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.
“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
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:
- A monocyte comes across a site of damage (such as modified LDL in the arterial wall).
- The monocyte lands on the site, forms into a macrophage and begins the inflammatory process.
- 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.
- 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
- HDL is called by the macrophage, which initiates Reverse Cholesterol Transport (RCT) for the clearance of cholesterol from the foam cells.
- 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:
- 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;
- 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
Awesome post Siobhan, looking forward to more in the future!
Thank you for the support! 🙂
“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;”
It would seam with a healthy diet ( and no seed oils based on what Ivor Cummins is saying), we could get to this endpoint based on what I have seen with the immune system.
Thank you! I am glad you like it. This is only just the beginning, for sure!
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!
What I have quickly figured out is there is no such thing as “bad” cholesterol (damaged, yes; ‘bad’, no)- all of the lipoproteins wear many different hats, and complete many different (important, necessary) functions. Yes these can manifest into detrimental effects, but so can a fever (another tool used by the immune system/body) if the system is overwhelmed! Dave has demonstrated the primary function of LDL – energy transport. But there are many others that should be touched upon to ensure we fully understand the system before trying to mess with it, or label LDL/etc as ‘risk factors’ (instead of ‘markers’, for example) – in my opinion. 🙂
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 will look into him, thank you! Always interesting to see what view others take on the subject, many angles to view the topic from!
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:
1a. Certain types of boats are even more likely to wreck and clutter their cargo on the beach (sdLDL)
From what I see it is a combination of 2 and 3 with the caveat that more LDL-p does not result in more plaque (necessarily) as you need something to damage the boat in the first place. E.g. ROS, pathogens, glycation, oxidation, etc. You can have as many boats as you want but if they can sail freely with no obstruction there is no issue. Another I would add is boats that have been in commission too long (apoptotic). This can happen with insulin resistance from what I see because they can’t drop off their passengers (or it takes longer to do so because they can’t drop off as many at each stop) due to overly full harbors… and thus they stay out and about too long and due to natural wear and tear get pulled over when they’re about to fully break down, as wreckage in the waters is dangerous for a whole host of reasons.
I don’t think 4 applies very well because “lipid build up” is exclusively from modified LDL (and other particles). E.g. the “repair boats” are different from the “quarantined boats”. So, e.g. with mechanical damage (shear stress) we do not see plaque development occur (typically). The inflammation is a reaction to the incoming modified LDL, as an immune response to help deal with the breakdown of the problematic particles (and other reasons too, possibly to sterilize the area and make sure the vulnerable area can’t get infected – like putting antiseptic on a cut). This is all just from what I’ve seen so far though so if you know of anything that contradicts this let me know 🙂
Additionally the receptors for repair boats (LDLr) is highly regulated, compared to Scavenger Receptors which are not downregulated (want to quarantine everything dangerous as the highest priority).
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 !
Could you expand on the LAD part a bit? Are you saying that a high trafficked artery has higher rates of disease? Just a bit of clarification before I reply further 🙂
If that is what you are referring to then could it not just be that there are higher rates of disease because more of the flagged material traffic through that area, or is there further evidence of something else going on? If so definitely let me know.
Also RE: LDL-p being a contributing factor, I think in some cases it is a marker for a disordered system, but considering Scavenger Receptors (the receptors that draw in materials for foam cells in the first place) do not draw in native LDL (e.g. unmodified) I find it doubtful that high LDL-p alone is a contributing factor in itself. It may be a marker that is further paired with other factors like high blood pressure, diabetes, etc, but there are other reasons for it to be raised which makes me believe it is not a risk factor per se.
Definitely agreed that there are multiple variables, and I am sure I will miss some along the way so thank you for bringing up these things.
Regarding other sterols, could you expand on that as well? Are you referring to oxysterols, or something else?
Elsewhere, I’d read that the plaques occur in arteries with high hydraulic stress, such as the coronary arteries but also the big vessels like the aorta, carotids, cerebral vessels, mesenteric — the places you get arterial disease. But not in veins, even the portal vein (as far as I know). So why does the oxidised LDL park in certain places (highly trafficked arteries), but no others? Just curious for your opinion on this.
Personally, at least for the macrophage mediated deposition, I think it’s *because* it’s a highly trafficked area. It makes sense to put more “patrols” there (scavenger receptors, on-duty monocytes, etc) to stay on the lookout for any damaged particles, so you can clear them quicker. Especially because oxidized LDL can create byproducts that will oxidize other materials (a chain reaction) so you really need to make sure you pull them out of circulation as quickly as possible to break them down and “disarm” the problem.
I don’t know that’s true for sure, but it’s just what makes sense to me as far as what I know so far. It could also be that high hydraulic stress areas already have macrophages and other immune cells on the scene to deal with minor damage anyway, so they’re more likely to see other stuff coming through and grab it as a matter of convenience.
So – there isn’t really anything conclusive on the “why” of this yet, but there are a few possibilities.
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.
Are you referring to why does it collect in foam cells in the first place, or why does it stay there and cause issues?
The first one appears to be pretty straight forward when you look at it – modified LDL, just like certain viruses and bacteria are pulled over by scavenger receptors as part of an immune response and stored away in a quarantine (foam cell) until they can be properly disposed of. That is the foam cell formation we see in the initial stages of atherosclerosis. Also, if there is usable material (like cholesterol that hasn’t been damaged/oxidized) it’ll be repackaged and shipped out for re-packaging to get back into the system. This is another component to lipid pools – stuff waiting to be picked up to be put back in the system, because as we can see in other situations generally we tend to recycle a lot of material if we can.
Why does it accumulate to dangerous levels? That is a tougher question because it seems there are a lot of things at play. I’ve even found studies suggesting that the pH level inside the lipid pools influence how well the cholesterol can be re-estrified (the cholesterol in foam cells goes through a continual process of re-estrification and hydrolisation until it can be given to HDL for the next step).
A couple things come to mind though which may contribute: ACAT (which is used to repackage the cholesterol into lipid droplets for further waiting, or to be effluxed to HDL) can’t keep up with the demand which means that the cholesterol is hydrolised and then can’t be estrified again – which is damaging in itself from what I’ve seen and understood so far.
Possibly very low HDL also relates to this in that the stuff that comes in can’t properly be sent out fast enough/reliably enough and then there is build up (I definitely do not think this is the only factor though, and am not sure if it is a for-sure factor at all – haven’t gotten there yet)
So basically I think it is a general overwhelming of the immune system that throws gunk in the gears and causes a partial breakdown resulting in build up that is toxic to the workers trying to clean up (macrophages, etc). I think though there are many, many, many different factors that may result in the same general end result. This is something I’m still looking into and do not fully understand, so if you ever come across anything regarding it definitely send it to me so I can take a look.
I hadn’t actually looked at this much before you asked but after a little bit of searching, basically yes – it can occur in any artery and result in Peripheral Artery Disease, Chronic Kidney Disease (if blood flow to kidneys is impaired), etc. I wouldn’t say any tissue but any artery the answer appears to be yes.
Funnily enough Ivor Cummins linked that same thing to me not too long ago. I did skim over it already, but need to go back over it in more depth when I’ve got some time. I did not know the endothelial layer had multiple… layers, which is quite interesting, I am not totally surprised that macrophages are depositing stuff a bit deeper than might be expected. If it were accidental, or an invasion, you might think they would deposit their payload as close as possible – but in fact considering they are being “invited” in by scavenger receptors, macrophages at work, etc they are housed much further away from the blood. This makes sense if the foam cells are truly a quarantine, as I suspect is true.
See, I really dislike the terminology of “crash”… because I have yet to see a case where a lipoprotein slammed so hard into the artery wall it actually “popped” through and stayed there. Yes, this will cause damage in cases like high blood pressure, but as for foam cell development – I don’t think this really contributes, but I could be wrong. At least not in the way it suggests. “Infiltrate” is another thing. You could say they were infiltrating the arterial wall if they got in unintentionally, but can you call it an infiltration if they are invited in by the immune response? I see a clear, linear system of flagging down modified LDL (remember, scavenger receptors only see modified LDL not native), parking them in place, and then monocytes find them and start the immune response, housing the cholesterol under the endothelial layer(s). That does not sound like a break in, but rather a system (that mirrors similar immune responses) for clearing out unwanted debris from the blood pathway, and these particles are brought in for a purpose.
Think of it this way: Would you say someone “invades” a jail cell if they are put there for breaking the law?
As for capillaries, I do not see anything regarding plaque build up, which doesn’t make too much sense if lipid build up is due to an “invasion” via LDL, but does make sense if you see it as an immune response. Scavenger Receptors are expressed on the endothelial wall, but I do not believe they are expressed in veins or capillaries, which would explain why plaque development doesn’t begin in those areas – modified lipoprotein isn’t pulled over in those areas. There are some reasons I could speculate as to why that is, but it could just be that since arteries are the super highways of the body it is more efficient/safe to capture/store/handle dangerous particles there.
A few added points to Siobhan’s response:
– The overaccumulation needs to be considered in the context of healthy vs unhealthy systems. Bear in mind that many, many more “sites” of atherosclerosis initiate and are generally resolved (Siobhan’s Outcome #1 above) than are not (Outcome #2). This is important as it shows both anticipation and *success* with resolution. That’s an extremely relevant thing to keep in mind, as it shows just how effective the system is at lower levels of inflammation (depending on genetic/environmental factors, of course).
Per her point above, what actually brings this accumulation to unresolvable levels is a much harder question to answer. But when you think all or even most developing atherosclerosis is a one-way ticket of progression, it’s easy to believe the lipid pools themselves are the problem since they’d characterize something more akin to malignant cancer growth. Knowing how effective this system already is at developing this inflammation, then (mostly) cleaning it back up relates it more accurately to skinning a knee and scarring — which is a far more analogous example.
Remember, inflammation is NOT a bad thing in and of itself — in fact, it’s vital to health! But *chronic* inflammation certainly is a problem and will break down your system!
Excellent points, Dave, and things I would want to highlight as well.
– I *definitely* feel it’s no accident that:
1) The system has the capability to bury these pools lower beneath the endothelial layer and
2) The scavenger receptors would be most active away from the capillaries.
I’d want the problem contained and preferably as far away from the lumen as I could get it that was still accessible for RCT (Reverse Cholesterol Transport).
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. .
The next post will cover particles that actually contribute to foam cell formation, namely modified LDL (and how it can become modified). This, I suppose, could count as an unbalancing of the system! Some amount of oxidation and pathogen-bound particles are to be expected (that’s life!), but a constant influx of high amounts of modified LDL appears to cause issues, due to an overwhelming of the system (as far as I see it). Hope that will fall in line with what you are interested in!
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!
Thank you for the praise! I absolutely love the topic at hand and am so happy I can share it with you guys 🙂
Sorry it took me a little bit to reply, I wanted to verify a few things before I got back to you. No issue at all about simple questions, that’s part of what this entire blog is for! My post included 🙂
Okay: So, there does appear to be an oxLDL and oxidative stress test – not on the VAP lipid panel, but something you could order separately. However they are new tests, so I haven’t seen anything confirming their accuracy, it’s another snapshot test that only tells you about that exact moment (not your status over time, which is important here because according to what I’ve found, if I am right then detrimental atherosclerosis is the chronic overwhelming of the system, not the system in itself).
I think it may actually be better to stick with things we know tell us about the over all health of the system compared to just one part of it – even if that part is a very key element to some disordered function.
Part of the reason I think this is not only the snapshot thing, but also that I think there could be situations of elevated oxLDL or oxidative stress that isn’t necessarily bad. Let’s say you get an infection, and oxLDL goes up as it binds to the virus or bacteria, or over all exposure to a pathogen influenced environment. Your CRP also goes up at this time because it binds to modified LDL (oxLDL in this case) so it can be recognized easier by scavenger receptors (for clearance). What does this tell you exactly? That your immune system is working properly. If that went away in say, a week – I wouldn’t be concerned about it. Your immune system functioned properly, reacted to an invader, and cleared it out. Good!
So instead I would look at things that tell you more information about how things have been working long term, as a system. Fasting insulin and HBA1C for example, because high levels of blood sugar and insulin resistance influence modification of LDL (coming up in more detail in next post). CRP, while it does fluctuate, also works as a marker when taken into consideration… for example it does fluctuate with hormonal changes (shown to be true in women so far), but say if you have a reading >3 that may point to something being disordered somewhere. Could be an infection, OR (paired with other markers) could be something you’d want to be alerted to.
Another thing would be very high triglycerides (assuming fasting about 12-14 hours, not more than that) as this, just like high fasting blood sugar, indicates energy that is traveling around and can’t get to where it needs to be as well as it should. Which, is part of what can cause apoptotic (past expiration date) LDL.
I think these would all be good markers if you want to look at how you’re doing over all, which would tell you – indirectly – the liklihood of high levels of modified LDL that would contribute to atherosclerosis.
I think this post, and the one I’m working on, goes very well with Ivor Cummins’ work (he has videos, talks, etc). I talk about what the mechanisms are on a micro view, and he goes very much into a macro view – which is helpful for people looking to lower risk as much as feasible.
So, while I’m not a doctor – just a citizen researcher – those are the types of things I would think are highly valuable when looking at how things are going over all as a system. I hope that helps!
Great article Siobhan! Something I will read a second (and third) time this evening. Looking forward to the next posts. Thank you.
Thank you, as well! I am glad people are enjoying it!
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?
I have not looked into this honestly, but I certainly will now that you’ve mentioned it! Thank you for a very interesting lead.
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.
So glad you like it, and I’m glad it’s easy enough to understand! Would really like to hammer that point home, because unless someone points towards me being wrong (haven’t seen yet through the papers I’ve read, but I encourage people to send me what they’ve got to refute it) it changes how we should be looking at atherosclerosis – and how we prevent and treat it.
Again, thank you for the support!
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.
What an excellent list of things for me to look into… 🙂
I do want to point out one thing though. This series is a very, very, very micro view of atherosclerotic development, as in what can atherosclerosis not do without? Rupture of a plaque, or blockage of an artery? Sure, definitely a hard end point for the disease. Foam cells? Important stuff. What’s in the foam cells? How did it get there? Etc.
This is not to suggest these are the only features only what I have found 1) kick starts the process and 2) leads to (and is critical in) the breakdown of the system (if overwhelmed chronically).
This breakdown can cause many other things as a consequence, and some of these things can cause a speed up or worsening of the condition, but that isn’t what I’m focusing on (right now…).
Bizarre shaped muscle cells, for example, as far as I’ve seen in my studies so far are due to exposure to Reactive Oxygen Species causing them to develop… abnormally. ROS not being quarantined away sufficiently (via immune response) would definitely indicate something is going wrong somewhere.
Ectasia, as another example – I believe this is due to a disordered form of arterial remodeling, yes (correct me if I’m wrong here, I’ve only seen it in passing and haven’t done deep down research into it yet)? And arterial remodeling recurs so as to “make room” for the foam cells in a way that does not invade into the arterial space and impede traffic, as it were. So, as a symptom of the break down of the system I can see it. As a necessary, can’t-do-without-it cause? I would not classify it as such (I may change my mind though if I come across evidence of otherwise!)
So I hope that better explains where I am coming from here. I intend to go into what causes modified LDL, as well, which helps better explain the processes and mechanisms leading up to required events (as in the build up and rupture we see doesn’t occur without it), and a lot of other things too! This is just the first post!
I should also note that I would not classify this as a lipid centric theory rather that this is an immune system overload based hypothesis. I think there is a clear difference in those two views. The first may lead you to say “well lower lipids”, while the immune system view I hope people will ask “Well what is overloading the system in the first place?” as well as “The lipoproteins in this situation are merely doing one of their jobs, or are damaged in the crossfire”. I can firmly say I have no vested interest in placing blame on lipoproteins or lipids here – they are very beneficial and crucial to our very existence. I’m also not one for the idea of lowering them for the sake of “prevention”. Rather I would look at what puts the stress on the system in the first place, what are the key things we can look at that start the whole breakdown of the system, and go from there.
In fact because I view it as a breakdown of a (very important) system I would honestly be quite surprised if there weren’t breakdowns and chaos as collateral damage, or related issues.
Thank you, additionally, for the very insightful comment, as well. I honestly do appreciate it.
Glad to hear you will be investigating the length and breadth of atherosclerosis. You will undoubtedly come to your own conclusion but my take is that it is a hemodynamic pressure phenomenon first and foremost. That is most of the aspects can be more easily explained by looking at hydraulic (blood) pressure within the system than by looking at LDL or other lipoproteins. You have probably seen it but I have another post explaining why high LDL levels are essentially irrelevant to atherosclerosis.
The subject is important because many people get scared when they start LCHF in an attempt to take charge of their own health, an admirable effort, and get high LDL as a result. Most are confused and the system is geared to take advantage of this fear by prescribing statins to lower cholesterol. This is IMO a tragedy so an investigation like yours with Dave behind you can do much to dispel these fears. This would be a tremendous public service.
I have posted similar things on FB mainly in the statins groups but have not received much in the way of questions or comments. I don’t have the clout that Dave does so I believe vital information gets ignored except to the very discerning.
I really welcome your review but I suspect you are in for a lot of work.
Considering there is not even correlative data with high LDL and atherosclerosis, I don’t think there is much (if any) association and most certainly it is not a root cause, even if it is stated that it is pretty often by mainstream.
You will likely see my view develop as I post more parts, I will be interested to see your view on them as the series comes along – was just reading comment about high shear stress actually. I have my own thoughts on that. 🙂
I agree on fears of high LDL and statin prescriptions – I think this is why it is so important to understand mechanisms. Once you look at the system as a whole, you can begin to see why statins may not be such a good idea (as evidenced by all cause mortality in trials…)
Thank you for the comments!
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 the support! What a wonderful comment to come home to!
1. I’ve had this pointed out to me a couple times, by Ivor Cummins as well about the thickness part. But I did not properly notice about the lipid accumulation before macrophage infiltration, and the location of this accumulation… So I suppose the question is how do they get there and do they do any damage per se? Let’s say for example you get to the point where the intima is thick enough to need vascular inclusion to feed the deeper layers, and then you turn things around, reverse insulin resistance/diabetes/hyperinsulinemia/etc in order to prevent what I describe taking place here (as far as I see the macrophage proliferation still appears to occur from endothelial layer(s) towards deeper layers of intima and not from the same entryway as these initial lipid deposits outwards) 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?
Question number two would be – as I interpreted the info in the paper, the vasculature type of remodeling occurs exactly so LDL (along with oxygen, etc) can access these deeper layers (nutrition, vitamins, cholesterol, etc) so 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?
Basically, there are plenty of things that occur way before what I am describing, which I will probably get to at a later point to bring it all together, so is this neovascularization contributing to the disease that results in mortality or is it an early marker for it?
This is definitely something I find fascinating and I’m glad you mentioned it, though.
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 hope that makes sense! I am not dismissing you on this point, but 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.
Either way – interesting!
2. Would you mind rephrasing? I’m able to read this in two different ways (“diabetes is ONLY correlated” e.g. not causative; “diabetes is the only thing that correlates” e.g. suggesting causation), I did read through the study and it said diabetes was the largest correlative factor, but I’m curious as to what you meant here.
3. Interesting! I should have “known” this considering I have seen the study wherein atherosclerosis was only able to develop with insulin present in animal studies, but it never “clicked” until you mentioned it. Thanks!
Again, thank you for commenting and critiquing! Hope you don’t mind all my questions 🙂 Lots of interesting info here – just left wondering if I’ve gotten something wrong in the post, or if you are just adding supplementary info on the systemic issue and development. Let me know!
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!
Gotcha, so likely I will not bring it up until the end of the series where I suspect I will go over systemic markers. Assuming I don’t find out it contributes directly – if I find out that it does after more research I’ll write a post to update the hypothesis stated here, moving back the “starting point” of the actual process of plaque formation, etc. Mostly here I am addressing the immune response that occurs as a reaction to the system being disordered in the first place. A very micro view.
The problem I have with this is as far as how complicated and intricate and precise everything is in the system, if anything happens that isn’t supposed to it is for a reason, not by accident. So, if a receptor for LDL is being expressed and “grabbing” it and bringing it in there has to be a pathway for that receptor to be expressed in the first place. So in order to understand what is going on, I would need to look at why it is being expressed in the first place. Issue being LDL is used for many different purposes, so it would need to be a case of narrowing it down.
So, either it’s needed and can’t be used (I would expect to see some sort of marker for damage here though, if something was supposed to happen and didn’t – I don’t see evidence of that), it’s being “stored” there for a reason (if so: why?), the receptor is being expressed improperly for some reason. I’d love to know what’s going on in those lipid deposits in extreme detail – would give me a better idea.
Perhaps it could be a sign of extreme construction going on (keeping building materials on hand?). So many possibilities…
“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. ”
Right, I do think it is the same process – obviously they’re related. Plaque development etc on the immune response side, and neovascularization on the damaged artery side? I believe intima thickness increases upon damage (as seen here: https://www.ncbi.nlm.nih.gov/pubmed/12643884) of some sort, but obviously there are probably other factors involved. Some damage would be expected over life (everyone has thickening from birth to adulthood) but excessive damage causes it to thicken to the point of being detrimental? Honestly no idea at this point – just speculating.
Gotcha, there’s something I didn’t know RE progression/incidence. Very interesting stuff (but not strictly surprising at this point). Very nice to have the info at hand though.
You are like a treasure trove for me – haha. Actually taking notes on this so I can follow up – thank you!
I think we are still learning in depth – all of us. 🙂
Just to clarify: I wouldn’t mind at all if you were saying I was wrong, I would frankly appreciate it rather than let the error go unnoticed on my part.
I think, unless you disagree, the post can remain unchanged. I reviewed it and don’t see anything that really changes with the addition of the info you provided. I already stated that macrophages embed in the intima, for example. But, if you spot anything I wrote in error, let me know and I’ll put a note up top correcting it. 🙂
I definitely will! If you have either facebook or twitter, I have both (twitter: @siobhan_huggins / facebook: /siobhan.huggins.509 ) I use them purely for science posting, and tend to update there more frequently than anywhere.
“So, if a receptor for LDL is being expressed and “grabbing” it and bringing it in there has to be a pathway for that receptor to be expressed in the first place. So in order to understand what is going on, I would need to look at why it is being expressed in the first place. Issue being LDL is used for many different purposes, so it would need to be a case of narrowing it down.”
–Right, I agree with you. I was trying to say maybe the LDL receptor is not being expressed by the endothelial cells. Either way, it is something that needs to be looked into
“Plaque development etc on the immune response side, and neovascularization on the damaged artery side? ”
–From my understanding, neovascularization and lipid deposition begins on the vaso vasorum side and macrophages begin on the arterial side. This may be due to damage or another issue that activates the same cellular pathways. Eventually they all merge to form a plaque. Let me know if this is wrong.
“Some damage would be expected over life (everyone has thickening from birth to adulthood) but excessive damage causes it to thicken to the point of being detrimental?”
–I agree that excessive thickening is what causes it to be detrimental.
“I think, unless you disagree, the post can remain unchanged. I reviewed it and don’t see anything that really changes with the addition of the info you provided. I already stated that macrophages embed in the intima, for example. But, if you spot anything I wrote in error, let me know and I’ll put a note up top correcting it.”
–I don’t think anything needs to be changed
I just sent a request on Facebook
Got it! Yes I think this is probably the most likely scenario, as the endothelial cells don’t appear to even be using them. Something else appears to be at work here, I’ll just have to see if there are any hints as to what.
Ah, yes, I meant in a less literal sense (as in processes, not location). As in intima thickening happens due to damage of the artery (for whatever reason; this is where my speculation starts) as a repair process (maybe something else?), and macrophage accumulation happens as a process of the immune system. You are correct about the location these happen in, definitely.
So another case of a normal process going haywire due to some (as of yet) not understood process. I will never cease to be fascinated. 🙂
Then nothing will be changed – thanks. 🙂
I was not considering the “leakiness” of capillaries before I just read this https://drmalcolmkendrick.org/2017/09/05/what-causes-heart-disease-part-xxxvi-part-thirty-six/
From what I can tell, vaso vasorum are continuous capillaries, not fenestrated capillaries. If the vaso vasorum did have fenestrations, then that could have major implications on how LDL gets into the intimal layer. Maybe even continuous capillaries are leaky enough to play a role.
Thanks Justin! I will check out the link – very new topic to me so not much to comment on at the moment! I hope to learn quite a bit more about it though 🙂
EDIT: Just read it – I would like to add one thing to his “LDL cannot breach the endothelial wall except via an LDL receptor” and add on “or a macrophage (type of white cell) in pairing with a scavenger receptor” (although I believe at that point it isn’t a whole LDL particle, but one that has been broken down into its components by a macrophage). As he says, macrophages can in fact part of the gaps of the endothelium and get past it.
Though that isn’t really what you were focusing on I bet. I just thought that part was interesting. 🙂
As for the leakiness of vaso vasorum it does, perhaps, add a hint. I would need to look at other sites of vaso vasorum and see how they interact with LDL/prevent the same problem. Or can LDL not get there normally? Honestly not familiar with this part enough to say – but I will hopefully find out.
It should also be repeated, I think that the collection of lipids in the vaso vasorum and the collection of lipids in the foam cells are two separate processes it seems. It could very well be that LDL is “leading” through the fenestrations of the vaso vasorum, but is being taken in via white blood cells through the lumen for two different purposes (or vascularization of a typically non-vascular area, and an immune response)
I know I probably am repeating myself here, but it is interesting at the similarities and differences between these two processes and their potential causes.
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?
First off – congrats on the 0 CAC score and other great markers!
Just based off of what I’ve learned so far as a citizen researcher (not a doctor) I speculate that the high CRP could be from something else. It is important to note that CRP is a part of the immune system and can fluctuate (rather rapidly!) for many reasons. From what I’ve learned it actually binds to pathogens (like bacteria and viruses and fungus and such), and oxidized LDL, so that they can be more easily recognized by Scavenger Receptors, etc. so that they can be cleared as efficiently/quickly as possible.
Which means CRP could be high for any number of reasons including an infection of some sort one may not even be aware of, or some other cause of oxidation of LDL like vegetable oils (omega-6), smoking, air pollution, or something else entirely. I have no idea if this is what’s happening for you, but it may give you some sort of hint. As I’m not your physician (or one at all) I can’t say for sure what it is, I can only provide my thoughts based off of the research I’ve done so far and perhaps give you something that may provide a hint. 🙂
As for LDL-p I believe this fits in with Dave’s Lean Mass Hyper Responder profile which you can read about here.
You also mention high triglycerides – how high were they? Triglycerides can also be influenced by various factors, including longer term fasting.
Hope this provides a clue about what’s going on! I hope you figure it out!
“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?
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…
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.
I can’t really respond to this much beyond that it makes a lot more sense than when you first brought it up! I think ultimately, after looking at it, that likely macrophage infiltration of the intima and the neovascularization are two sides to the same problem (like insulin resistance and hyperinsulinemia). I can’t say that for sure… and I think they probably play off of one another. Neovascularization occurs first – due to intimal thickening and macrophage infiltration later on due to the immune system clearing out various types of debris (mentioned in article). These are ultimately due to the same root cause, I would guess. Too much coincidence otherwise.
This is certainly an interesting hypothesis I will have to look into. I am betting there is a whole lot research on the vascularization of the cornea that I could take a peek at and get some hints.
Apologies if my answers on this are unsatisfactory as of yet! I am still learning about this part, so I don’t want to comment on it too much yet. I will endeavor to learn more about it though 🙂
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.
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.
Well it certainly doesn’t orbit around LDL in general, but modified LDL does appear to contribute quite a lot to this small part of it. And I really want to stress here that I’m only focusing on a very small part of what’s going on in this series. Other people (like Ivor Cummins) focus on the macroview much more succinctly, but I think it is a worthy cause to really explain what is going on with foam cells, immune response, etc! The better we understand it, the better we can look at high LDL very critically and ask “is this, in itself, really a risk factor? Or is there something else contributing here?”
In truth, it all appears to tie into a system-wide disruption affected by many things in-part described by Ivor.
So, I think it is worth mentioning that this is not meant to be a “what’s the root cause” but rather “how does it work, and what contributes to what we commonly talk about when we talk about heart disease?” (lipid accumulation, inflammation, fibrous plaque, etc) I think if people understood better, we could really throw out LDL as anything else but a generally innocent bystander (if I am correct in my writings here) and look at the factors that are modifying it (which is a much bigger topic over all).
I hope that makes sense, and thank you for the comment and support!
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.
The presence of oxLDL in itself signals scavenger receptor expression, which bring in the oxLDL and this in turn triggers the formation of macrophages from traveling/crawling monocytes that come across the area. Macrophages do also appear at sites of mechanical/other damage, but they will also specifically come to sites where oxLDL are and begin the inflammatory process. This is the process that I came across time and time again in my studies… if this process is wrong in any way please let me know. Note that this is not creating damage, it is a process to handle the particles that are damaging when left in the bloodstream. I also do not propose we lower inflammation, macrophages, scavenger receptors, or even stop LDL from becoming modified – because honestly if you want better health and not just less heart disease you need to address root causes.
For now though, I am talking about the mechanisms of what we typically think of when we think “heart disease” (e.g. lipid accumulation, inflammation, plaque rupture, or build up of plaque) as I want people to really understand (like I’m trying to) how this stuff works, because once you do you can use that to begin questioning things. Like, for example, if someone says “A high carb diet causes heart disease” if you know how it works you can say “How?”. If the answer makes sense – e.g. “A high carb diet has been shown to cause more oxidative stress, along with glycation of LDL, as well as increased insulin presence” you can critically think about it (assuming what I write here is correct) compare it to the mechanisms and see if it makes sense.
So, basically I am saying I agree with you, but for this series I’m focusing on the mechanisms of this aspect of the disease as 1) I don’t think it’s been covered in depth before 2) I find it interesting and 3) I find people may benefit from understanding it.
If people want to talk root causes, they can watch Ivor Cummins material on the topic, as he covers it very well. If they want to understand why the root causes create the downstream damage they do I am hoping I will explain some part of it.
Believe me, I am not blind to the insulin tie in here! I am just focusing on a different aspect of the topic for now.
As for the arterial thickening that begins before the lipid accumulation, I don’t see any direct action upon what I discuss here… but I am aware it is a another sign of the whole system being whack. I intend to look into it more depth in my studies to see if I can find any hints as to its cause. I agree insulin is a likely factor, I would just like to know exactly why.
All that said – thank you for the comment! It is very insightful and I appreciate the time you took to write it. I suppose I should have put in the introduction why exactly I’m writing about this aspect, as micro of a view as it is. I am aware what I describe are not root causes, but an important aspect in any case to understand, or at the very least interesting I hope.
The presence of high levels of oxLDL is mostly due to PUFA consumption – oxLDL can also be decreased with a variety of poly-phenols, but poly-phenols can also mess with the insulin system – causing weight gain. We don’t have good studies showing the optimal amount one might target in one’s diet.
It is easy to reduce the size of foam-cells – lose weight. Not only that – the average thickness of the intima goes down with weight loss.
I’m focused on the CAUSE of CAD – not the symptoms. I think it is likely that a huge number of people have the cause and effect backward.
The only kind of LDL that i would worry about is oxLDL – which is easily reduced
I’m a lot more concerned about the introduction of purified plant oils in the early ’60s that greatly increased the consumption of PUFA’s particularly LA(Linoleic Acid) which can form HNE-4. We know that PUFA’s are obesogenic – likely cause of a number of diseases – likely cause of the obesity pandemic.
See my messy notes here
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.
Hi! I am on twitter (@siobhan_huggins) and facebook (/siobhan.huggins.509)
My TC is still high, I should say (from “over 300” 2 years ago, at age 19, to between 255-286 [that fluctuation was all in 1 week!], at 21) but based off of Dave’s work I am not too worried about it as my HDL is okay (generally around the 40 range) and my TG is <65, CRP is <2, fasting insulin is 4.2 and all other markers look good. Total Cholesterol in itself is a really poor marker from everything I've read - even LDL is not great (for reasons mentioned in the post...). But I am on the lookout for more research to make sure I am okay from a heart attack risk standpoint.
I will gladly follow you on twitter and look forward to updates on your end!
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
Btw LEAR = alias for canola
Siobhan…a little over my head too, but I’m still with you. Keep up the fight to figure it out.
I will definitely do that! If any sections are confusing, or if you ever have any questions please let me know and I’d be happy to see if I can rephrase to make more sense 🙂
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?
I haven’t yet, but it’s certainly on my list!
So neither LDL-c nor LDL-p are a problem unless they get modified?
I can’t really say that for sure at this point, but going from the studies I’ve seen so far (both experimental and epidemiological) that the case for LDL-C and LDL-P being harmful in and of themselves is surprisingly weak. There are a couple studies here which raise interesting questions on the topic, and some additional ones brought up in Dave’s LMHR talk from KetoCon.
Even beyond that I think it’s more than just LDL becoming modified that’s an issue, because as outlined in the article there are ways to handle that situation to dispose of them in short term/acute environments. It’s an environment that promotes chronic modification of LDL which in my opinion is worrisome for health and from what I’ve seen this is the same type of environment that promotes insulin resistance.
This is why I try to look at the bigger picture – LDL can be high due to worrisome environments (infection, stress, smoking, poor diet) but also due to possibly benign ones (energy distribution, paired with low inflammation/etc). Taking all the markers together (HDL, TG, CRP, insulin, etc) can provide information as to which environment that is, as reflected in the studies/talk linked above.
Yeah that’s pretty much my current way of thinking as well. However, I do still think that LDL-C and LDL-P are relevant markers to take into account.
I definitely agree they’re both a part of the larger picture – I definitely don’t ignore them when checking through my labs.
Thanks! Glad you enjoyed 🙂
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…):
HDL Large Particles 3950/5742
LDL Small Particles 437/334
Ldl pattern B/A
Trigs 146/199 (due to alcohol consumption to assist in sleeping while on keto…)
I like the look of most of these trends, but the triglycerides are something I’d want to address if I were in your position. Is it possible to remove the alcohol and re-test, and perhaps find some other way to help your sleep? I’m fairly wary of anything that raises triglycerides to those levels, including the other culprits.
Thanks for taking your precious time.
When the nurse called me about my second results she was panicking and praying that i will still arrive living when visiting the doctor… (but i am not one of these that are intimidated by doctors)
I am very happy with the results, as you can see, the first test showed non-Ldl at 26 (which has for sure some bad vldl) [TC 291-LDL214-HDL51=26], and my 2nd test showed ONLY 3 [TC 351-LDL293-HDL55=3]
Also, the HDL particles skyrocketed – so i guess i am doing something good.
In regards to the triglycerides, last night was the 3rd night i slept without it (wasnt easy nor hard). I stopped alcohol cold turkey.
I am wondering how long to wait for retesting?
Some (1 & 2) of the other culprits do apply to me (wasnt really fasting, drinking a few K-cup coffees a day) – lets first try with abstaining from alcohol.
Ah, yes, I suspect likely the not properly fasting 12-14 hours, plus alcohol are the biggest suspects here. For re-testing try after 10 days are so, and make sure when you re-test that you are 12-14 hours water fasted (this part is important, especially for triglycerides). 🙂
Great News! Checked again (after abstaining 3 weeks from alcohol and after fasting 15 hours before test) and got 102 Trigs.
Thanks for the advice!
Hooray! Perhaps the alcohol is best left for an occasional treat, if that’s what was causing the high trigs. I’m glad you were able to figure it out. 🙂
Tremendously enjoyed your insights. Very impressive and informative.
Glad you enjoyed! 🙂
Impressive, very impressive! I am not a robot… or Darth Vader.
Thank you 🙂
Glad you enjoyed (robot or not!)
Great info, but what’s your take on the vasa vasorum in the whole process?
From what I’ve read lipid deposition via vaso vasorum is an indicator of arteries that have thickened so much they need additional routing via the back. As for why the lipid deposition happens on that end – I’m not sure, yet. I’ve been looking into it for a while and the proteoglycans involved appear to only show up in injured tissues – so there’s a hint. Thickening of the arteries also appears to happen when the artery is injured in some way, as well.
I think one thing I didn’t emphasize enough in the post is that foam cell formation and plaque development is a pretty late stage process. It’s just something I heard talked about the most in common discourse so I wanted to look at the mechanism for why it happens. It’s definitely not the earliest part of the disease though.
Thanks for putting it into words that I can (mostly) understand. Would love to be able to explain some of this to my parents. They believe every word their doctor says.
You’re welcome – perhaps you could mention some of the research in passing, but some people really prefer to hear it from their doctors. I don’t think there’s much that can be done about it, hopefully they find the information if they need it, though.
Looks like Fred Kummerow’s research.
Thanks for the link! I’ll have to read through it. 🙂
This is a powerful quote from the Book. Because oxLDL could be DIRECTLY tracked and correlated with higher Omega 3 consumption, elimination of seed oils like Canola oil and cessation of smoking.
An interesting feedback loop for patients to directly track the effects of lifestyle interventions…
“More recently, we have reported results from of a nested case–control study, which wasconductedwithintwopopulation-basedMONICA/KORAAugsburgsurveys(214). The association between plasma oxLDL and risk of future CHD was investigated in 88 middle-aged men with an incident CHD event and 258 age-matched controls during a mean FU of 5.6 years. Baseline oxLDL concentrations were significantly higher in CHD cases compared with those in controls. After multivariable adjustment, plasma oxLDL was the strongest predictor of CHD events compared with a conventional lipoprotein profile, and other traditional risk factors for CHD, with the HR for a future CHD event being 4.25 (95% CI 2.09–8.63) if the top tertile of the oxLDL distribution was compared with the bottom tertile. “
“HR for a future CHD event being 4.25 (95% CI 2.09–8.63)”.
Statistically, this means that the Hazard Ratio is 4.25 for the elevated oxLDL, oxidized LDL. The confidence interval is at a LOW of 2.09 and a HIGH of 8.63. In other words, oxLDL is a likely high predictor AND ‘tuneable’ parameter based on the lifestyle choices made above.
The exhibit shows the action of MPO to downregulate the healthy Reverse Cholesterol Transport process and processes that lead to artery sclerosis. Note that the active foam macrophages release the MPOs or Myeloperoxidase.
Looking at Chapter 5,
C-Reactive Protein and Other Inflammatory Markers in Cardiovascular Disease
And sure enough, we see a hugely statistical impact for this testable blood marker:
“In line with these findings are the results of two studies in patients with ACS,
which evaluated MPO as a predictor of major adverse cardiac events (MACEs).
MPO mass concentrations have been measured in the CAPTURE (…) trial in 1090 patients with ACS. Baseline MPO levels predicted an increased risk for adverse CV events, and this effect was
even more pronounced (HR 7.48 [95% CI 1.98–28.29]) in patients without myocardial
necrosis (negative for cardiac TnT <001g/L at baseline) "
A hazard risk(HR) factor of 7.48!! Definitely a marker worth testing.
Very good explanation of the likely connection between Macrophages, Low Vitamin D, HDL and modified LDL (including oxLDL)
[…] Once LDL is oxidized, LDL receptors no longer recognize it. Instead, the immune system takes over. When LDL is oxidized your body actually intentionally pulls it into your artery walls to prevent them from causing damage elsewhere [*] […]
[…] Once LDL is oxidized, LDL receptors no longer recognize it. Instead, the immune system takes over. When LDL is oxidized, your body intentionally pulls it into your artery walls to prevent them from causing damage elsewhere [*]. […]
[…] Once LDL is oxidized, LDL receptors no longer recognize it. Instead, the immune system takes over. When LDL is oxidized your body actually intentionally pulls it into your artery walls to prevent them from causing damage elsewhere [*] […]
In labs done last year my CRP was 7.28 and my insulin was 13.7. Last week labs showed LDLc and total cholesterol went up but insulin in now 6. I’m confused. Glucose is 5.6. Weight down 19 lbs.
Hi June, we can’t say whether you should be concerned or not as we’re not doctors and can’t give medical advice. Did you happen to get a new CRP on your latest to compare? To notice, CRP can be a bit finicky, and things like exercise or a slight cold can elevate it, so I try to keep that in mind.
Typically a fasting insulin of 6 or below is considered ideal by people like Ben Bikman (who studies insulin), and it’s what I look for in mine as well, a fasting insulin of 13 would have been something I’d be looking to troubleshoot if I saw results in myself – it’s one of the markers I pay very close attention to. For the total cholesterol and LDL would you mind posting the full results? E.g. the actual numbers for total cholesterol, LDL, HDL, and triglycerides?
I don’t typically look at any marker in isolation, especially results from a lipid panel. You can put your numbers into our report tool (new and old) to compare as well. This gives predicted risk from a couple different studies, as well as our comments, which may be of interest.
Thanks for the patience in waiting for a reply, once I have further details on the lipid panel I can comment a bit better and provide relevant resources.
OK. I just read Part I. Fascinating stuff.
Is there a higher density of scavenger receptors in coronary arteries?
It really depends on which scavenger receptors and under what context. This review, for example, mentions that LOX-1 isn’t highly expressed in vascular endothelial cells, but with endothelial cell activation (from shear stress, oxidative stress, inflammation, etc) expression can be upregulated. Other scavenger receptors are most highly expressed by immune cells generally, etc. As with a lot of receptors, context matters a lot as far as what is expressed and where. But there are scavenger receptors on endothelial cells, and if there’s something to pick up (and a signal indicating that) upregulation will occur to increase their presence. Hope that makes sense!
Hi, Trying to interpret NMR and apoB results. Do you have a tool or info that may help me. Thanks for all of the info you share.
total chol. 311
small ldl-p 386
ldl size 22.1
apo-b 162. Apo-a was not tested for some reason.
lchf 1 year
Active, Great health except high cholesterol, no metabolic risk factors, on no meds, age 70 female. I am trying to understand NMR and apoB. I did plug my numbers into your report. Thank you.
Hi Stella, we don’t currently have an NMR/ApoB calculation tool. And although we’re not doctors and can’t give medical advice, I can share some observations in case they’re of general interest.
For example, from what we’ve seen in ourselves and others LDL-P tends to be LDL-C x10 +/- 15% or so in metabolically healthy people. For example, for an LDL-C of 214 I’d expect an LDL-P of between 1819 and 2461 according to that pattern (matching the result you posted).
Likewise, the pattern we’ve seen in the same people who’ve shared their panels (and in our own) small LDL-P tends to be less than 30% of total LDL-P (with LDL-P of 2395 I’d expect LDL-P of less than 718 or so.
As far as ApoB, you may be interested in this post on the topic.
It’s also worth noting that it looks like you fit the profile of a Lean Mass Hyper-responder e.g. someone who is typically lean, active, and powered by fat (e.g. on a low carb/ketogenic diet). You may be interested in the Lean Mass Hyper-responder facebook group as there are many there with similar profiles who explore the latest research regarding it, their experience, their perspective, and how they’ve approached having the profile (e.g. taking steps to move away from the profile and how they did so, sticking with it but getting additional testing to keep an eye on things, etc).