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: LDL Modification.



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

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

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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 out and contact mines to make the waterways safe. Damaged boats land on the beach to safely finish cleanup of the mines. More mines (ROS) mean more plaque. More damaged LDL-p is actually healthier than damage in other places.
  • 4. Boats respond to distress signals from coastal villagers, landing to offload their cargo, which is used to repair the village. More distressed villages (inflammation in artery walls, ROS) mean more plaque. Again, LDL-p is helpful and necessary.



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 to house it.

Main takeaway: Maybe LDL isn’t randomly crashing into ROS unexpectedly. Maybe it’s completely by design. Free radicals are, after all, one of the worst things you can have bouncing around your bloodstream.


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 and excellent thoughts in your post !


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 wall toward the endothelium and the subsequent infiltration of macrophages from the endothelium layer inward.

P.S. Another thing I have been thinking about, but not sure how it fits in. The linear velocity of blood flow in arteries is about 100 cm/sec compared to capillaries (<0.1 cm/sec) (http://physiologyplus.com/total-cross-sectional-area-of-different-vascular-groups-and-its-implication-on-the-velocity-of-blood-flow/), but the velocity of a liquid in a pipe near the inside surface would be expected to be much lower (theoretically zero for the cross-sectional velocity profile). If so particles are probably moving too slow to crash, but possibly slow enough to infiltrate.

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 be looked at as a system. Ratios are an important number for balance.
Throw the vascular system out of balance by overwhelming the buffering systems and disease occurs.

So I hope in your next segment you can expand on how a diseased vascular system is out of balanced. .



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 understand your post correctly). Is there a test that measures that?

Thank you for your effort!

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? Or likely to be showing one?

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 associated with fragility, loss and destruction of elastica, medial thinning and the complications.

Atherosclerosis is a disease where virtually everything within the vessel wall is dystrophic and bizzarre. Lipid deposition is a factor to be sure but only one among hundreds. Historically lipid centric theories have been pushed by vested interests to the detriment of a more useful approach to the disease.


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 coincide with macrophage infiltration http://www.sciencedirect.com/science/article/pii/S1359644616301921
2. Progression of coronary artery calcium is only associated with diabetes, even including blood sugars below the diabetic threshold https://www.hindawi.com/journals/scientifica/2012/812046/
3. Other factors also interact with receptors. For example, here are two studies showing insulin levels affect the LDL receptor of macrophages

Anyway, that’s just my critique. Keep up the good work!


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 it is more of a marker of systemic issues and then later progresses to actual damage. I don’t think there are signs of damage at this point, but I am not certain.

“why do lipids accumulate instead of getting used normally? If they weren’t able to be used properly for some reason to do with the abnormal structure/situation, I would expect to see cell death if the cells there were starving/couldn’t repair themselves – yet I don’t see this mentioned. Any ideas?”
–I think that is an excellent point and I am not certain of the answer. I would hypothesize that the lipids accumulate because the cells either do not need them or are unable to use them. For example, maybe the cells are only mildly deprived so they only need oxygen and the lipids are just accidentally there. I think the hypothesis put forward in the article is that the extracellular matrix in that area is “extra sticky” to cholesterol.

“so is this neovascularization contributing to the disease that results in mortality or is it an early marker for it?”
–I think both

“If it is contributing or I have gotten something wrong I can make a separate post to revise where the “starting point” is, or revise what I’ve gotten wrong/add a note but if it is a marker and doesn’t contribute directly it will likely go into a larger post of the systemic disruption that is the true root cause that this sort of leads up to (not a coincidence that the different types of modified LDL tend to have things in common)” … “I am focusing on mechanisms that tie in directly to development of heart disease as we see it (e.g. leading to plaque rupture or blockage) – but this will not be the end of my deep diving and other topics will come up later as well. I will look more into it and dive as deep as I possibly can to understand it better either way, it is more a question of whether I need to include it in the series (that deals with development of foam cells, plaque, etc) because I got something wrong here or whether it will be a separate post later.”
–I think they may simply be different stages or compounding factors of the same disease process. For example, it may start with vaso vasorum neovascularization but when the macrophages attach from the arterial side they may interact with oxidized LDL to cause foam cells and plaque rupture. This area is largely unexplored in the literature as far as I am aware because the majority of studies are looking at the late stages when there are already foam cells or plaque rupture.

2. I meant the largest correlative factor as you said. The interesting part I thought about it is that although other factors may be associated with incidence, they are not associated with progression.

3. No problem! Insulin (with a properly functioning receptor) is also needed for the LDL receptor of other cells. It also decreases LDL receptor mRNA production and decreases PCSK9 as well as increases ApoB secretion. These may be unrelated to plaque development, but they do emphasize that there are many complex, systemic interactions.

I’m just trying to chime in with the knowledge that I have, not say whether you are right or wrong. I won’t claim to know the cause of CVD. I don’t know if anyone truly knows. If I had to take a guess, I would say that upregulation of the MAPK pathway (via hyperinsulinemia, shear stress, dysfunctional adiipocyte signaling, etc) starts the cellular growth and neovascularization. But it could easily also be due to hypoxia from downregulated PI3K pathway or mitochondrial damage. Or some combination of these or something else entirely.

Let me know how your continued investigation goes!


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 maybe 2 years. I feel great, work out on a regular basis with both weights and hiking in strenuous terrain. I have never been more than a few pounds overweight my entire life, and at a perfect weight now.

I only found out my abnormally high readings when I got a NMR, inspired by Dave's experimentation. And was I in for a shock! The first was LDL-P = 1627, the second (a couple days later to confirm) was LDL-P = 1730, and the third (last week, after a vacation) was LDL-P = 1737. My HS-CRP numbers were 6.95 (taken with the 2nd NMR), and 3.48 (taken with the NMR last week).

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. Veggies limited to cruciferous and leafy greens.

In the middle of it all, I went in for a CAC scan after seeing the first numbers, along with a full metabolic panel. My CAC score is zero and everything on the metabolic panel was fine. My doctor is at a loss, and says there is nothing wrong with me, not to worry about it!

A genetic test on 23 and Me revealed that I do not have familial hypercholesterolemia.

These readings seem to support the theory that the high LDL particle counts and HS-CRP numbers are coming from something else, not anything related to keto or atheroschlerosis. Any ideas?



“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 animal fats I eat. I can only speculate why the last test saw a significant drop. Before my vacation I was doing bulletproof coffee every morning with 2 tbsp of C8 MCT, butter and heavy cream. During the vacation (and as an experiment to see if it would help my numbers) I stopped the bulletproof and went to only cream or half and half (whatever was available). I also did more intermittent fasting (only 1 meal a day sometimes). The few days before the last test I ate normally (2 meals a day). But interestingly, only the trigs came down, the LDL-P stayed just as high.

Here is another thought on the hyper responder suggestion – although I mentioned that I don’t have familial hypercholesterolemia, after I posted yesterday I went back and checked my APOE genes in my 23andMe data. I found out that I am a heterozygous APOE2 carrier (I actually have APOE2/3). APOE2 is associated with type III hyperlipoproteinemia, but as far as I can tell from the medical literature, only in APOE2 homozygotes (with 2 copies of the APOE2).

Do we know of any other genes that may impact hyper responder status besides APOE?

I think your research into whether LDL-p is implicated in causing atheroschlerosis is really valuable. I know I have been confused because you have some like Peter Attia coming out and saying yes, LDL-p causes atheroschlerosis, while you have others like Petro Dobromylskyj of HyperLipid saying LDL-p doesn’t matter. In my case, my CAC score is zero!

The other thing is that I still am suspicious that the high HS-CRP and high LDL-p are somehow related…

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.


Does it begin in childhood? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812791/ And my CTA didn’t reveal my disease, I didn’t get a diagnosis until I after I was symptomatic and had a cath. Consider EECP for angiogenesis, it’s benign, no one seems to be talking it up (except me http://www.whatnobodytoldme.com, but it’s really helpful to most.


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 proven concepts in biology and medicine without well-grounded reasons.

(2) Atherosclerosis occurs in arteries with normal DIT, while sparing the rest of arterial bed. However, while normal DIT exists in numerous arteries [120,194], some of these are never affected by atherosclerosis; coronary arteries are almost always the target. On logical grounds, an arterial disease that never affects some arteries but usually affects certain others is not systemic.

(3) Coronary atherosclerosis is not an inflammatory disease, as multiple clinical trials demonstrate no correlation between anti-inflammatory therapies and risk of disease.

(4) High LDL levels are not a fundamental cause of coronary atherosclerosis, as lowering such levels protects only 30-40% of those at risk. Furthermore, humans and animals with normal LDL levels can suffer from coronary atherosclerosis.

(5) Neovascularization of the normally avascular DIT is the obligatory condition for coronary atherosclerosis development. This neovascularization originates from adventitial vasa vasorum and vascularizes the outer part of the coronary DIT, where LDL deposition initially occurs.

(6) It is suggested that excessive cell replication in DIT is a cause of DIT enlargement. Participation of enhanced matrix deposition is also plausible. An increase in DIT dimension impairs nutrient diffusion from the coronary lumen, causing ischemia of cells in the outer part of coronary DIT.

(7) Ischemia of the outer DIT induces angiogenesis and neovascularization from adventitial vasa vasorum. The newly formed vascular bed terminates in the outer part of the coronary DIT, above the internal elastic membrane, and consists of permeable vasculature.

(8) The outer part of the coronary DIT is rich in proteoglycan biglycan, which has a high binding capacity for LDL-C. While in avascular DIT, biglycan has very limited access to LDL-C due to diffusion distance and LDL-C properties; after neovascularization of the outer DIT, proteoglycan biglycan acquires access to LDL-C particles, and extracts and retains them.

(9) Initial lipoprotein influx and deposition occurs from the neovasculature originating from adventitial vasa vasorum – and not from the arterial lumen.

(10) Although lipoprotein deposition in the outer part of the coronary DIT is the earliest pathological manifestation of coronary atherosclerosis, intimal neovascularization from adventitial vasa vasorum must precede it.

Therefore, in the coronary artery tunica intima, a previously avascular tissue compartment becomes vascularized. All other tissue compartments are developed (both phylogenetically and ontogenetically) with constant exposure to capillary bed and blood, therefore their tissue components were selected not to bind LDL. This is why atherosclerosis is mostly limited to the coronary arteries. To my knowledge the only other example – the avascular cornea – shows the same lipid deposition after neovascularization.”


So atherosclerosis develops (or at least the lipid aspect) because the normally avascular tunica intima receives blood and LDL-C via microvascularization, due to hypoxia, in an enlarged wall that cannot receive nutrients by diffusion anymore. This diffusion did not previously supply lipoproteins. The LDL-C becomes bound because the biglycan and possibly lumican tissues are NOT selected not to bind LDL whereas they are in other body compartments that habitually receive blood and plasma constituents. The only other place this happens is the avascular cornea.

As a theory on lipid deposition this makes some sense but as a view on atherosclerosis I think less so.

How are the other morphological features of atherosclerosis explained (as per a previous post):
For instance calcium deposition.
The preference for larger vessels, areas of disturbed flow particularly branches, bifurcations, the eccentric selection of vascular beds.
The increased danger of rapid re-stenosis from implanted stents and grafts.
The strong relationship to hypertension.
The dystrophic presentation of smooth muscle.
The abundance of matrix vesicles.
The abnormal and dystrophic basement membranes and their separation from smooth muscle cells and endothelium.
The dystrophic collagen, particularly the deranged elastin.
The vascular fragility with intimal tears.
Why does hypertriglyceridemia with small/dense LDL, low HDL and higher TG still make a difference if lipoproteins are freely available to the lipoprotein binding agents in the neovascularized areas.

Most of these are still far better explained as hemodynamic pressure effects, or these combined with an acquired or predisposed lack of structural integrity.

The localization and development of intimal thickening that precede lipid accumulation may now be explained by the natural and age related vascular remodelling in response to changed hemodynamic stress throughout life, and the localization of atherosclerosis to the arteries because they are one of the very few avascular areas of the body. This is important and an improvement over mainstream lipoprotein migration from the lumen.

It makes sense in this scenarion that lowering cholesterol levels would make the problem slightly better, but high LDL remains as a confounding, not the primary, factor.


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 and some co-factors.

There is a false narrative that insulin just is around to regulate blood glucose – while true – it is false in it misses the long list of other effects. Insulin is a growth factor – and people with super high insulin via genetic disorders have supper high heart disease.

The other bit is the cortisol chain – stress response. I’ve wondered if some product of the stress response is ultimately is the co-factor combined with insulin that causes the over thickening that actually causes the disease – and all the LDL – Crp – long list of markers – are an effect of the disease not the cause. That they have the arrow of causation backwards is hinted at the fact that among the long list of drugs that lower LDL only Statins do any good ( NNT of 84 over 5 years – nothing to brag about). If LDL was causative – it would seem that lowering it with the other drugs would reduce mortality – but that is not the case.


[…] 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 extracted ?) and produced less severe lesions and fewer in number …… All this is in front of their noses and front pages are reporting an alarming rise in heart disease ? ? Saturated fat with less damage ? even when it was hydrogenated soybean to get it saturated than the PUFA’s “my presumtion” extracted with “commercial hexane” how many contaminates are in this unpurified form ? Does anybody know ? Are they unsaponifiable ? Does the petroleum industry even know or care or required to analyze ? oxidized LDL ? Final stage in all these oils ? Deodorization ? involves ? using various peroxides ? what happens when a lipophilic alkane w/contaminates holds hands with a peroxyl ? im No chemical engineer but , a small steady supply ingested regularly that has potential to stick around awhile seem ill advised from my “uneducated” perspective …. but they DID know some thing was a miss and did not blow the whistle ,,,,indeed unblew the whistle and gave the green light ……look for this title FDA ..pdf
> 95s-0316-rpt0354-056-Ref-F-FR-Rules-Regualtions-1985-vol273.pdf

Roger Smit

Btw LEAR = alias for canola


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


Siobhan…a little over my head too, but I’m still with you. Keep up the fight to figure it out.
Thank you.


[…] the two previous parts of this series I covered what I had learned about how foam cell and plaque formation occur, and the process and circumstances of LDL modification. Throughout learning and writing about those […]


Have you read Malcolm Kendrick’s theory on what causes cardiovascular disease? It makes a lot of sense to me.


Have you read Malcolm Kendrick’s theory on CVD?


So neither LDL-c nor LDL-p are a problem unless they get modified?

David Porter


Samuel Klein

I started Keto on 4/8/18 Lost 32LB (from 198 to 166) lost 5.5 inches (39 to 33.5), had a “CARDIO IQ ADVANCED LIPID PANEL” test on 4/10 and then again last week 8/19.
wanna share the results and listen to some advice (I am the “portable lab” type of person, where i know exactly what and how much i eat, an i never cheat…):
TC 291/351
HDL 51/55
LDL-Direct 214/293
HDL Large Particles 3950/5742
LDL Small Particles 437/334
Ldl pattern B/A
Lipo(a) 28/24
Apob 160/176
Trigs 146/199 (due to alcohol consumption to assist in sleeping while on keto…)
A1c 5.2/4.9