipoprotein-Related Mortality Risk) study favor apoA-I (10), whereas others, such as the Framingham Offspring Study, strongly favor HDL cholesterol (11). Here more information is required. Even worse, although we know that HDL matters, the fact is that we do not know why. Do its benefits relate to removal of cholesterol from the artery? And even if they do, how does the plasma level of HDL cholesterol relate to that? Or is HDL “good” because it is anti-inflammatory? And if so, which component(s) count most?
What then are the large lessons from this study by Juonala et al. (1)? First, although the plasma lipoproteins are only risk factors for clinical events, they are prime causes of disease within the arteries. Second, transformation of a stable silent arterial lesion into an unstable one that produces a clinical event is a complex and unpredictable process. We know what causes disease within our arteries but can only guess at precisely what precipitates clinical events. It follows that prevention of coronary disease would be much simpler and much more effective if we focused on preventing disease developing within our arteries rather than trying to predict who is just about to become a victim and then trying frantically, at what might be just 1 min before their final midnight, to rescue them (12). The high-risk approach to prevention is often too high-risk for the patient and too late for his or her arteries. The bottom line is that, just as we need to revise how we measure the lipoprotein-related risk of vascular disease, we also need to revise when it is appropriate to correct the proatherogenic imbalance of the apoB and apoA-I lipoproteins to prevent the initiation and progression of advanced arterial disease. If we prevent the disease, we will prevent the events.
For supplementary references, please see the online version of this article.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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