Dr. Davis,

I continue to be amazed at how much value you are providing all the time to those of us deeply concerned about heart disease.

Whether it's at this blog, at LEF.org, at your TrackYourPlaque.com site, or in your Track Your Plaque book, your contribution is pretty astounding.

I only found your work in the last 2-3 weeks and already it has made a deep impression on me and I'm getting clearer about what I need to do to combat heart disease in myself and in family members.

Thanks for all you're doing!

Wow!

Thanks for the feedback. I'm glad it's helping you. It is wonderful to hear back about the impact the program is having.

Excellent article!  I especially liked the tie-in to poor kidney function.

Dr. Davis: In your excellent LEF article, I found your reference to a fascinating statement about statins and vitamin D by Dr. David Grimes of the UK. For those interested, here is the Lancet source article (reprinting for educational purposes):

The Lancet 2006; 368:83-86
DOI:10.1016/S0140-6736(06)68971-X

Are statins analogues of vitamin D?
David S Grimes MD, Blackburn Royal Infirmary, Blackburn, Lancashire BB6 8HE, UK

Summary

There are many reasons why the dietary-heart-cholesterol hypothesis should be questioned, and why statins might be acting in some other way to reduce the risk of coronary heart disease. Here, I propose that rather than being cholesterol-lowering drugs per se, statins act as vitamin D analogues, and explain why. This proposition is based on published observations that the unexpected and unexplained clinical benefits produced by statins have also been shown to be properties of vitamin D. It seems likely that statins activate vitamin D receptors.
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During the late 19th century, conventional wisdom held that masturbation was the cause of epilepsy, a more plausible explanation than the previous notion that epilepsy was the result of possession by the devil, and illness in general the result of divine interference. Since bromide was thought to reduce sexual desire, it became the logical treatment. Although reasonably successful, bromide worked for reasons that are different from the theory on which it was based. Can the same be said of statins for heart disease?

The emergence of coronary heart disease (CHD) in the 20th century required an explanation. Some had noted that cholesterol accumulated in the walls of the arteries, and a process of accretion was hence described as the major mechanism. Cholesterol was assumed to originate from diet, and the diet-cholesterol-heart hypothesis was established. The logical treatment was to reduce dietary and serum cholesterol concentrations.

Many inconsistencies in this hypothesis have emerged and been disregarded. In the London banking and transport study,1 for example, men with the highest dietary cholesterol intake had the lowest incidence of CHD. Furthermore, the results of the Framingham study2 showed that raised concentrations of serum cholesterol were predictive of CHD only in men younger than age 55 years. Findings of studies from Honolulu3 and Paris4 suggest a protective effect of high serum cholesterol concentrations, and the Leningrad paradox5 indicates that those exposed to famine subsequently have a high incidence of CHD, the opposite of what is expected. In Europe, populations that consume a large amount of dietary fat and cholesterol have a low incidence of CHD (the French paradox),6 and the lowest incidence of CHD is seen in European nations with the lowest consumption of wine and the most socioeconomic deprivation (the Albanian paradox).7

Initial treatments to reduce serum cholesterol were not effective. When introduced, however, statins did greatly reduce serum cholesterol concentrations by interfering with its synthesis; the beneficial effects of statins in CHD have been assumed to be the result of cholesterol-lowering, an assumption that I believe is a serious mistake.

Statins and the heart

The first statin trial was the Scandinavian Simvastatin Survival Study (4S),8 and its findings indicated a significant clinical benefit from simvastatin. The results of the West of Scotland Coronary Prevention Study (WOSCOPS)9 also showed clinical benefit from statins (pravastatin) and of a greater magnitude than expected; the mortality reduction was about 35%, whereas the reduction in cholesterol concentrations predicted a mortality reduction of only 25%. WOSCOPS9 showed no association between cholesterol-lowering and clinical benefit,10 indicating that cholesterol-lowering was not the mechanism by which pravastatin reduced coronary events.

In WOSCOPS, statins lowered serum cholesterol concentrations, but also raised concentrations of HDL cholesterol and lowered those of serum triglyceride, indicating that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase was not the only metabolic action. The clinical experiment of cholesterol-lowering was thus intrinsically flawed, and what must be understood is that 4S and WOSCOPS were trials of statin therapy and not trials of cholesterol-lowering.

Unexpected benefits of statins

It is noteworthy that the participants treated with pravastatin in WOSCOPS had a reduced incidence of diabetes compared with controls.11 Additionally, when pravastatin was given to recipients of heart transplants in an attempt to reduce the likelihood of CHD, a reduction in the rate of rejection and an increase in overall survival was noted, irrespective of CHD status.12 The same pattern was seen in recipients of kidney transplants.13 Clinical benefits of statins have also been noted in a placebo-controlled trial14 of atorvastatin for rheumatoid arthritis. Furthermore, simvastatin has been used successfully to treat patients with multiple sclerosis.15 As with CHD, diabetes, rheumatoid arthritis, and transplant rejection, the benefit noted with respect to multiple sclerosis is independent of any effect on serum cholesterol.
Statins also have an effect on bone, and women who take statins have a greater bone density than those who do not.16 Moreover, the findings of the 10-year follow-up study of participants in 4S17 indicate a significantly reduced risk of cancer, particularly colorectal, lung, and prostate cancer, in those who received simvastatin. Results of a population study from Israel18 also show a greatly reduced risk of colorectal cancer in those taking statins.

In 1974,19 a group of illustrious diet-cholesterol-heart researchers studied the association between cholesterol and cancer. They noted that high serum cholesterol concentrations conferred protection against colon cancer. The effects of statins mentioned above hence present a major paradox: how can a drug that lowers serum cholesterol concentrations reduce the risk of colon cancer when high serum cholesterol concentrations are, in fact, protective?

A drug can act as a poison by blocking normal metabolic processes, but to produce a beneficial effect (other than antibacterial) we should assume that it is switching on or enhancing a normal metabolic process. I therefore suggest that statins mimic many of the actions of vitamin D and can be considered analogues of vitamin D.

Sunlight and vitamin D

Heart disease

In Europe, there is a higher rate of mortality from CHD in the northern than in the southern countries, with the lowest rates noted along the Mediterranean coast.20 This pattern suggests that susceptibility to CHD is affected by duration of exposure to sunlight. This notion is supported by findings from the USA21,22 that the higher the altitude of residence, and hence the greater the sunlight intensity, the lower the risk of heart disease.

Furthermore, the only dietary change that consistently protects against CHD is an increase in consumption of oily fish and fish oil, which contain large amounts of vitamin D.23 In the Netherlands, mortality from CHD was more than 50% lower in men who consumed at least 30 g of fish per day than in those who did not eat fish.24 A similar result was reported in women from a 16-year follow-up study in the USA.25

Multiple sclerosis

Multiple sclerosis also shows a latitude gradient in Europe, with the world's highest incidence reported in Scotland.26 The risk of developing the disease is reduced by a third by regular supplementation with vitamin D.27

Cancer

The risk of breast cancer and colon cancer is high in northwest Europe and much lower in the Mediterranean countries.28 And, in the UK, people die more readily from cancer in the north than in the south of the country. After being diagnosed, 34% of men with cancer and resident in Oxfordshire survive for 5 years compared with 26% of those who live in the northwest and Yorkshire. Men with stomach cancer who live in London survive on average twice as long as those who live in the northwest of England; the same applies to bladder cancer.29 Patients with colon cancer also have a greater chance of survival if they live in the south of England rather than in the north.30 The benefits of sunshine and vitamin D would explain these associations.
Results of a study31 done in 1941 in the USA and Canada showed that the cancer death rates among residents of the most northern cities were two and a half times those of the most southern cities. An extensive study32 of more than 5000 locations in the USA has shown that incidence rates of cancer are lowest where ultraviolet light exposure is greatest. Bladder, breast, colon, kidney, oesophageal, ovarian, prostate, rectal, stomach, and uterine cancers, and non-Hodgkin lymphoma are associated with low exposure to ultraviolet light.32

In the USA, cancer of the prostate has an increasing incidence with distance from the equator, suggesting a protective effect of sunshine. The incidence is highest in the eastern states and lowest in the west.33 This is exactly the same as with CHD, and is probably the result of a high altitude being protective because of greater ultraviolet light exposure. The association between prostate cancer and insufficient access to ultraviolet light has also been noted in the UK,34 with men exposed to low levels of ultraviolet light developing cancer at a younger age than those exposed to high levels (median age 67•7 years vs 72•1 years).

In a study35 of 456 people with early-stage lung cancer who had undergone surgery, those diagnosed and operated on in the summer, spring, or autumn had a significantly higher 5-year survival rate than those diagnosed and operated on in the winter. The survival rate was 29% in those who took no vitamin D supplements and had treatment in the winter compared with 72% in those who took vitamin D supplements and were treated in the summer.35


Diabetes

The international distribution of diabetes in children is very similar to that of CHD, with incidence increasing with distance from the equator,36 again suggesting a protective effect of sunlight and vitamin D. Furthermore, children of women who do, compared with those who do not, take cod liver oil during pregnancy have a reduced incidence of type 1 diabetes.37 The findings of a retrospective study,38 undertaken in Finland and involving 10 821 children born in 1966, indicate that the incidence of diabetes in adulthood is almost ten times higher in those who do not, compared with those who do, take vitamin D supplements in childhood. The benefit of vitamin D supplementation during infancy has been further strengthened by the findings of a large study undertaken in Norway.39

Rhematoid arthritis

Kröger and colleagues40 noted that 16% of 143 women with rheumatoid arthritis, compared with the general population, had very low concentrations of serum calcidiol. During the winter, 73% had levels of calcitriol below the seasonally adjusted normal range and the lowest levels were in patients with very active disease. In another study,41 of 19 patients with rheumatoid arthritis given vitamin D supplements, nine reported a complete remission of symptoms, and eight a satisfactory response. Inflammatory markers also improved: the mean erythrocyte sedimentation rate fell by 43% and the mean concentrations of C-reactive protein by 52%. This study is a small one but although far from conclusive the results conform to a pattern that should not be ignored.


Testing of my hypothesis

In view of the above, there is a striking similarity between the benefits of vitamin D and the benefits of statin therapy. I believe that the unexpected and unexplained beneficial effects of statin therapy might be mediated by activation of vitamin D receptors by this group of drugs. This hypothesis is, in theory, easy to test.
A prospective study should be undertaken in cancer treatment and prevention, with a factorial design, so that patients receive statins, vitamin D, a combination of statins and vitamin D, or placebo. A similar outcome in the three treatment groups would lend support to the suggestion of statins acting via vitamin D receptors. If vitamin D and statins are activating the same receptors, then if both are given in sub-maximum doses, the two together would have a greater effect than each individually. Intervention studies should also be undertaken to look at the relapse rates of established illnesses, including CHD, multiple sclerosis, and rheumatoid arthritis, comparing statins and vitamin D.

The difficulty in doing these studies is that we know only the minimum dose of vitamin D necessary to prevent and heal rickets: we do not know the dose necessary to increase to a maximum the other effects, especially those that enhance immune competence. The same applies to statins: their effect on serum cholesterol concentrations is easy to measure, but we do not know what to measure as a biochemical surrogate for the other effects, again probably those enhancing immune competence. As such, a range of treatment doses of vitamin D and statins need to be investigated. Additionally, clinical trials of established treatments—eg, statins for CHD—are difficult to design because of the ethics of not giving an established medication (a statin), but in place a trial medication (vitamin D). Comparisons with vitamin D supplements could be undertaken, but only once the optimum dose of vitamin D has been established.

Colonic mucosa and colonic cancer cells contain vitamin D receptors,42 strengthening my suggestion that vitamin D is biologically active in these tissues. Furthermore, vitamin D has an inhibitory effect on colonic carcinoma cell lines.43 Do statins have a similar effect? In-vitro experiments are one way that the effects of statins on vitamin D receptors could be investigated directly.

Conclusion

Anomalous results, such as the unexpected benefits of statins detailed here, lead to the advancement of science. Such an opportunity for research should not be overlooked. Statins should be looked at objectively and the diet-cholesterol-heart hypothesis on which the treatment was based disregarded. Statins have been described as wonder drugs because of their unexpected benefits; my hypothesis gives an opportunity for new thinking. The explanation of statins as analogues of vitamin D, if correct, would be reassuring to the millions of people who take them every day. Finally, sunlight and vitamin D might at last be recognised for their widespread health benefits.

Conflict of interest statement
I declare that I have no conflict of interest.


References

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14. McCarey DW, McInnes IB, Madhok R, et al. Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004; 363: 2015-2021. Abstract | Full Text | PDF (101 KB) | CrossRef
15. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607-1608. Abstract | Full Text | PDF (59 KB) | CrossRef
16. Edwards CJ, Hart DJ, Spector TD. Oral statins and increased bone-mineral density in postmenopausal women. Lancet 2000; 355: 2218-2219. Abstract | Full Text | PDF (59 KB) | MEDLINE | CrossRef
17. Strandberg TE, Pyörälä K, Cook TJ, et alfor the 4S group. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study. Lancet 2004; 364: 771-777. Abstract | Full Text | PDF (101 KB) | CrossRef
18. Poytner JN, Gruber SB, Higgins PDR, et al. Statins and risk of colorectal cancer. N Engl J Med 2005; 352: 2184-2192. CrossRef
19. Rose G, Blackburn H, Keys A, et al. Colon cancer and cholesterol. Lancet 1974; 1: 181-183. MEDLINE | CrossRef
20. Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart disease. Q J Med 1996; 89: 579-589.
21. Mortimer EA, Monson RR, MacMahon B. Reduction in mortality from coronary heart disease in men residing at high altitude. N Engl J Med 1977; 296: 581-585. MEDLINE
22. Voors AW, Johnson WD. Altitude and arteriosclerotic heart disease mortality of white residents of 99 of the 100 largest cities in the United States. J Chronic Dis 1979; 32: 157-162. MEDLINE | CrossRef
23. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989; 3342: 757-761.
24. Kromhout D, Bosschieter EB, Coulander C de L. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985; 312: 1205-1209. MEDLINE
25. Hu FB, Bronner L, Willett WC, et al. Fish and omega-e fatty acid intake and risk of coronary heart disease in women. JAMA 2002; 287: 1815-1821. MEDLINE | CrossRef
26. Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Acta Neurologica Scand 1975; 51: 137-157.
27. Munger KL, Zhang SM, O'Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62: 60-65.
28. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer in five continents VIII. International Association of Cancer Registries (IACR). Scientific publication number 155. Lyon: IACR, 2002:.
29. Silman AJ, Evans SJW. Regional differences in survival from cancer. Community Med 1991; 3: 291-297. MEDLINE
30. Coleman MP, Babb P, Damiecki P, et al. Cancer survival trends in England and Wales, 1971–1995: deprivation and NHS region. London: Stationery Office, 1999:.
31. Apperly FL. The relationship of solar radiation to cancer mortality in North America. Cancer Res 1941; 1: 191-195.
32. Grant WB. An estimate of premature cancer mortality in the US due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002; 94: 1867-1875. MEDLINE | CrossRef
33. Hanchette CL, Schwartz GG. Geographical patterns of prostate cancer mortality: evidence for a protective effect of ultraviolet radiation. Cancer 1992; 70: 2861-2869. MEDLINE | CrossRef
34. Luscombe CJ, Fryer AA, French ME, et al. Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer. Lancet 2001; 358: 641-642. Abstract | Full Text | PDF (61 KB) | MEDLINE | CrossRef
35. Zhou W, Suk R, Liu G, et al. Vitamin D predicts overall survival in early stage non-small cell lung cancer patients. American Association for Cancer Research April 16–20, 2005, abstract LB-231.
36. Matthews DR, Spivey RS, Kennedy I. Coffee consumption as trigger for diabetes in childhood. BMJ 1990; 300: 1012. MEDLINE
37. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of type 1 diabetes in the offspring. Diabetologia 2000; 43: 1093-1098. MEDLINE | CrossRef
38. Hyppönen E, Läärä E, Reunanen A, Järvelin M-R, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358: 1500-1503. Abstract | Full Text | PDF (77 KB) | MEDLINE | CrossRef
39. Stene LC, Joner Gfor the Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large population-based case-control trial. Am J Clin Nutr 2003; 78: 1128-1134. MEDLINE
40. Kröger H, Penttila IM, Alhava EM. Low serum vitamin D metabolites in women with rheumatoid arthritis. Scand J Rheumatol 1993; 22: 172-177. MEDLINE
41. Andjelovic Z, Vojinovic J, Pejnovic N, et al. Disease modifying and immunomodulatory effects of high dose 1α (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol 1999; 17: 452-456.
42. Kane KF, Langman MJS, Williams GR. Vitamin D3 and retinoid X receptor mRNAs are expressed in human colorectal mucosa and neoplasms. Gut 1994; 35 (suppl): S2.
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Affiliations

a. Blackburn Royal Infirmary, Blackburn, Lancashire BB6 8HE, UK

Also, a full-length booklet that contains just about everything you want to know about vitamin D (or at least a right-this-moment summary of what is known about it) will be available to Track Your Plaque Members for free before the end of the year.

Hi Dr Davis,
I am an apoe4 carrier. My trig=62, HDL=69; LDL-C=175 after 16 months on a carbohydrate restricted, gluten free diet. Wondering whether I need to also reduce my fat intake. But then what is left to eat? Making up the calorie difference with protein does not sound too healthy.

David

Hi, David--

I would urge you to NOT rely on the calculated LDL value, since on a low-carb diet with potential conversion of small to large LDL particles calculated LDL can substantially overestimate true LDL.

The best: LDL particle number through NMR lipoprotein analysis. The next best: apoprotein B, widely available from nearly all labs.

When you're armed with this information, then you can make an intelligent decision about diet changes.

Regarding Item 6

There was some traffic between Chris Kresser and Jimmy Moore on Twitter yesterday regarding whether low carb caused low T3 in susceptible individuals. Clearly bad news for heart health.

I am a treated hypothyroid and this was my recent experience - I had gone low carb and ended up with an abscess in the roof of my mouth that needed antibiotics.  When tested, my T3 had fallen from 5.5 to 3.8 (RR 4 - 6.8) - however, my TSH was 0.672 (RR 0.35-4.5).  In the UK, this low T3 would normally would have been missed as there is a TSH only testing policy here unless the TSH is found to be outside the reference range - I elected to pay privately for the T3 test.

I remain on low-carb (and wheat free of course) as it is the only approach which allows me to lose weight, and have increased my meds from 75T4+20T3 to 100T4+40T3.

I would query whether you consider hypothyroidism to be rare. I suspect it is very common.

Hi Dr. Davis:
What if the patient  followed the above diet, had a particle count of 2,100, but only 200 were small and HDL 69 and Trgs 66.  Would this be acceptable, and better than a particle count of 640, less than 90 small, HDL 64, Trgs 45, but on statin and Zetia?  Assume thyroid and D all normal, and Apo E3/3
Thanks for all the input

Hi Dr Davis,
This post really hit home with me (and ironically this is my first visit to your site).  I had a heart attack 2 years ago (34 years old, ate well or so I thought, in great physical condition at 5'9" 150 lbs).  My cardiologist advised the usual low fat diet and pravastatin, and while my lipids are better than they were, I'm still very concerned they are not near where they should be.

About 5 weeks ago I found the primal diet and began eating that diet.  Last week I had another lipid test and my numbers actually got worse (not by much).  Would you mind reviewing my numbers and if you have any suggestions I would appreciate it.

8/31/2009 heart attack
total chol 115
LDL 74
HDL 16
Triglycerides 126
VLDL 25

07/19/2010 checkup
total chol 138
LDL 64
HDL 33
Triglycerides 203
VLDL 41

03/21/2011 Healthfair
total chol 122
LDL 69
HDL 31
Triglycerides 111
VLDL 22

8/19/2011 walk in lab:
total chol 159
LDL 98
HDL 34
Triglycerides 135
VLDL 27

Glucose 97
hsCRP 1.2
A1c 5.5

Do you suggest giving the "primal" diet more time or do you suspect I may have another condition causing this?

Also in May of this year I had the following tests done at the cardiologists:
Date of service: May 13, 2011
CAT Scan MRI & NMR
Diagnostic Radiology X-Ray
Cardiovascular Stress Test

I was told everything was fine.

Track Your Plaque once gave a desirable level of ApoB  as under 70 mg.dl as surrogate marker for the desirable LDL particle number (which is less than 700 nm/l) if one only has ApoB testing.  Maybe some one else can recall the conversion ratio of ApoB into LDL particle numbers.

A cholesterol fractions normal transfer from HDL to ApoB is governed by  the cholesterol ester transfer protein (CETP). Genetic variants of CETP can cause differences in the numbers of  small LDL and sparse CETP can cause cholesterol to stay stuck in HDL  ( CETP has little impact on numerical % of HDL). So genetic variants of ApoB can influence the levels of cholesterol shunting around.

In  the liver ApoB normally gets it's lipids when ApoB goes into a cell's endoplasmic reticulum. And if the ApoB doesn't improperly degrade ( ApoB needs "enough" microsomal triglyceride transfer protein SREBP-1c, the sterol regulatory element binding protein, to avoid degrading) then ApoB can pick up triglycerides to form VLDL molecules. So, if there is not enough liver SREBP-1c  then lipids can't be transferred over to make triglyceride rich VLDL; conversely lots of liver SREBP-1c provokes extra VLDL.

Doc says carbohydrate related  post-prandial high glucose not only induces  more VLDL output  from the liver but that this is part of the mechanism whereby carbs can boost body fat. High carbohydrate intake causes extra lipo-genesis in the liver because a significant  reflex of high post -prandial liver insulin is a signal that upregulates SREBP-1c. Then SREBP-1c expression rises and that in turn activates genes for the lipogenic enzymes (ex: fatty acid synthesase & acetyl CoA carboxylase),

Rogue readings of VLDL may be due to viral hepatitis proteins, flavivirus and pestivirus, which can decrease VLDL formation and secretion while dropping levels of ApoB. Viral proteins "smear" onto lipids and this blocks SREBP-1c action and viral proteins can also "stick" on to the HDL protein fraction ApoA1 inside of the  liver cells' Golgi Apparatus. Thus in chronic liver disease and hepatitis circulating VLDL associated triglycerides eventually decreases so there are more non-VLDL  triglycerides in play.

Hi Dr. Davis,

I was just wondering, due to many healthy cultures including the kitava, okinawan's...etc, who indulge in rather high carb intakes and retain rather pristine health, is it possible that high trigs, low hdl..etc may just be a lipid profile reflecting high carb* intake rather than suggesting atherogenic buildup ?

*when based on safe starchy type carbs

Hi, Paul--
In the population I see, hypothyroidism is exceptionally common, both in people on low-carb but also in people prior to initiating their low-carb efforts. So, without a formal analysis, I'm skeptical that low-carb in and of itself causes free T3 to drop.
There are also numerous inhibitors of the 5'-deiodinase enzyme that converts T4 to T3, including perchlorate residues from fertilizers in vegetables and polyfluorooctanoic acid, the residue of non-stick cookware, just to name a couple.

This is the BIG unanswered question. Sadly, there are next to no data that speaks to this question.
My day to day answer has been to 1) eliminate small LDL, then 2) maintain LDL particle number 1500 nmol/L or less. But that is pure speculation on my part.

Hi, Chris--
Something doesn't compute: Every panel you list is the pattern of excessive carbohydrate consumption and/or sensitivity. So something is sneaking through. There is no question that a "primal" or low-carbohydrate approach works for this pattern.  

You might also have an Apo E2 gene that amplifies carbohydrate sensitivity.

Hi, Might--
As always, you are an incredible fountain of unique insights!

Sorry, Jack, I didn't understand your question. Could you rephrase?

Thanks.  I've only been eating primal/paleo for about five weeks, so only the last panel would reflect this (if thats enough time to be reflected in my lipid panel).  I will re-test after another few months.

Dr Davis. Jeez. This sounds similar to my story (Frustrated's #s). I have eaten Paleo for over a year now, I have done exceedingly well with body composition in that time. See my "Share You Paleo Before and After" here ---> http://paleohacks.com/questions/7058/share-your-paleo-before-and-after/28493#28493. But this only adds to the confusion for me (and others).

For some reason, my labs came back on July 8, 2011 with small dense LDL and pathetic HDL at 40, despite a diet rich in GF beef, pastured eggs, bacon, pasture butter, coconut oil, ghee, veggies, starch and fruits only for carb sources, etc etc. I spend mega money to eat well. We don't mess around. I posted my VAP panel results on PaleoHacks last month and it has resulted in a lot of attention on this very subject. Chris Masterjohn weighed in with his thoughts. Dr Kruse wrote a blog all about it.

http://paleohacks.com/questions/50347/hack-jack-kronks-vap-test-results

I will be retesting again in about a month, as I have made some changes, like eliminating bananas, less heavy cream and pasture butter, etc.

My lab said it's $390 just to do the ApoE test. Is this a normal price? If not, where do you recommend people get the testing done?

I'm genuinely confused. It's like my body is saying... "Yes Jack. Good job. I am very happy with what you are eating. I will continue to keep fat off and pack on muscle." But then my heart is saying "Nooooo. Stop!!"

How can this be?

I was questioning if your pathological interpretation of a blood lipid profile that exhibits low hdl and high triglycerides, could instead just be a reflection of a high carb diet rather than suggesting an increased risk for CVD. I was referencing a couple high carb cultures, such as the Okinawa and the kitava, who exhibit a similar lipid profile but have very small incidence of CVD. Compared to other cultures with similar lipid profiles, such as the Swedes and Americans, who have much higher rates of CVD would suggest it's more about quality of blood lipids rather than their certain partitioning. Hopefully that's a better re-phrasal?

This is the BIG unanswered question. Sadly, there are next to no data that speaks to this question.
My day to day answer has been to 1) eliminate small LDL, then 2) maintain LDL particle number 1500 nmol/L or less. But that is pure speculation on my part.

My understanding related to your above comment is that large LDL is nearly as athrogenic as small LDL and that you want the particle number low with mix between largle and small LDL taking secondary importance.  Of course, that is based on a diet that the avg american consumes,  and not on the low carb with wheat sugar and cornstarch elimination you advocate.
Am i under a correct understanding regarding large LDL being dangerous as well and therefore the need to minimize this even with your dietary recommendations?  Also, i thought you advocated a total LDL particle number to approach 600?  Is your 1500 number a revised viewpoint based on newer diet or clinical observations?
Thank you again.

Server error blocking me again ... testing after hour passed.

ApoE is crucial to VLDL & chylomicron formation. Variant ApoE 2 less efficient at transfering lipids to liver and is binding lipids up an extra +/- 2%; result is that lipids take longer to clear from circulation and more can go wrong. From my notes, here is the rate some ancestral populations have at least 1 copy of ApoE2: 2-4% of Mexican-american & American Indian, also  3-4% of Japanese & West African. There is 0% of South American Indians with ApoE2 and one wonders which variation of  ApoE  might be in Kitava melanesians. .
ApoE4 degrades easiest of all ApoE forms, leaving protein fragments in cell's cytosol which then can affect a mitochondria's lipid binding region impairing the performing of  tasks. In addition ApoE4 fragments diminish gene PPAR gamma expression; and this depresses the desirable bio-genesis of mitochondria. The affects on mitochondria may be why high levels of dietary fat is problematic for ApoE4 individuals; there may be too sparse output of viable mitochondria and mitochondria membranes are involved in how efficiently we burn fat or glucose.  .
In light of these ApoE4 nuances it is interesting to know that fasting raises free fatty acid levels (from fats in the body and not loose fats from recent food); and then those free fatty acids upregulate  gene for PPAR gamma in the liver. Fasting makes one put out ketones  because of the extra PPAR gamma programing and this ketogenesis is also one way that activating more PPAR gamma improves insulin sensitivity. This suggests to me that individuals with ApoE4 may (?) find some benefit from modified fasting; possibly something like decidedly fewer meals in a day and also simply not grazing on snacks (ie: in addition to just trying to select what foods to eat) between meals that are regularly spaced apart (ie: very early breakfast to let meal times spread put more evenly) .

Finally again from my notes, here is the rate some ancestral population have at least 1 copy of ApoE4: .14-19% Germans & Finns, also 7-12%  French & Italians. Of course America is one of the world's melting pots so an individual's propensity for ApoE 4 & ApoE 2 is hard to pin point.

This is fascintaing Might. I have been guilty of snacking too much. All healthy snacks, but still the concept of grabbing bites of delicious foods between meals might be messing with my liver. For my VAP test, I did not fast. Chris Masterjohn believes this was the reason (or at least the reason for dismissal) of my increase in triglycerides in the blood. I am most concerned about my low HDL, because if I raise my HDL, I believe my LDL will become more dominantly pattern A.

Thank you for the reply.  I would like to share a speculation.  Strict low carb means gluconeogenesis means an increased cortisol demand? OK in young fit Paleo men, but what about long-term un(der)treated hypothyroid individuals?

In "Safe Uses of Cortisol", Dr William Mck Jefferies (p. 183/4) observes that low dose (20mg/day) of hydrocortisone taken by a patient with hypothyroidism increases T3,  lowers T4 and improves patient energy levels suggesting such low dose cortisol enhances T4 to T3 conversion.

Could VLC, by putting demands on potentially weakened adrenals, have the opposite effect?

HDL molecules hold triglycerides (there are 45 different variations of triglycerides in circulation, which are based on what their esterified fatty acid component is), cholesterol esters (about 13 - 27% of the HDL surface particles), shingomyelins and glycerophospholipids. HDL's principle proteins are +/- 70% ApoA1 and +/- 20% ApoA2;  yet any changes in the ratio of ApoA2 from genetics (Kitavans?, I propose so) or drugs (ex:fibrates) can have effects.  

Usually people with low levels of  HDL have more trigs on their HDL surface (compared to those with high levels of HDL) and low HDL is associated with the passing of more cholesterol esters to VLDL & chylomicrons. Also, when HDL trig levels go up that makes it easier for the liver enzyme hepatic lipase to cleave off more ApoA1 for the kidneys to clear away; and that further tends to keep HDL levels low.  

In comparison people with high levels of HDL have more cholesterol esters on their HDL; which may be due in part to cholesterol esters affinity for ApoA1 in HDL. And statisticly high levels of HDL are usually associated with bigger ("large") HDL molecule size. Both large HDL and ApoA1 are considered to be more protective factors against atherosclerosis.

I suspect that Kitavan melanesians' low HDL fortuitously correlates with a geneticly higher than normal % of ApoA2; and ApoA2 configures more deeply nestled into the HDL complex than ApoA1. It (ApoA2) influences molecular  interactions all the way to the HDL surface and limits certain lipid dynamics.

ApoA2 holds ApoA1 off of mature HDL molecules and this results in a shunting of ApoA1 into forming up the pre-Beta HDL; these lipid poor ApoA1 configurations are great at doing reverse cholesterol transport that brings back cholesterol  to the liver for excreting as bile acids. Those pre-Beta HDL are small, yet notably excellent at taking cholesterol away from nefarious macrophage foam cells (the large HDL  molecule also picks cholesterol nicely from foam cells).

Experiments see that preceeding type of change with fibrate drug doses, which only minimally raise HDL & ApoA1 yet increase the ApoA2 amount in HDL by over 25%. Since fibrates are agonists activating the peroxisome proliferator activiated receptor PPAR alpha it might be instructive to see if anything in the Kitavan diet is a similar agonist, such as heirloom tuber roots derived from wild yam with high diosgenin content (diosgenin is well known to affect PPAR gamma).

Thanks for the excellent post! Bookmarked! Will come back again…

Hi, Steve--
There really is no final word on what the desired endpoint is when small LDl has been eliminated and you have pure large LDL. In a perfect world, I'd wish for a particle number of 600 nmol/L with pure large LDL. But I'm no longer entirely sure this is necessary. But this remains anecdotal. There are no formal data, nor do I have any formal analysis of our own data on this question.

Hi, Jack--
Don't know, since I've never seen any genuine lipoprotein data on these populations. Most of the data I've seen has been total cholesterol, which is far too crude to draw any conclusions from.

Have you seen lipoprotein data on these populations?

Might. Do you suspect that I have low HDL and highish Trigs/VLDL in the blood for this reason? I do take in a fair amount of protein (including a whey isolate daily). Also, plenty of eggs. Does dietary protein consumption have any actual affect on HDL's principle protein and/or surface cholesterol esters?

Yes Jack Kronk, it seems that you have low HDL and highish Trigs, I do also think.

Just wanted to comment. I've been a long time low carb person, gluten-free too. I also had my thyroid ablated with RAI many years ago. I have found, as have many low carbers, that my reverse T3 is very high and Free T3 is scraping the bottom or below the range.

Unfortunately this does seem to be a common side-effect of low carb eating. It's even documented in studies on the topic.

We had a low carb eater recently watching his LDL climb to very high levels after he began eating low carb. He started taking cytomel and his LDL is coming down very nicely.

Did he get a sudden onset of hypothyroidism that just coincided with low carb eating? I suppose that's possible, but I do think there's something more going on.

I'm taking Armour thyroid myself, but I still have the tendency to turn T4 into reverse T3 and I suppose that means the Free T3 can't get to the receptors. I'm going to experiment with raising my carbs a little higher and sticking to things like yams and squash for my carbs.

Dear dr. Davis,
I just attended the annual cardiology congress of the European Society of Cardiology. Amongst others, the new guidelines on dyslipidemia were presented and I had the opportunity to ask the working group the question you mention above in your first of opportunities : What about measuring lipids during an ongoing substantial weight loss? The were not able to give me a proper answer.
Do you have any scientific references saying that weight loss induce a temporary dyslipidemia or is it based on your experience?
I would be most thankful for your comment on this.
Best regards
Espen Rostrup, MD, PhD-fellow
Bergen, Norway

Dr. Rostrup--

Unfortunately, I know of no published data documenting this effect. However, I have seen it hundreds of times. It is, in fact, quite predictable: drop in HDL, rise in triglycerides, variable small LDL effects, increased blood glucose. It all subsides and improves over time.

It would indeed be an interesting study to chronicle the changes serially in a small number of people.

I am also seeing a heck of a lot of omega-6 intake there.  Also, the healthfulness of monounsaturated fats is a bit overstated.  I've heard of studies where they had 3 groups of people.  One got their normal saturated fat, one group replaced the saturated fat with olive oil and the third group replaced the sat-fat with corn oil.  The corn oil eaters did the worst in health outcomes, but the olive oil group wasn't great either--both groups that replaced the sat-fat did more poorly.  I've heard of other studies where lard was compared with olive oil and the lard-eaters turned out better.  Bottom line, the human body seems to like saturated fat best.  (Lard is not as saturated as butter, but it is more saturated than olive oil.)  If I were in a position to make medical recommendations (I'm not), I'd tell someone like this to ixnay on the plant oils for a while and see what happens.

It should be noted that one of the more dubious selling points of grass-finished meat is that it is lower in saturated fat.  To me, this is not a selling point.  If this person were only getting PUFAs from their grass-finished meat it would be one thing--at least then it'd be closer to a 1:1 omega-6/omega-3 ratio.  But that's not what's going on here.  If they were just eating the fish they might still be OK (depends on the fish--cold-water is better).  But they're adding in walnut oil and chicken consumption and those are going to add more omega-6, even if the chicken's pastured.

I'm curious what this person's inflammation markers are.  If they're off the map the LDL may still be high because the body's trying to repair the inflammation.  That would explain the low HDL too; LDL takes cholesterol out to the body from the liver, and HDL returns it to the liver.  If the cholesterol is *needed* elsewhere in the body then of course it won't be returned to the liver.

Even if inflammation markers are normal, this person's diet may not be meeting their needs for saturated fats in the cell membranes, which may mean they need more cholesterol in their cell membranes to try to make up the deficit.  Not an ideal situation.

Get the PUFA reduced, get the inflammation down if any, see what the lipids do and then we can talk about weird genes.  Absent the necessary DNA profile we really don't know, anyway.

"just eating the fish" = in addition to the pastured beef.  I would not drop beef in favor of fish, there's too much good nutrition a person would be giving up, but fish in addition to beef's not bad.  Chicken used to be a luxury food, you had it on Sundays if then.  Best that it's relegated to that role again.  The white meat is too dry and the dark meat's rife with PUFAs.  Other fowl are not much better.  A foray into the USDA's nutritional database is an eye-opener.

[...] Genetics: Dr. Davis has argued that some combinations of ApoE alleles may make a  person “unable to deal with fats and dietary cholesterol.” [...]

"As the scramble for heart patients intensifies, you are going to feel like you are being pulled closer and closer into the jaws of this hungry monster called the American cardiovascular healthcare machine."

I wish our primary care doc understood this.  When we expressed some reservations about a follow-up CT angiogram (and entering the CVD "machine" prematurely) after my husband's EBT heart scan score of 282 (and the recommendation for a statin Rx STAT without a chance to try diet, lifestyle and supplements), we were reprimanded in no uncertain terms and accused of distrusting Western medicine, and what we wanted to try (TYP) was malpractice if he agreed.  I really thought this PCP was one of the more enlightened PCPs in our system because he was informed on and recommended optimal Vit D levels, bioidentical hormones and compounded Rx, and EBT coronary artery calcium heart scans.

I take your point here and thank you for putting it so clearly. But I'm not sure that the system has "outgrown demand" in any absolute sense. As people conquer some kinds of illness, they live to grow old and encounter new kinds. Perhaps if switch resources are switched from procedures to preventive and geriatric medicine, hospitals can maintain their size?

Anna, welcome to the real world.

Nowdays, I just go to the doctor to have one or other test done and then to hear the results and the diagnosis. Then I choose my own path. Of course I say I need time to think things over and I will get back to him when I have decided.

Scary stuff. I do things the same way Vin does.

it is so ironic to see Google ads for major procedure-driven local heart centers and hospitals alongside your wonderfully insightful blog!

If anyone doubts the truth of this most recent Heart Scan Blog entry "Wag the Dog", just take a look at the targeted marketing Google slips in.  In my case it was ads for Houston areas gigantic Memorial-Hermann and Texas Heart Institute, your content may differ.

madcook

Hi, Mad--

You noticed?

All ad revenues, by the way--the modest amounts--go towards defraying the continuing development costs of the Track Your Plaque website. It does not go into my pocket.

It's even worse in Diabetes World. The ADA, Diabetes UK etc. sponsored by manufacturers of high carb foodlike substances and drug manufacturers, tell you to eat lots of carbs and offset their effect with lots of meds, thus providing a ready feed to the cardiovascular disease industry (The ACCORD effect)