The skeptical cardiologist recently gave a lecture on the prevention of atherosclerotic cardiovascular disease (ASCVD) to the cardiology trainees at Saint Louis University School of Medicine.
Initially, I sought to define atherosclerosis.
Typing “What is atherosclerosis?” into Google this morning yields almost 60 million results, headed by a promoted Ad for a website paid for by Novartis (which would like to promote its, twice-yearly injectable LDL-C lowering drug, inclisiran, which is approved in Europe but not the US.)
The Novartis website gives a definition that emphasizes the role of LDL-C, the so-called “bad” cholesterol:
Atherosclerotic cardiovascular disease (ASCVD) is a type of cardiovascular disease caused by high levels of bad cholesterol (LDL-C) in the blood. This leads to the buildup of plaque on the walls of the arteries, which over time can lead to heart attack or stroke.
This is a simple, somewhat antiquated concept of atherosclerosis and I prefer the following more detailed definition:
-Atherosclerosis may be described as chronic inflammation of the arterial wall. It is caused by a complex interplay between lipoproteins, white blood cells (macrophages), the immune system, and the arterial wall’s normal elements.Axel Siggurdson
Furthermore, despite the simple messaging that there is a “bad” cholesterol which is the cause and must be lowered, evidence in the last decade has accumulated that it is not LDL-C that is the culprit that initiates this arterial inflammation but rather apolipoprotein B, one of a family of apolipoproteins which shepherd triglycerides and cholesterol through our blood.
This evidence is presented very convincingly in a 2019 JAMA insights article by Alan Sniderman and co-authors who conclude that:
Trapping of apolipoprotein (apo) B particles within the arterial wall is the fundamental step that initiates and drives the atherosclerotic process from beginning to end, from the first appearance of fatty streaks to the ultimate development of the complex lesions that are vulnerable to the acute transformations, such as plaque rupture and endothelial erosion, that are the immediate precursors of clinical events.Sniderman, et al.
Thus, the apolipoprotein B molecule initiates atherosclerosis which, in advanced stages, when localized to coronary, cerebral and peripheral arteries, leads to heart attacks, strokes, angina, and claudication.
Lifecycle of the Apo B Particle
Apo B particles are formed in the liver and begin their lifecycle as triglyceride-rich VLDL
As triglycerides are removed, the Apo B becomes denser, ultimately turning into LDL.
Because 90% of its lifecycle is spent as LDL, LDL-C serves as a reasonable surrogate for the number of apo B particles in circulation.
ApoB and atherosclerosis
Data from Mendelian randomization studies and randomized trials strongly suggest that the risk of ASCVD is determined by the total concentration of circulating apoB particles regardless of the lipid content they carry, and therefore the clinical benefit of any lipid-lowering therapy should be proportional to the absolute achieved reduction in apoB concentration regardless of the corresponding changes in LDL-C or triglycerides.
The 2019 European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemia became the first major inter-national guideline to write that measurement of apoB levels “is recommended” to help assess ASCVD risk and thus estimate the expected clinical benefit from lipid-lowering therapy.
In my practice, since 2019 I have utilized apo B levels rather than NMR-derived lipoprotein particle size (LDL-P) to measure the level of atherogenic particles in my patients at baseline and after initiating treatment. Apo B levels are inexpensive (typically 12-20$ at Quest or Labcorps or Boston Heart) and they are standardized and reliable whereas full NMR LDL particle size and number panels are expensive and lack similar standardization.
Here is my full presentation on lipid-lowering therapy to reduce ASCVD risk which goes on to discuss identification of those at high risk and management of higher-risk individuals with medical therapy.
Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiol. 2019;4(12):1287–1295. doi:10.1001/jamacardio.2019.3780
Ference BA, Kastelein JJP, Catapano AL. Lipids and Lipoproteins in 2020. JAMA. 2020;324(6):595–596. doi:10.1001/jama.2020.5685 (From which the lifecyle graphics were taken.)
16 thoughts on “What Really Initiates and Drives Atherosclerosis?”
I can’t help wondering if niacin has not been found to be effective because some people who think that they’re taking niacin are actually taking fake niacin. Flush free “niacin” is fake niacin. A niacin flush can be very uncomfortable if you start on high dose but it doesn’t last very long. I have not experienced a significant flush from taking timed release niacin. Also a severe flush can be avoided by starting on a low dose and then gradually increasing it.
The randomized trials that studied niacin were using real niacin with the flushing side effect.
I totally agree with your comments on handling the flush from niacin.
In the days when I was using it I utilized all those techniques but still had patients waking up in the middle of the night feeling like they were lying on a beach in St. John in the middle of the day without a palm tree around.
Really appreciate this article. Just found out that my ApoB is now 109 mg/dL (down from 125 mg/dL in December). Started Rosuvastatin in December. My GP considers my new level to be good enough but I’ve read on Peter Attia’s site that 60 mg/dL would be much better. So now the decision: do I push for more aggressive treatment?
I would say that the goal should be based on primary versus secondary prevention. If primary prevention then aggressiveness would be based on level of subclinical atherosclerosis
Dr. Pearson, thank you for this clarification. I must admit that I had to look up primary vs secondary prevention. I have a coronary-artery calcium score of 234 and family history of heart disease (father died of a heart attack at age 38), and I’m 67. In addition to the Rosuvastatin, I’m taking 81 mg of aspirin. I’m beginning to think that my GP is taking a hybrid primary/secondary prevention approach. If this is enough info for you to comment further, I’d be very interested in your thoughts. Thank you.
I would say your PCP is on the right track. When you have advanced subclinical atherosclerosis as demonstrated by your high CAC score it carries risk equivalent to a prior event (secondary prevention)
The goals should be more aggressive. Based on the small drop in your apo B I presume you are on a low dose of rosuvastatin or you have a high lipoprotein (a).
I discuss benefits of further lowering with patients versus risks and we come up with a goal that makes sense for them.
The most aggressive goal in this situation would be <60 for apo B. In primary prevention I recommend that goal for those with high lipoprotein (a) or with very advanced subclinical atherosis who wish to be very proactive.
Does coronary artery atherosclerosis normally parallel generalized atherosclerosis over the entire body or are they different phenomena?
Your lecture was very interesting and I thought you did a wonderful job in explaining the importance of moving beyond LDL-C and focusing more on APOB to better quantify burden to your students. This is an interesting time in that much of the data from trials of lipid lowering therapies utilizes the LDL-C metric for reference. However, moving forward, I hope more trials looking at lipid lowering therapies utilize the APOB metric to provide data that supports utilizing APOB testing and more widespread adoption of the biomarker in lipid panels.
Regarding the cause of atherosclerosis, I feel that another contributing factor is the circulating lifespan of APOB100. Since macrophages have low affinity scavenger receptors to lingering LDL particles and macrophages that get trapped in the sub endothelial space can be reservoirs for oxidized phospholipids (foam cells) it begs the question when will see a reliable assay to measure the longevity of this molecule. I have read OxLDL might be a potential measurement into this phenomenon but I’m not sure of its value, consistency or acceptance in the medical world. I wonder if diagnostics could accurately quantify the circulating longevity of these particles if a much stronger case could be made to insurance companies to cover PCKS9 therapies in that they have an impact (sometimes dramatic) on removal of APOB and therefore I would guess would reduce residency time in the bloodstream preventing less macrophage uptake.
PS Can you post more of your lectures?
OxLDL is likely going to be a better parameter to follow but we need more studies in this area.
I just gave a talk on the diagnosis of aortic stenosis which I’ll try to post.
That would be great and thank you. Should I check on vimeo or will there be a separate post on the TSC?
Do you lecture on TEE and TTE or just general echo for diagnosis? I know you an extensive b/g in that and I would be really interested in hearing your insights on that as well.
I am working on tracking down the videos of my talks. If I find them I would upload to vimeo then post on TSC about the same time.
So far, in my new position, I have only discussed TTE in the diagnosis of clinical conditions
What is the treatment if the patient can’t take statins?
This is a great article, very clear. Other than ApoB, can you please comment on other causal factors for Atherosclerosis/CVD?
Then, are Statins still the recommended treatment?
Yes. Statins are still first line therapy as they are very effective at lowering apo B.
Great summary! I have ordered my apo B test!