Plaque is the stuff of coronary heart disease. It is CONTROLLABLE, it is STOPPABLE, it is REVERSIBLE.
But you must be equipped with the right information on diet, nutritional supplements, and hopefully the avoidance of medication.
This is the blog that accompanies the 
I witness spectacular results restricting carbohydrates, both in the office as well as in my online experiences, such as those in Track Your Plaque. Of course, the diet I advocate is not just low-carb; it starts with elimination of wheat (for a long list of reasons). So the diet is wheat-free in the setting of low-carbohydrate.
What does this accomplish? Here’s a partial list:
–Weight loss-Specifically, loss of visceral fat, the kind hinted at on the surface as “love handles” or what I call “wheat belly.”
–Reduced blood sugar and HbA1c (reflecting prior 60-90 days glucose)
–Marked reduction in small LDL and triglycerides, increased HDL
–Reduced inflammatory measures like c-reactive protein
–Reduced leptin and leptin resistance, increased adiponectin
–Reduced estrogen and prolactin in men, accompanied by shrinkage or loss of enlarged breasts (“man boobs”); reduced estrogen in females accompanied by reduced risk for breast cancer
Pretty impressive. But there’s one group of people who can experience unexpected effects with this diet: The 25% of people with apoprotein E4.
Everybody has two genes for apo E; the most common type is apo E 3/3. Around 1 in 4 people have 1, less commonly 2, genes for apo E4.
I hate apo E4. I hate apo E4 because it means I’ve got to dust off the nonsense I used to tell patients about cutting their fat, cutting their saturated fat. But that’s what apo E4 people have to do. But it doesn’t end there.
Apo E4 people also typically have plenty of small LDL particles triggered by carbohydrates. Put fats and carbohydrates together and you get an explosion of small LDL particles. Remove fats, small LDL goes down a little bit, if at all. Remove carbohydrates, small LDL goes down but total LDL (mostly large) goes up. The large LDL in apo E4 does seem to be atherogenic (plaque-causing), though the data are fairly skimpy.
So apo E4 creates a nutritional rock and a hard place: To extract full advantage from diet, people with apo E4 have to 1) go wheat-free, low-carb, then 2) not overdo fats, especially saturated fat.
It still gives me the creeps to tell an apo E4 person that they’ve got to watch their fats, worse than watching Starsky and Hutch reruns.
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ApoE4 degrades more readily than ApoE 3 or ApoE2; ApoE4 protein fragments that get into a tissue cell’s cytosol can have bad effect on that cell’s mitochondrial membrane lipid binding . This decreases the mitochondrial efficiency when they try to perform glycolysis for generating energy.
ApoE4 degradation in a cell cytosol can decrease the level at which that cell advances it’s bio-genesis of robust mitochondria; this is due to how ApoE4 fragments depresses PPAR gamma expression & PPAR gamma is what promotes making good mitochondria. (Specificly in the case of human fat tissue PPAR gamma is what regulates transcription of pre-adipocytes differentiation into true adipocytes. Hence Avandia & glitazone drugs that target the receptor of PPAR gamma do short out adipocyte differentiation; and yet risk the side effect of increasing heart disease due to mitochondrial impairment.)
In Alzheimers the form of ApoE makes a difference; and the brain amyloids react to insulin differently with different ApoE iso-forms. The ratio of insulin in cerebro-spinal fluid as compared to insulin in plasma changes with different genotypes of ApoE. Alzheimer patients tend to have lowered glucose utilization in their brains with less insulin and insulin-like growth factor receptors, despite the Alzheimer brain harboring fewer insulin degrading enzymes. Which engenders a paradox whereby diabetic brain neuro-pathy experimentally improves with administration of nasal insulin; and similarly, individuals with ApoE4 receiving nasal insulin improved their cognitive function, with the boost being higher in ApoE4 carriers than folks with any other alleles of ApoE.
Higher amounts of Alzheimer amyloid formed tangles are seen in Type 2 diabetics and in those with ApoE4; leading to the conclusion that “normal” ApoE3 fortuitously forms a complex with brain amyloids.
Apparently ApoE iso-forms other that ApoE4 can more readily bring an amyloid to where the molecule LRP-1 (lipo-protein related protein 1) can move that amyloid out across the brain blood barrier .
With regards to the large LDL content. Again I am not a cardiologist, but a neurosurgeon. The heart and brain work on the same principles of biochemistry. And since these two organ take up much of the CO in the body they share much in common. It is also why when we see neolithic disease affect the heart their is also a similar effect in the brain. The Apoe4 story is one such case. But so is the large LDL story. Cardiology CW today believes that LDL matters. In neurosurgery today its clear in neurodegenerative disorders we are lacking LDL and cholesterol more often than not. This is incongruent to biochemistry. Dr davis has said here in this thread the jury is out on large LDL in his field. I am submitting that LDL matter little in any field. Why? If it did the body would have a specific detailed regulatory control method in place to deal with it and it does not. In nature, with the consumption of organic, unprocessed parent essential fats rather than adulterated oils (PUFA’s) and transfats, LDL cholesterol is supposed to be made up of significant amounts of properly functioning “parent” omega-6, linoleic acid (LA), and is not supposed to be harmful. It is the natural transporter of parent omega-6 and parent omega-3 into the cells. It is thus not critical to lower LDL cholesterol, nor is the absolute LDL number as important, if the diet contains sufficient unadulterated parent essential fats. These are unadultered PUFA’s of both the omega 6 and 3 variety for clarity sake. Also take note that the body has no natural “cholesterol sensor” in the bloodstream—it would if its levels had to be maintained within exact limits; such as, sodium, calcium, and glucose levels are monitored in many systems. For example, glucose levels are maintained to an amazingly tight 0.1% in each of us! So Nature implemented biological mechanisms if required. There is no need for a cholesterol sensor because the absolute number is irrelevant. That was my advice to Jack Kronk three weeks ago when he posted his VAP numbers and when I blogged about his numbers. I understand that Dr Davis may not want to go out on a limb as I have here. But I dont view it as a limb when the biology and biochemistry support my beliefs fully that LDL cholesterol levels are completely irrelevant to heart disease propagation. This is why I advocate copious amounts of coconut oil to patients with heart disease and all neurodegenerative disorders including brain tumors and seizure patients. In fact, my literature is loaded with thousands of papers supporting my belief made here. I think its long over do that cardiologists start reading “other pathways” of data to reach conclusions that their own field muddies. As a neurosurgeon, I read Dr Davis literature quite a lot and in comparing the two it is clear that our two fields are on a collision course from two different paths. I got extreme clarity reading circulation over the last thirty years that cholesterol has nothing to do with heart disease. Dr Davis has reach conclusions that are quite different from most of his fellow cardiologist as well. I applaud him. I just think he is still caught in the lipid hypothesis nightmare and that is the only reason he is not traveling down the road with me in unison. Since he is a fine doc and one who clearly is ahead of his peers……i’ll gladly wait for him on that road because we need him to alter what ails his branch of medicine to get to where we both need to be going for all patients.
Dr. Kruse,
What is your response to the fact that people with familial hypercholesterolemia (FH) have an exaggerated risk of CVD versus those who are not lacking ldl receptors? Why do so many of them have cardiac events in their 20′s and 30′s? Surely, you would not relegate this phenomenon to increased consumption of PUFA’s and/or higher insulin?
There are five major classes of FH due to LDLR mutations. FH is a collection of genetic defects. Many believe that the end result of these defects (IE high LDL or cholesterol) cause the diseases associated with it. I do not. Why? When these people live past their 6th decade they have extremely low levels of neurodegeneration. I believe the cause of the early on set CAD is tied to secondary effects of what the primary genetic disease does to the liver to alter its function. If one looks at FH patients and their VAP results one sees a pattern of chronic gut inflammation that is the real source of the atherosclerosis that causes higher incidences we see in FH. These patients all have altered gut biofilms and some of the lowest levels of Vit K2 and vit D. They also have extremely low DHEA S and pregnenolone levels are pointing to a chronic inflammation……due not to the high cholesterol level but to an altered gut axis. Read my blog on this here. http://jackkruse.com/your-vap-brain-love-not-war/ My views on this topic are radically different because even with severe LDL lowering treatments the disease patterns these people face remain unchanged. Why? because their gut remains the source of the inflammation that damages their arteries for their entire life. We need to focus our efforts on the gut side of the equation and not the LDL side. Ironically Dr Davis has done this with his assault on wheat. Wheat drives sdLDL via what mechanism? It screws up the liver and increases gut permeability to cause issues. His current ideas and mine are very close…….but no one is tying this together. I think my VAP post on the gut provides you the link.
All patients with FH need to have their thyroid optimized. This issue was hashed out at the Ancestral Health Symposium on August fifth at UCLA. Jack Kronk’s VAP is helping many patients learn how to raise their HDL to increase endotoxin clearance from the portal circulation to prevent oxidation of slow moving cholesterol because of A lack of their LDL receptor. Thyroid optimization can overcome this to a degree but it requires a physician who knows precisely how to do this and not create an unsafe situation. Their diets has to be a strict low carb moderate protein paleo diet high in coconut oil.
Dr K. -
I am inquiring with the my Doc about getting tested for ApoE. I will let you know how that goes.
Regarding hypothyroidism, yah the issue that I’m running into is that “it requires a physician who knows precisely how to do this and not create an unsafe situation”.
This is the problem with our medical system in America. I live in San Diego, one of the biggest, most advanced cities on earth, and I am having trouble finding anyone over here that can truly help me with this. My doctor situaiton is pathetic. Sorry to say that, but I’ll call a spade a spade. All they want to do is put me on Lipitor and go low fat whole grain. So then I am stuck with doing my own diligent research, and appyling knowledge that I can learn from people who actually know what they are talking about, and right now, for me, that means the internet. Incredible when you think about it.
When you say low carb, do you mean no starch as well, not even potatoes? By the way… the name of this post is “The Exception to Low Carb”. So… that’s why this is so confusing. Some very knowledgable people think it’s best to raise my intake of starches and lower my fats. If my body is creating more LDL (even small dense) because of my saturated fat intake, then it makes sense to replace sat fats with something else. I already get enough protein, so then I am left with carbs. If it has to be carbs, isn’t safe starch my only real option? It can’t be ‘sugar’. It can’t be ‘fructose’, or grain starch, right? Should I eat loads of salads? Or I am on the wrong track completely? Should I look at upping my mono fats in place of saturated, like using mac nut oil for cooking? Or would mono fats be just as problematic?
You see? Honestly, I know this stuff stone cold. I know what *most* people do well with, but if we don’t figure out how being pre-disposed to having issues with LDL receptors really changes things, we are going to (deservedly) get hammered by the low-fat whole grain camp when a fair amount of people who thought they had it all figured out are dropping dead from eating fats because they are ApoE and had no idea.
I’m genuinely glad that my example is helping people. No doubt I am. But I’d be alright with feeling like I’m getting somewhere with all this in my personal case as well. At the moment, I can’t really say that I feel that way just yet.
Genetic high total cholesterol is related to the over 50 amino acid variations of PCSK9 (pro-protein conertase subtilisn/kexin 9, which comprises 692 amino acids). Individuals producing an excess of PCSK9 more extensively degrade their cholesterol receptors with surface defects; and so don’t readily take up LDL out of circulation, which lets blood levels of LDL rise higher. Conversely, those making sparse PCSK9 can’t degrade their LDL receptors, which pull lots of cholesterol into a tissue cell where it can pile up over time in that cell’s lysosome; and blood levels of LDL seem to drop.
PCSK9′s worst version is D3744; where total cholesterol trends to 4 times normal and risk of death is estimated to be even +/- 10 years sooner than even other problematic PCSK9 genetic variations that affect maybe 1 in 500 westerners and account for +/- 5% of all pre-mature coronary heart disease. As regards the “older” age survival ability of those with familial high cholesterol this may be due to the way over time plaque holds less lipid content and acquires more collagen with calcium infiltration. In other words younger plaque is less stable and more likely to burst free and be perilous.
If fretting about plaque be aware that the average duration of carotid plaque is +/- 9.6 years; according to Carbon 14 dating from autopsies. Plaque may even form multiple times during one’s life and the statistically dangerous symptoms take 5 – 15 years to manifest. Increased levels of circulating plasma insulin accelerate the rate that plaque forms; and also adds to a plaques instability (ie: potential to rupture) due to insulin’s interaction with genes involved in the immune response; like how those with insulin resistance make more pro-inflammatory cytokines. This bolsters Doc Davis’ insistance to control glucose, since the down stream result is a more stable plaque.
Noteably, there is the so called “protective cytokine” TGF beta which can allay plaque rupture. This is hard to predict for individuals because we have no way to assess who has what types of TGF beta receptors around , since normal and then plaque ridden blood vessels can harbor different TGF beta receptors. TGF is considered a vital player inside vascular smooth muscle cells because it forms part of the interactive sequence that stops the smooth muscle cells from altering; and it bears mentioning that excess cholesterol can inhibit some TGF beta pathways.
This too can be assessed by looking at thyroid beta receptors……it is associated with down regulation or resistance of this specific thyroid receptor. A company in Denmark has a clinical trial on going about this specific receptor. Thyroid hormones bing to both thyroid alpha and beta receptors. But disease that affect the LDL receptors seem to preferentially knock out the thyroid beta receptor.
For those who asked (Jack Kronk, Peggy, et.al.) about where and how one can get tested for ApoE it’s simple: Virtually any large commercial lab in the U.S. can do the test, e.g., Labcorp, Quest, etc. Also, Atherotech (VAP) and Berkeley Heart Labs will do the test as well. Since it’s a genetic test, it’s only run once during a person’s lifetime. The test can run anywhere from around $100 on up, depending on which lab runs it for you.
I got quote at $390 for just an ApoE genetic test. Is that normal?
In my last lipotropen test, I do not absorb chol not do I make it. Am I a closed system? My lp[a] is 41. I am very puzzled.
Dee
That was from the Boston Heart lab. I am a AP03/3.
Super interesting!
Do you know what SNP is PCSK9 ? I’d like to look up it in my 23andme info.
Thanks,
George
Plasma PCSK9 levels correlate with cholesterol in men but not in women
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References and further reading may be available for this article. To view references and further reading you must purchase this article.
Janice Maynea, , , Angela Raymonda, Anna Chaplinb, Marion Cousinsb, Nadine Kaefera, Charles Gyamera-Acheamponga, Nabil G. Seidahc, Majambu Mbikaya, Michel Chrétiena and Teik Chye Ooia, b
aHormones, Growth and Development Program, Ottawa Health Research Institute, The Ottawa Hospital, University of Ottawa, Ottawa, Ont., Canada
bClinical Research Laboratory, Division of Endocrinology and Metabolism, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ont., Canada
cLaboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Que., Canada
Received 29 June 2007. Available online 18 July 2007.
Abstract
Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that negatively regulates low density lipoprotein receptor (LDLR) levels. Several single nucleotide polymorphisms (SNPs) in PCSK9 have been linked to autosomal dominant hypercholesterolemia (ADH). Conversely, hypocholesterolemia associates with both ‘loss of function’ nonsense and missense SNPs in PCSK9. We examined the association of plasma PCSK9 with lipoprotein parameters in 182 normolipidemics. For men (n = 98) plasma PCSK9 averaged 6.08 ± 1.96 μg/ml and Spearman analysis revealed significant correlation between it and total cholesterol (TC), LDLC, and TC/high density lipoprotein (HDLC) (r = 0.276, 0.282, and 0.228, respectively). For women (n = 84) plasma PCSK9 averaged 6.46 ± 1.99 μg/ml having no correlation with TC, LDLC or TC/HDLC. The ratio of plasma PCSK9/LDLC increased in men carrying ‘loss of function’ PCSK9 variations. Our results suggest a gender difference in PCSK9 regulation and function with PCSK9 correlated to TC and LDLC in men but not women.
Keywords: Plasma PCSK9; Loss of function; Hypocholesterolemia; Hypercholesterolemia; Single nucleotide polymorphisms
Article Outline
Materials and methods
dI found this on the internet, I’m not sure if this is what you need?
Dee
I apologize if I sent the wrong ifo. Didn’t read it through.
Dee
Following your diet I took an NMR last summer and this summer. The small LDL particles went down (835 to 709) but the total particles went up (1800 to 2100). Should I stick with your diet (low carb, no wheat, D, omega3′s), one Walmart glucometer) or go back to rice and beans?
I’ve been eating paleo/primal for about a year, dropped 10 pounds, and brought my triglycerides down from a high of 325 three years ago to 130. Unfortunately, my LDL-p is over 2600 (first time it was checked), and I found out I’m APO e4/e4.
The doctor says e4/e4 should go vegan, which seems about as anti-primal as you can get.
Any suggestions for where to start looking for eating guidelines?
My goodness, how very confusing!! I’m hypothyroid. My HDL is 95. My total C is 285. Ny LDL is 186. But my LDL fractions are mostly big and plumb and my small total 23. So, I think I’m ok…buy my doc thinks I should go vegan. I want coconut oil, little red meat. I evercise 5x week. My heatt stress tests were all ‘well within’ So, it sounds as though I need to get the E4 tested More?