The Skeptical Cardiologist

What Really Initiates and Drives Atherosclerosis?

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.

Antiatherosclerotically Yours,



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.)

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