Aug 24

Beyond the Lipid Hypothesis: Plaque Development

Note from Dave–

Rarely have I been so impressed with the aptitude and intelligence of a researcher as I have with Siobhan. Her tenacity and resolve to absorb this subject is nothing short of jaw-dropping and I’m incredibly excited to have her fill in our deep dive on this crucial subject. Enjoy!


In the Beginning…

Even before starting the ketogenic diet in August of 2016, I already had a vague notion that the diet heart hypothesis did not have much weight to it: the hypothesis, that is now considered “common knowledge”, is that high cholesterol (LDL-c) causes heart disease. Always an avid reader, and a stubborn critic, I had a decent sense of “something’s not right” surrounding the supposed causes of heart disease. As a result, in 2015, when my doctor told me to take statins at the age of 19, due to my total cholesterol readings of over 300: I refused. I knew enough from my own, curiosity based, research that I did not want them because I was not convinced of the often touted benefits. The topic of heart health and high cholesterol was a sore one, given that my father had had a heart attack in his forties, leaving me with a sense of inevitability that it was in my genes and lurking around every corner.

I did not know much about the mechanisms regarding the development of heart disease and atherosclerosis, beyond the idea that heart disease was likely an inflammation problem. I found some hints in books such as The Case Against Sugar (Gary Taubes), and The Big Fat Surprise (Nina Teicholz), and knew the disease was at least correlated to insulin and sugar consumption. Watching some of Ivor Cummins videos on the topic gave me even more insights towards insulin being a correlative – perhaps even causative – factor, but not how or why this was so. I thought perhaps there was something to the “LDL sticking to the arterial wall and oxidizing” theory, that I had heard in the mainstream, but I began to doubt this as fact when I met Dave at Ketofest, and he asked a very pertinent question.

The Question 

“What if LDL is oxidized before it sticks to the arterial wall?” Dave suggested. He later followed up with the idea that perhaps plaque was a beneficial mechanism of the body that later becomes disordered or overwhelmed and develops into the unhealthy manifestation of plaque buildup. Perhaps too, these two aspects together – the oxidation of LDL and plaque development – work in tandem to form some type of specific, helpful, purpose. With little time at the Ketofest afterparty, and not much time for in-depth discussion, I was left with those two questions simmering at the back of my mind as I talked to him more over the evening.

Further conversations with Dave, which took place over the next few hours, presented me with the idea that the system of cholesterol and fat transportation – with the main characters of LDL, HDL, and chylomicrons – were far more complicated, intuitive, and interesting than I had ever considered before. After Dave’s presentation earlier that day, I became further intrigued by the topic, and found myself excited at the prospect of gaining a better understanding of this oft overlooked and denigrated system. Just like having an enthusiastic teacher in high school genuinely in love with the topic – the excitement for this student was contagious.

The Studying Begins in Earnest

The next day, based on Dave’s recommendation, I began reading Peter Attia’s “The Straight Dope on Cholesterol” series. Admittedly, after reading the first few parts, I knew I was in way over my head. The material was headache-inducing and too complicated for my novice barebones knowledge, but because of my stubborn and determined nature to learn, I set about learning the concepts and terminology to the best of my ability. I took in as much as I could and bided my time until I got home and had better access to information. As soon as I could I was in front of the computer, with a notepad and pen ready, reading through the first part of “The Straight Dope on Cholesterol” again, when I saw the recommendation to read “Therapeutic Lipidology” given by Attia if one wanted to become “an aspiring lipidologist” – I immediately found a copy, and began reading.

The first part of the book focused on basic makeup and functions of lipoproteins, which helped form the building blocks of understanding how they all worked together to form a coherent system. After reading through “Therapeutic Lipidology”, and moving on to “Clinical Lipidology”, I began to investigate the role of plaque formation in cardiovascular disease. I asked myself whether their formation was a mechanism that provides any benefit under normal conditions. I suspected that plaque was part of an inflammatory response, and indeed, not long after plaque was mentioned, so were macrophages and inflammation.

Macrophages – Traveling Doctors of the Immune System

Macrophages are the traveling doctors of the immune system, I soon discovered, roaming through the bloodstream, and tissues, until they find a site of infection or damage – ranging from a physical cut on your finger to a virus sequestered in the artery wall1. The macrophages then land on the site, and depending on the situation, have multiple tools at their disposal. They can increase production of various growth hormones to use for repair of damaged cells2, can induce phagocytosis to envelop and digest viruses and harmful bacteria3, or can initiate inflammation. This inflammation is actually a useful tool that can be used to kill bacteria, just like a fever but in a localized area. I found this relationship, between macrophages and inflammation, interesting as it appeared that the relationship was more complicated than it first appeared, even in the case of atherosclerosis.

For example, macrophages don’t only cause inflammation in the artery wall, contrary to my original belief, but come in different ‘types’ used in various circumstances throughout the course of the disease. M1 type macrophages, for example, are responsible for initiating and sustaining an inflammatory response, and are found in developing atherosclerosis. M2 macrophages, on the other hand, have properties that are primarily anti-inflammatory and associated with either resolution of an infection / injury4 or a chronic infection5. In receding atherosclerosis, M1 as well as M2 macrophages can be found inside the plaque, and an increase in both types of macrophage are present in vulnerable plaque as well. Thus, the presence of M2 type macrophages is not entirely straightforward, as it is not only associated with resolution of atherosclerosis but also worsening development6. Perhaps, then, what causes macrophage sites to appear in the first place will provide a hint as to how atherosclerosis develops.

In other words, if macrophages are causing an inflammatory response in the arteries, as is found in atherosclerosis, then what are macrophages creating inflammation in response to? Surely, such a specialized mechanism would not arbitrarily be called upon to invoke an inflammatory response unless needed. The response must inherently be responding to something disrupting the system. Indeed, upon studying further I found that monocytes, the precursor to macrophages, come upon modified LDL lodged in the arterial wall7, 8, and initiate inflammation. So perhaps there is some unintentional lodging of modified LDL in the arterial wall which kick-starts the whole process – however, I did not find any evidence to support the theory of “unintentional” lodging of modified LDL. In fact, it was quite the opposite.

Not So Unintentional

Consider, for example, Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) and Scavenger Receptor class A I (SR-AI), two of at least ten so-called ‘scavenger receptors’, some of which appear at the endothelial layer in the increased presence of modified LDL9, and are able to recognize harmful particles, including modified LDL10, and pathogens11. The role of scavenger receptors is to halt the progress of dangerous material through the bloodstream, and some of them are uniquely able to recognize modified LDL, but do not recognize/signal to unmodified, healthy LDL12, and as such only ‘see’ low density lipoproteins that are damaged or otherwise modified13. This receptor signals to this changed LDL to pull over out of the active bloodstream, park at the artery wall and stay there until a roaming monocyte comes across it. In other words, just like a police officer who pulls over a driver for having a flagged license plate, this system appears to be a form of ensuring that certain types of LDL are taken out of the system to be dealt with – a healthy immune response.

This caused me to believe that the hypothesis of LDL “crashing” into the artery wall, as is speculated in common discourse, was an inaccurate one, and in fact, LDL was intentionally taken out of circulation so that it could be passed off to roaming macrophages for clearance. Further, endothelial cells are not the only ones to utilize scavenger receptors in this modified LDL clearance pathway, either14, 15. Macrophages, likewise, once at the site where modified LDL has been ‘parked’ produce their own scavenger receptors which, again, specifically take in modified LDL and other debris such as pathogens16. Once these particles are taken in, macrophages continue encouraging inflammation17, 18, 19 – perhaps to neutralize damaging particles that have been ‘pulled over’ and contained.

Pattern of Development, and Potential Outcomes

The Macrophage

Contrary to my original inclinations, which was that macrophages drew in LDL at the beginning stages of atherosclerosis for repairing damaged cells, it appeared that once taken in via scavenger receptors, the materials of modified LDL et al. are contained in lipid pools20, 21, 22, thus forming foam cells. These lipid pools are later cleared through Reverse Cholesterol Transport (RCT) via HDL23, 24, which appears to not only be beneficial in regards to atherosclerotic development25, 26, but also may help prevent the development of a necrotic core inside the foam cell which contributes to vulnerable plaque formation27, 28 (I will expand more on this in upcoming parts of the series). The development of foam cells and plaque appeared to me to follow a pattern, and marks the beginning of the true derangement in the atherosclerotic process, in my view. The pattern, as I saw it, was as follows:

  1. A monocyte comes across a site of damage (such as modified LDL in the arterial wall).
  2. The monocyte lands on the site, forms into a macrophage and begins the inflammatory process.
  3. At the same time scavenger receptors form on the macrophage, pulling in more modified LDL and storing them in lipid pools, which create foam cells.
  4. Plaque forms in the arterial intima (the lining beneath the endothelial layer) with foam cells surrounding the artery, housing the modified LDL. It is important to note here that the foam cells and plaque do not encroach on the caliber of the artery at this stage. Everything is housed underneath the endothelial layer and the lipid pool underneath the surrounding plaque.29, 30
  5. HDL is called by the macrophage, which initiates Reverse Cholesterol Transport (RCT) for the clearance of cholesterol from the foam cells.
  6. Phagocytes (e.g. macrophages, etc) are used to contain apoptotic cells, or other debris, from the affected area and initiate a ‘controlled breakdown’ throughout the entire process.31

After this process there are two basic outcomes:

  1. The lipid pools housed in the foam cells eventually, over time, deplete. This leaves non-breaching stable plaque around the artery, characterized by a smaller lipid pool, and thick cap (plaque)32;
  2. The lipid pool becomes engorged, and develops a necrotic core composed of OxLDL, etc. If sufficiently exposed, macrophages may undergo programmed or accidental cell death33, which may result in weakening and destabilization of the plaque covering the foam cell site34. Finally, if the plaque is sufficiently weakened this chain of events can culminate in either a partial burst of the cap or a complete rupture (thrombosis) resulting in a cardiac event35. If the burst is not fatal, or in some cases ‘silent’ or asymptomatic, then the plaque can be repaired from the interior of the artery resulting in a patch. However, if the lipid pool fails to be cleared sufficiently, these silent ruptures will continue, over the course of decades, and the patches of the plaque will accumulate, one on top of the other, resulting in partial or complete blockage of the artery.36, 37

An Important Realization Leads to More Questions

I found that one of the things that stood out to me most after learning about these initial stages of atherosclerosis, and something that should be emphasized, is that non-modified LDL being drawn into macrophages via LDLr (the receptor for native/non-modified LDL) does not encourage foam cell formation38, nor do scavenger receptors recognize unmodified LDL as previously mentioned. Which means that normal, healthy LDL presence in macrophages does not contribute to foam cell formation. I repeat: normal, healthy, LDL presence in macrophage sites does not promote foam cell formation. I found this especially striking considering the current hypothesis that high LDL-p encourages mechanical crashes and build-up of lipids in the arteries, which then promotes plaque formation. However, it is only modified LDL, not healthy LDL, that encourages foam cell formation and plaque accumulation.

After realizing this and learning the mechanisms of how the plaque actually forms, I began to ask myself: if I am right about everything up to this point being normal, healthy mechanisms to clear out pathogens, endogenous or exogenous, from the blood – e.g. an immune response – what exactly is drawn in by scavenger receptors? What exactly is stored in foam cell lipid pools? Perhaps most importantly, what causes this derangement of a seemingly normal immune response in the first place? This is what I focused on the next phase of my journey to find out the mechanisms of atherosclerosis and the complex involvement of lipoproteins, which I will address in detail in the next post of Beyond the Lipid Hypothesis in Part 2: Inside the Lipid Pool.



1Koh, Timothy J., and Luisa Ann DiPietro. “Inflammation and Wound Healing: the Role of the Macrophage.” Expert Reviews in Molecular Medicine, vol. 13, 2011, doi:10.1017/S1462399411001943.

2Wynn, Thomas A., and Kevin M. Vannella. “Macrophages in Tissue Repair, Regeneration, and Fibrosis.” Immunity 44.3 (2016): 450–462. PMC. Web. 12 Aug. 2017.

3Weiss, Günter, and Ulrich E Schaible. “Macrophage Defense Mechanisms against Intracellular Bacteria.” Immunological Reviews 264.1 (2015): 182–203. PMC. Web. 21 Aug. 2017, doi:10.1111/imr.12266

4Bobryshev, Yuri V. et al. “Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis.” BioMed Research International 2016, Web. 12 Aug. 2017, doi:10.1155/2016/9582430

5Benoit, Marie, et al. “Macrophage Polarization in Bacterial Infections.” The Journal of Immunology, American Association of Immunologists, 15 Sept. 2008, doi:10.1097/QCO.0b013e328344b73e

6Shirai, Tsuyoshi et al. “Macrophages in Vascular Inflammation – From Atherosclerosis to Vasculitis.” Autoimmunity 48.3 (2015): 139–151. PMC. Web. 21 Aug. 2017, doi:10.3109/08916934.2015.1027815

7Shih, Peggy T., et al. “Minimally Modified Low-Density Lipoprotein Induces Monocyte Adhesion to Endothelial Connecting Segment-1 by Activating β1 Integrin.” Journal of Clinical Investigation, American Society for Clinical Investigation, 1 Mar. 1999, www.ncbi.nlm.nih.gov/pmc/articles/PMC479707/.

8Frostegard, J., et al. “Oxidized Low Density Lipoprotein Induces Differentiation and Adhesion of Human Monocytes and the Monocytic Cell Line U937.” Proceedings of the National Academy of Sciences, vol. 87, Jan. 1990, doi:10.1073/pnas.87.3.904.

9Pirillo, A, et al. “Upregulation of Lectin-like Oxidized Low Density Lipoprotein Receptor 1 (LOX-1) Expression in Human Endothelial Cells by Modified High Density Lipoproteins.” Biochemical and Biophysical Research Communications., U.S. National Library of Medicine, 16 Nov. 2012, doi:10.1016/j.bbrc.2012.10.020.

10Levitan, Irena, Suncica Volkov, and Papasani V. Subbaiah. “Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology.” Antioxidants & Redox Signaling 13.1 (2010): 39–75. PMC. Web. 12 Aug. 2017, doi:10.1089/ars.2009.2733

11Abdul Zani, Izma et al. “Scavenger Receptor Structure and Function in Health and Disease.” Ed. Alexander E. Kalyuzhny. Cells 4.2 (2015): 178–201. PMC. Web. 12 Aug. 2017, doi:10.3390/cells4020178

12Yoshimoto, R, et al. “The Discovery of LOX-1, Its Ligands and Clinical Significance.” U.S. National Library of Medicine, Oct. 2011, doi:10.1007/s10557-011-6324-6.

13Greaves, David R., and Siamon Gordon. “The Macrophage Scavenger Receptor at 30 Years of Age: Current Knowledge and Future Challenges.” Journal of Lipid Research 50.Suppl (2009): S282–S286. PMC. Web. 13 Aug. 2017, doi:10.1194/jlr.R800066-JLR200.

14Park, Young Mi. “CD36, a Scavenger Receptor Implicated in Atherosclerosis.” Experimental & Molecular Medicine 46.6 (2014): e99–. PMC. Web. 13 Aug. 2017, doi:10.1038/emm.2014.38.

15Chen, M, et al. “LOX-1, the Receptor for Oxidized Low-Density Lipoprotein Identified from Endothelial Cells: Implications in Endothelial Dysfunction and Atherosclerosis.” U.S. National Library of Medicine, July 2002, doi:10.1016/S0163-7258(02)00236-X.

16Areschoug, T, and S Gordon. “Scavenger Receptors: Role in Innate Immunity and Microbial Pathogenesis.” Cellular Microbiology., U.S. National Library of Medicine, Aug. 2009, DOI:10.1111/j.1462-5822.2009.01326.x.

17Chen, Chong, and Damir B. Khismatullin. “Oxidized Low-Density Lipoprotein Contributes to Atherogenesis via Co-Activation of Macrophages and Mast Cells.” Ed. Omolola Eniola-Adefeso. PLoS ONE 10.3 (2015): e0123088. PMC. Web. 13 Aug. 2017, doi:10.1371/journal.pone.0123088.

18Hayashi, Chie et al. “Protective Role for TLR4 Signaling in Atherosclerosis Progression as Revealed by Infection with a Common Oral Pathogen.” The Journal of Immunology Author Choice 189.7 (2012): 3681–3688. PMC. Web. 13 Aug. 2017.

19Leitinger, Norbert, and Ira G. Schulman. “Phenotypic Polarization of Macrophages in Atherosclerosis.” Arteriosclerosis, thrombosis, and vascular biology 33.6 (2013): 1120–1126. PMC. Web. 13 Aug. 2017.

20Mori, M., H. Itabe, Y. Higashi, Y. Fujimoto, M. Shiomi, M. Yoshizumi, Y. Ouchi, and T. Takano. “Foam cell formation containing lipid droplets enriched with free cholesterol by hyperlipidemic serum.” J. Lipid Res. 2001. 42: 1771–1781.

21Chen, Shuang et al. “IL-17A Is Proatherogenic in High-Fat Diet-Induced and Chlamydia Pneumoniae-Infection Accelerated Atherosclerosis in Mice.” Journal of immunology (Baltimore, Md. : 1950) 185.9 (2010): 5619–5627. PMC. Web. 23 Aug. 2017, doi:10.4049/jimmunol.1001879

22Rosenfeld, M E et al. “Macrophage-Derived Foam Cells Freshly Isolated from Rabbit Atherosclerotic Lesions Degrade Modified Lipoproteins, Promote Oxidation of Low-Density Lipoproteins, and Contain Oxidation-Specific Lipid-Protein Adducts.” Journal of Clinical Investigation 87.1 (1991): 90–99. Print.

23Ohashi, R, et al. “Reverse Cholesterol Transport and Cholesterol Efflux in Atherosclerosis.” QJM : Monthly Journal of the Association of Physicians., U.S. National Library of Medicine, Dec. 2005, doi:10.1093/qjmed/hci136.

24Tall, A R. “Cholesterol Efflux Pathways and Other Potential Mechanisms Involved in the Athero-Protective Effect of High Density Lipoproteins.” Journal of Internal Medicine., U.S. National Library of Medicine, Mar. 2008, doi:10.1111/j.1365-2796.2007.01898.x.

25Rothblat, George H., and Michael C. Phillips. “High-Density Lipoprotein Heterogeneity and Function in Reverse Cholesterol Transport.” Current opinion in lipidology 21.3 (2010): 229–238. Print.

26Rader, Daniel J. et al. “The Role of Reverse Cholesterol Transport in Animals and Humans and Relationship to Atherosclerosis.” Journal of Lipid Research 50.Suppl (2009): S189–S194. PMC. Web. 23 Aug. 2017.

27Ghosh, Shobha. “Macrophage Cholesterol Homeostasis and Metabolic Diseases: Critical Role of Cholesteryl Ester Mobilization.” Expert review of cardiovascular therapy 9.3 (2011): 329–340. PMC. Web. 16 Aug. 2017.

28Tabas, Ira. “Consequences of Cellular Cholesterol Accumulation: Basic Concepts and Physiological Implications.” The Journal of Clinical Investigation 110.7 (2002): 905–911. PMC. Web. 23 Aug. 2017.

29Schoenhagen, Paul, et al. “Arterial Remodeling and Coronary Artery Disease: the Concept of “Dilated” versus “Obstructive” Coronary Atherosclerosis.” Journal of the American College of Cardiology, Aug. 2001, doi:10.1016/S0735-1097(01)01374-2

30Glagov, S, et al. “Compensatory Enlargement of Human Atherosclerotic Coronary Arteries.” The New England Journal of Medicine., U.S. National Library of Medicine, 28 May 1987, doi:10.1056/NEJM198705283162204.

31Schrijvers, D M, et al. “Phagocytosis in Atherosclerosis: Molecular Mechanisms and Implications for Plaque Progression and Stability.” U.S. National Library of Medicine, 1 Feb. 2007, doi:10.1016/j.cardiores.2006.09.005.

32Braganza, D, and M Bennett. “New Insights into Atherosclerotic Plaque Rupture.” Postgraduate Medical Journal 77.904 (2001): 94–98. PMC. Web. 17 Aug. 2017.

33Tabas, Ira. “Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis.” Arteriosclerosis, Thrombosis, and Vascular Biology 25.11 (2005): 2255-2264. Web. 16 Aug. 2017.

34Tabas, Ira. “Macrophage Apoptosis in Atherosclerosis: Consequences on Plaque Progression and the Role of Endoplasmic Reticulum Stress.” Antioxidants & Redox Signaling 11.9 (2009): 2333–2339. PMC. Web. 17 Aug. 2017.

35Lafont, Antoine. “Basic Aspects of Plaque Vulnerability.” Heart 89.10 (2003): 1262–1267. Print.

36Burke, Allen P., et al. “Healed Plaque Ruptures and Sudden Coronary Death: Evidence That Subclinical Rupture Has a Role in Plaque Progression.” American Heart Association, Inc., 20 Feb. 2001, doi:10.1161/01.CIR.103.7.934.

37Mann, J, and M Davies. “Mechanisms of Progression in Native Coronary Artery Disease: Role of Healed Plaque Disruption.” Heart 82.3 (1999): 265–268. Print.

38Linton, MacRae F., et al. “A Direct Role for the Macrophage Low Density Lipoprotein Receptor in Atherosclerotic Lesion Formation” Journal of Biological Chemistry, 2 July 1999, doi:10.1074/jbc.274.27.19204

Leave a Reply

61 Comments on "Beyond the Lipid Hypothesis: Plaque Development"

newest oldest most voted
Notify of

Awesome post Siobhan, looking forward to more in the future!


Simply awesome!


Awesome! Maybe I’ll finally be able to understand cholesterol now that it’s presented in a way that makes more sense than seemingly random designations of “good ” and “bad” particles. Looking forward to the sequel!


Hi Siobhan.

Wierd coincidence I put up a long post on Daves site today on the very same subject, then went back to FB and discovered your post immediately.

You are right about LDL.

In your quest to find out about atherosclerosis, if you haven’t already, check out Stehbens. He has it nailed.


I’ve been toying with a fun analogy for some of the competing theories of disease for atherosclerosis. Using the LDL lipoprotiens as boats analogy, here they are: 1. Boats frequently have accidents and crash against the rocks. Faster currents (BP) and more traffic (LDL-p) cause more plaque. (conventional wisdom) 1a. Certain types of boats are even more likely to wreck and clutter their cargo on the beach (sdLDL) 2. Boats may be damaged by passive collisions with mines/debris. Damaged boats wreck against the rocks. More mines (ROS) or boats (LDL-p) mean more collisions and more plaque. 3. Boats actively seek… Read more »
I’d like to offer a different analogy if we’re expanding on the boats. Instead, we have “multi-use” boats. They carry food, primarily, but they likewise double as the Coast Guard. For the most part, they drop off their food and head home (the liver), but a certain contingent remains on “patrol” (Final LDL stage VLDL-originating). They either look for ports that need extra help (endocytosis) or they look for “trouble” such as pathogens to bind to. In the latter case — like a cop pulling over a criminal — they want to make their way to the next available jail… Read more »
So, e.g. with mechanical damage (shear stress) we do not see plaque development occur (typically). No sure i would agree with this given the architecture of coronary arteries with high level of disease in the LAD, for ex. Also, examination of carotid artery dissections show high degree of non LDL, but of other sterols. This is a complex disease with many variables likely contributing to it and high LDLP is probably a contributor. With an aging population and the incidence of CVD being high, plague regression or at least stabilization also needs to be strategized beyond just a statin. Interesting… Read more »

I think sk is referring to potentially higher levels of atherosclerosis where sheer stress is greater, such as at branch points in the arteries.

So sk, here’s the catch — things like ROS are playing by the same rules of physics as the LDLp. Thus, I’d fully expect these to likewise have more contact at these areas of higher sheer stress exposure. So how can be sure LDLp isn’t actually the response to a problem rather than the problem itself?

Very impressive! I have not done as a deep dive as you. Perhaps in your intellectual travels you will come across answers to some of my questions. Good luck. Why does the lipid build up in the first place? Could this create more systemic problems in smaller arteries or capillaries across many organ systems? Does LDL deposit and precipitate the formation of plaques in tissue other than artery walls? Have you seen (Subbotin Theoretical Biology and Medical Modelling 2012, 9:11 (http://www.tbiomed.com/content/9/1/11). This paper contains micrographs of the buildup of lipid in the artery wall from the middle of the artery… Read more »
Steven Horvitz
Doubt there are crashes. If so, people who exercise a lot and have higher heart rates would cause more turbulence and have higher rates of vascular disease. We know this is not the case. I tend to go with the BB theory of disease. Balance and Buffer. Most of our body systems do best in a state of balance. All of our different cells must function in a way to keep our body healthy. THRhete must be many great buffers to keep this balance. Ex: when testing lipids, I no longer look at any one value independently. They all just… Read more »
Siobhan, You are too humble in your estimation of your abilities. Thank you for creating a post that I could understand about such an incredibly multifaceted system. I’m a really a noob, so forgive me for the simple question: When looking at an in-depth cholesterol panel (I think my cardiologist ordered a “VAP lipid panel”), is there a part of that test that actually measures the amount of damaged LDLp in my system? I saw so many different things measured, but am not certain if one of them actually measured the damaged lipoprotein that quite possibly causes atherosclerosis (if I… Read more »
Juha Kankaanpaa

Great article Siobhan! Something I will read a second (and third) time this evening. Looking forward to the next posts. Thank you.

I recently found this site and very much looking forward to the next one on what modifies LDL. One thing I am wondering about in the context of your article and this entire site, is that it has been stated elsewhere that in populations eating traditional diets (and generally living more traditional lifestyles) that cholesterol does not generally get above 260 for women and 220 for men. Have you looked at any of this information? Is it accurate? The reason I am asking is that if we see a cholesterol of 300 or more, is that showing a disordered system?… Read more »
Gregg Mack

Wow, great article! It took me a long time to read through it, and I had to back up several times to make sure that I comprehended exactly what you were saying, but when I got to the end, and read this phrase, it all seemed to come together: “However, it is only modified LDL, not healthy LDL, that encourages foam cell formation and plaque accumulation.” Thank you for putting this “out there”, and I am truly looking forward to the future articles that you write in this series.

Hi Dave. The problem with a lipid centric model whether of native or damaged LDL is that it ignores most of the aspects of the disease. Lipid is only one prominent feature of atherosclerosis in its advanced stages and the many other features have been virtually ignored ie intimal thickening which precedes lipid deposition, ectasia, tortuosity, calcification, bizarre-shaped smooth muscle cells, abnormal basement membranes of both endothelium and smooth muscle with patchy separation from the plasma membranes, abundant matrix vesicles derived primarily from viable or degenerative muscle cells, abnormal collagen fibres at times resembling those in hereditary connective tissue disorders… Read more »
Hi Siobhan, First, congratulations on all your hard work! I think it is great that you are looking beyond the lipid hypothesis. However, I think you may need to look even further beyond the lipid hypothesis for the following reasons: 1. The intimal layer (endothelium) is much thicker in normal healthy people than typically portrayed. It is something like 20-30 cell layers thick in contrast to only 1 layer. Additionally, lipid accumulation only starts in this layer when the vaso vasorum starts growing into it, and lipids accumulate from that side, not the arterial side. Furthermore, these deposits do not… Read more »
Thank you for such a thorough and thoughtful reply. 1. “So I suppose the question is how do they get there and do they do any damage per se? … would this lipid depositing cause any damage/mortality risk on its own? Or is it more of an initial marker to the over all systemic displacement happening via IR? Do we know? Are there signs of damage?” –I don’t think we know for sure, but I would guess that the initial infiltration does not cause permanent damage if the causative factor is stopped. At the initial point, I would say that… Read more »
Thank you Dave and Siobhan for your fascinating research and experimentation! I am very interested in these discoveries, because I have been having lab results that don’t make sense to me. I have abnormally high HS-CRP, total LDL-P and small LDL-P numbers (I had multiple NMRs, CRP, and other blood tests taken just to confirm), and high trigs too. However, all my other numbers are great (A1C < 5, fasting insulin < 4, CAC score = 0, all other metabolic blood readings normal). I have been on keto for a year and a half now, and before that paleo for… Read more »


“This is not doing anything weird, just eating a normal keto diet of eggs, fatty meats, some cheese, butter and heavy cream in the coffee…”

I’m nowhere near expert on the subject, but I can recall that the book “The Great Cholesterol Myth” mentions that saturated fats can be mildly inflammatory. Try switching to mainly MUFAs for a while and check CRP?

Hi Siobhan, Sorry I should have provided some more details. I have never smoked, live out in the country where the air is clean, and avoid all seed & vegetable oils. I would have never known about my high CRP if my first NMR hadn’t scared me with the high LDL-p – I had both the second NMR and the CRP in response! I feel great. Here are the trig and HDL readings on the 3 NMRs: 203/41, 182/40 and 122/44. I was also very surprised at the HDL – I would have expected it to be higher given the… Read more »
Abhishek Anand

A CAC score of 0 doesn’t mean you don’t have dangerous plaque in your arteries, especially if you are young. Young people often have non-calcified plaque:

As an example, I am ~29 years old and had a CAC score of 0. Yet, I had a 99% blockage in my LAD. My LDL-P was slightly above 2090 nmol/L.
For a complete peace of mind, get a CT angiogram. This can detect even non-calcified plaque.

The Subbotin view is interesting but still lipid centric, although less so than mainstream views. What he is saying, I think, is that lipid deposition occurs because of neovascularization of a previously avascular compartment and that lipoprotein binding is not normally a function of the compartment so the components of it have not been selected to NOT bind lipoproteins as almost all other body compartments have. His summary is: “(1) A hypotheses underlining our efforts to approach coronary atherosclerosis must be consistent with undisputed facts concerning the subject. Furthermore, a hypothesis should incorporate logical evaluation, and not contradict established and… Read more »

Tim, I agree Subbotin’s theory is incomplete. There are, as you said, too many other factors involved in atherosclerosis. I think it is simply a good reference point to try to find the underlying connections of all the factors.

Malcolm Kendrick

I was pointed at your page by a reader of my blog. Good to see you are not accepting the party line and thinking about this for yourself. I would start by discarding the entire LDL/cholesterol hypothesis. That is the Geocentric view of CVD, whereby all must orbit round LDL.

While oxLDL triggers the receptors of macrophages – increasing the formation and size of foam cells – I think it is likely that the macrophages are there as the result of damage – not to cause it. So should be be focused on preventing a scab from forming or preventing the cut? The real question is what causes the initial thickening of the inner intima where the disease starts? Insulin is a prime suspect. Insulin levels in the obese remain about 10 times those of a normal person even under complete starvation. I have a hunch that it takes insulin… Read more »

[…] very own Siobhan Huggins was on 2 Keto Dudes for a really fantastic talk. They got into Full Geek with a lot of in-depth […]

David Casebeer

What is a good way to keep in contact with you? Sounds like you are starting out like I did. My TC was around 260 by the time I was 21. I am making understanding lipids my focus right now so I would like to share info with you as we both research this field. Hopefully you can avoid the path I have been on for the last 24 years as I watched my lipids skyrocket unless treated with statins. I am @awokelife on twitter and Instagram if you use either of those.


[…] part one of Beyond the Lipid Hypothesis, I covered the general process of plaque development, from the appearance of endogenous and […]

Roger Smit
i think this may have a clue ,,,,,when looking at the comparison to all the oils , that were already approved and then the comments about the ones the showed an improved result of arterial lesion when blended with the other oils ? Alarming that the fda actually is on record here stating that saturated fat shown to reduce myocardial lipidosis in laboratory animal tests back in 1985 publicly they promoted the opposite of the these stated observations,,,,,,,look for where lard (extraction technique?) and another place,,, oliveoil (extraction technique?) were blended with seed ,bean, nut, or grain oils ( commercial… Read more »
Roger Smit

Btw LEAR = alias for canola


[…] Beyond the Lipid Hypothesis – Plaque Development […]