March 14, 2021


Early risk assessment markers to delay cardiovascular disease

Identifying risk decades before disease manifests

Read Time 4 minutes

Half of solving the longevity equation comes down to delaying the onset of chronic disease. The longest lived among us do not live longer with chronic disease; they live longer without them. Atherosclerotic cardiovascular disease (ASCVD), the most prevalent disease in the developed world, is the disease most likely to cause death into old age. That is why I am so interested in assessing ASCVD early, so that the wheels of prevention can be set in motion. And when I say early, I mean in the ballpark of adolescence. If you’re not familiar with some of my previous writing on this topic, I suggest reading this piece from a few years ago about how early in life heart disease actually begins. Guided intervention with early risk assessment markers like non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB) can delay the onset of ASCVD. 

A recent study in JAMA concluded non-HDL-C is an important early predictor of ASCVD, the emphasis here being on the early part. The study reported that an elevated non-HDL-C in adolescence—people between the ages of 12 and 18 years old—had the strongest association with ASCVD in midlife. This finding is especially compelling since our aim is to predict the risk of having cardiovascular disease long before it occurs. The earlier that atherogenic risk can be identified by cholesterol risk markers, the better chance there is to address it and prevent disease at a later stage in life.  

The study uses non-HDL-C to assess atherogenic risk because it can estimate the mass of cholesterol molecules contained in potentially atherogenic lipoprotein particles. Think of a lipoprotein as a vehicle that carries lipids through plasma. Non-HDL-C is a calculated value derived by subtracting HDL-C from total cholesterol (i.e., all the cholesterol being carried in all lipoproteins, less the cholesterol being carried in the HDL particles). So the formula aims to estimate the amount of cholesterol in very low density lipoprotein (VLDL), low density lipoprotein (LDL), and intermediate density lipoprotein (IDL) particles (this also includes the cholesterol carried in lp(a) particles).

One limitation of the value is that it is calculated as opposed to directly measured. A second limitation is that it estimates the cholesterol mass contained in particles, which is a surrogate for the actual particle count. By contrast apoB, a peptide found on the surface of certain lipoproteins, is a direct measurement providing the best assessment for the number of the lipoproteins capable of causing atherosclerosis. For the purposes of this discussion, apoB essentially measures the quantity of potentially atherogenic LDL particles, since about 90% of apoB is located on LDLs. So to summarize, non-HDL-C estimates the quantity of the cholesterol mass within particles, whereas apoB measures the number of the potentially atherogenic particles. Even though apoB has a greater predictive ability for ASCVD, non-HDL-C is still a good initial screening tool that generally correlates with apoB measures. Ideally, both can be used to guide individual management. 

Back to the JAMA study. This prospective cohort study began in 1980 (before measuring apoB was as easy as it is today) and followed 3 population groups over a 28-year period. The study recorded non-HDL-C, which was determined for 3 different life stages: adolescence, young adulthood, and mid-adulthood. The measure was classified as either “normal” or “elevated,” using guideline-based recommended cutoffs. In the final year of the study, the 589 participants, who were by then between 40 to 46 years old, received a coronary artery calcium (CAC) scan to assess the presence and extent of coronary artery calcification, a manifestation and marker of very advanced coronary artery disease. A CAC scan is a strongly validated and well-accepted indicator of the advanced stages of coronary atherosclerosis.  

With mean values for non-HDL-C taken at 3 time points across the study period, and CAC scan results in the final year, the study then correlated the association of non-HDL-C and the presence of CAC in mid-adulthood. About 1 in 5 participants in the study had calcification in their coronary arteries at the end of the 28-year study period, when they were in their early-to mid-40s. The study reported that, compared to having normal non-HDL-C, elevated non-HDL-C in adolescence was associated with a 16% increased likelihood of developing CAC in mid-adulthood. When non-HDL-C was elevated in either young adulthood or mid-adulthood, there was also an increased likelihood of CAC by the end of the study period (14% and 12%, respectively) (Figure).

Figure. The likelihood of developing coronary artery calcification in mid-adulthood with the presence of elevated non-HDL-C in 3 different life stages: adolescence, young adulthood, and mid-adulthood. Source data: Armstrong et al., 2021

It is not surprising that the study found what it did. I like to explain to patients that cardiovascular disease is a time-course disease, which is why age is such a strong predictor of risk. The longer your artery walls are exposed to atherogenic particles, the more likely they are to incur damage, which is why earlier exposure to these particles incurs more risk and most strongly correlates to disease later in life. In other words, the damage from atherogenic particles accumulates over the course of a lifespan, which means more disease, manifested as CAC, or worse: a cardiovascular event, such as a heart attack or sudden death.

The study results tell us that measuring non-HDL-C as a marker of atherogenic risk early in life can help identify young adults at risk for midlife coronary artery disease, decades before disease manifests. The takeaway here is that we need to stop considering ASCVD as a 5-year or 10-year risk or waiting until someone has already developed damage. Surveilling non-HDL-C (or better yet, apoB) early in life—much sooner than we typically do—provides the opportunity for early lifestyle and pharmacologic intervention to delay the onset of ASCVD.


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  1. Great article but would you start medical intervention (and its side effects) with out confirmation of calcification on a CAC scan?
    In addition are there any non pharmaceuticals you would recommend early in lifetime to prevent ASCVD?

  2. So the results are clear, have you written anything to prevent …I live in uk so can’t visit

  3. In this study was diet of the participants considered for the final results? In other words, what is the impact of eating patterns on this results?

  4. Peter – What level would be considered a high non-HDL? Is that total chol to HDL ratio of any value?

  5. I am in my early 60s and live in Canada. What blood tests do you recommend at my age to detect and heart disease. Thankyou, love your podcasts

  6. Hello from South Africa!
    I’m a doctor working in a rural clinic with lots of hypertensive and diabetic patients.
    Loving the blog and content so much!

  7. Is there a medical practice that I can go to for testing and treatment on these ASCVD issues? I’m in NY area but will travel. Thank you.

  8. Peter,
    I’ve written via this method before, but have not rec’d any confirmation that these types of messages are integrated into the podcasts.. it’s understandable that you’re forward focused on putting out content..and not as much by feedback from the cheap seats…however, it seems there may be a blind spot in your rationale regarding Lipidology… I have listened to your podcasts re;Dayspring,et al. and the others,.. and I keep returning to the thought that in each of these podcasts, whether it be a Cardiologist, interventional-, Int. Med, etc. there is always this logic jump between tracing non-HDL-C levels(or Apo-B) and the ‘CAC’ Score… with no real attention paid to the jump from “lipogenic atheroma’ to ‘calcified atheroma” in which you establish well that the calcified atheromatous plaque is certainly bad, or an omen of bad infarcted outcomes… herein lies the rub… what is the process that converts a lipo-atheroma, to a calcified atheroma. Presumptively there must be a ‘calcification’ process occurring, for some time ‘-n’, ..maybe as long as you say Non-HDL-C takes to build plaque, or maybe some time ‘n-x’, but why so much attention on the cholesterol, and NO attention on the ‘calcification’ process… No attention on the physiology of calcification. You have spoken several times/written about “Vit D” which is good, you’ve written/spoken about the benefits of Magnesium…which is good… but maybe your scratching the surface.. need a deeper dive… Vit D is derived from cholesterol…in the skin, via UVB exposure, ..and is a far different entity(1,25 dihydroxycholecalciferol) than supplemented 25-dihyd–,.. which is derived from dubious/different places than cholesterol, ie. lanolin(sheep sweat,.. OBTW, yields a sheep farmer $300,000/sheep to cultivate)…or soy, etc.,etc. Magnesium is a co-factor for proper Vit D assimilation, and integration…ie. the benefits of Vit.D largely go as an unrealized gain,(and very likely a harm) in the presence of a Magnesium deficiency…To state again…low Magnesium!,.. and all that Vit D actually may be harmful!!! And finally! Vitamin K2 (the menaquinones,.. MK4, MK7, Mk13,etc,etc.) play a HUGE role in carboxylating the Matrix GLA proteins, for proper ‘adjutication’ as it were for how calcium is properly placed on the collagen matrix.., which exists EVERYWHERE in our body… no Vit K2, no proper calcium placement…yet Vit K2 is mentioned NOWhere in your podcasts… maybe a slight mention of ‘Vit K’ is made…but Vit K (phytoquenone) is quite a different biochemical entity altogether than Vit K2… and in most americans, the physiology of Vit K does not correlate to a 1:1 conversion to Vit K2… low Vit K2 intake…low matrix GLA carboxylation… and calcium problems… Bottom Line; It seems to this miss the issue with Matrix GLA proteins, and their measurement, and correlation at low levels, with BAD cardiac outcomes… every time I listen to the arguement… this issue does not even scratch the weak biostatistical correlation of statins with outcomes… but lowering cholesterol, without addressing improper calcium physiology seems to miss the ‘MacGuffin’ altogether.. it leads to a cascade of downrange physiological issues of “too low cholesterol”… which ultimately can lead to… well, a “hyperoxidized, hypercalcified, s/p x2 CVA’s, POTUS on statins…that is.. well.. demented cognitively.” The MacGuffin is Vitamin K2,.. and it’s role in the physiology of Omega-3’s.. prevention of calcification at the site of phospholipid bilayers along the intimal lining.. and the myelin sheath of the billion neurons of the brain. You have a gift of making the complex sound simple, with you language ability, confidence, and intelligence,.. BUT I do think you are missing a MacGuffin here! Just saying.

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