Cardio Controversies: Dr. Superko, MD

“It is not good to settle into a set of opinions. At first
putting forth great effort to be sure that you have
grasped the basics, then practicing so that they may
come to fruition is something that will never stop for
your whole lifetime. Do not rely on following the
degree of understanding that you have discovered,
but simply think. . . This is not enough.”

Hagakure, Yamamoto Tsunetomo (a Samurai)
September 10, 1716
Quoted by Dr. Superko, MD



Often at TrackYourPlaque I've been curious as to why regression on CT isn't admittedly easy as pie... like one-two-three... ?? A-B-C...??

Routinely now I would say all the lipoproteins I've been coaching or those that refer to us from Paleo/ Primal/ Protein Power sites are being reported at goal and optimal within months of starting TYP or after only 4-5 weeks of tweaking the diet. These wonderous and spectacular results are reported by members, both new and old, with HORRIFIC family histories of premature CAD events. Lp(a) is a risk factor for 90-100% of these individuals, the toxic vascular plaque accelerant.

Yes, all are Paleo or lacto-Paleo.
Yes, all are moderate to HIGH dietary saturated fat.
Yes, all are lower carb or VLC (very low carb).

No, they do not necessarily lose weight.
No, no changes in the $200+ supplements per month. (or...even better taking virtually none)
No, it was not hard. (OK, maybe... !debatable, but hey members pay $80/yr to learn how to live the 'spartan' *ironic laugh* tasty, high fat life where you feel younger, more vital, enjoy better skin/hair and at the same time beat subclinical CAD and stroke risks!??)

Yes, some LOWERED THE DOSE OF THE STATIN by extreme measures (sometimes against the advice of their LDL-centric-fool-cardiologist... SSSSSHhhhh)
because of the, remember, low-trig-statin- i-n-t-e-r-a-c-t-i-o-n.
Yes, repeat, they lowered the stupid-statin-red-pill and obtained BETTER RESULTS.



Or... unequivocally better no statins at all.

Yes, they are not unlike the previous Paleo/semi-Paleo (statin-free) peeps I profiled earlier HERE including Doug/dcarrns regression story.




No Statins

Why do statins ruin results often? Maybe because they are actually ineffective in this world of 'whole grain happiness' and veggie oil madness? Maybe because Lp(a) is not responsive to statins and, in fact, statins raise Lp(a)? Maybe because IDL, another frequent and overlooked cause of premature and subclinical atherosclerosis, is not responsive to statins? Maybe because statins completely fail to shift lipoproteins to the desirable Pattern 'A'? Maybe because statins do not lower coronary calcifications on EBCT or MDCT in over a dozen of trials that I've reviewed? Maybe because statins block wound-healing which may not exclude plaque lesions? Maybe because statins cause muscle tissue breakdown, mitochondrial defects and coenzme Q10 depletion? Maybe because statins inhibits nerve ending re-myelination of our nervous system?

Maybe because statins prevent the formation of Large LDL which are the primary/only transport units in our circulatory system for cancer- and heart-protective antioxidants like Vitamin K2 (MK-4 through MK-9), Carotenoids (Astaxanthin, Lutein and the 200+ others), Vitamin E tocopherols tocotrienols, and cholesterol which comprises 20+% of our nervous system, integral to every cell membrane and the provides the backbone structure to ALL our vital hormones necessary for life, survival and reproduction?? (Vitamin A, another fat-soluble 'hormone-like' nutrient, on the other hand is so important it has its own transporter known as retinol binding proteins.) For regression and hard clinical event reduction, Dr. B.G. Brown showed in the landmark 3-yr HATS trial in post-CAD men and women (see below graph), the treatment group achieved a high rate of large buoyant LDL (~70% of participants) and HDL2 increased by 61% (total HDL increased 30% from baseline low-30's mg/dl). About 25-30% of participants had Lp(a).

Many cardiologists are starting to speak out about statins' frank lack of outcomes and even their dangerous side effects. Stanford doctor Dr. Mark Hlatky, MD is no exception in an NEJM editorial HERE. How scary is it that the statin industry is trying to peddle these teratogenic Category 'X' drugs to S.A.D. obese teenagers (who might have s*x and might get pregnant)? Obese children are their targets too, children who have rapidly growing brains and nervous systems which require cholesterol?

How about... Lack of regression? Marginal regression? 'Sucky' lack of clinical reduction in coronary events when comprehensively compared to niacin trials and omega-3 trials? Do cardiologists even know regression if it smacked them in the knee? Like those that sit on committees? In the AHA?




Question: Which drug/vitamin, which mimics ketosis, trumps statins in comparisons of CAD outcomes, all-cause mortality, AND angiographic-regression studies, by raising Large HDL2, lowering small dense LDL and controlling toxic Lp(a)? (Figure 1, from the below reference)


Lipid management to reduce cardiovascular risk: a new strategy is required.
Superko HR, King S 3rd.
Circulation. 2008 Jan 29;117(4):560-8; discussion 568. Free PDF




"Myopic Focus on LDL"

Soon I'll be meeting a patient of Dr. Superko's from 10yrs ago; this gentleman was on niacin and doing NMR subfractionation of cholesterol lipoproteins before it became en vogue at places like TrackYourPlaque. I find it be a quite a coincidence because I've been reading much of Dr. Superko's work the last few weeks. Dr. Superko was no longer his physician after he became busy on the lecture circuit and with Berkeley Heart Lab. It appears this eminent cardiologist, prolific researcher, and author is still pretty busy and now earnestly trying to prevent more Americans from dying from the coronary artery disease epidemic. Will it be enough?

"Although this level of success in the fight against heart disease is laudable, a great danger for our patients’ future health lies in the assumption that cholesterol reduction alone will stem the tide of coronary heart disease (CHD). It is wise and prudent to remember the words of Yamamoto Tsunetomo that “this is not enough.” The purpose of this article is to challenge healthcare workers to consider the possibility that the cholesterol-lowering program has in large part failed to stem the epidemic of CHD and that the well-meaning focus on LDL-C reduction has deflected interest in other therapeutic aspects of lipoprotein treatment that provide equal or greater benefit. This myopic focus on LDL alone is not surprising because, so far, guidelines have not adequately addressed other evidence."

"Statistical Significance Does Not Necessarily Mean Clinical Relevance"

Which strategies appear to lower CAD risk the most? It appears from Superko's provocative assertions that raising Large HDL2-cholesterol is the most critical according to current secondary prevention studies (niacin: HATS HATS-MetSyn FATS FATS-10yr CDP CDP-15yr CLAS-I CLAS-II ARBITER). With trials like the well-designed secondary trial in post-MI men and women, the Lyon Diet Heart, it was observed how mildly re-balancing the n-6:3 ratio resulted in 73% reduction in CAD events as well nearly an equally impressive 70% reduction in all-cause mortality (cancer, accidents, suicides, etc). In fact, in the Lyon Diet trial, LDL increased 1.7% and HDL decreased (yikes) 3%. Could the improvements in death rates be from increases in the Large HDL2? Subfractionation of the lipids were not done (or at least I can't find them) but that is necessary to see below the surface how omega-3 fatty acids work. Omega-3 PUFAs, like saturated fatty acids, bind PPAR and effectively lower small LDL (which are toxic) and raise Large HDL (which are regressive). Quite literally, in clinical trials, fish oil does not change total HDL-Cholesterol hardly at all but instead invokes dramatic, TECTONIC shifts in HDL2, sometimes even increasing by 150-300%. Niacin has a similar shifting effect on subfractions enlarging and enriching small particles into larger, buoyant, fluffier particles. Like omega-3 PUFAs and saturated fatty acids, niacin improves both HDL and LDL particle content and functionality.

"Statistical, or mathematical, significance is a tool useful in calculating how likely it is that the results of an experiment are due to chance alone and not really due to the intervention. Achieving statistical significance generally means that the results observed probably were not due to chance alone and probably were the result of the intervention used in the clinical trial. A value of P=0.05 indicates that there is still a 1 in 20 chance that the results were due to chance alone and not the intervention. Thus, statistical significance is a mathematical tool to test the hypothesis that the results observed were probably due to the intervention, but it does not necessarily mean the results are clinically significant or even meaningful..."

"The potential harm in the assumption that mathematical significance is equivalent to clinical significance is that many public and professional individuals have the misleading impression that if they just get their LDL-C low enough, they will be free of CHD risk. The results of 5 large statin trials show that this is a dangerous misconception in that it leaves large numbers of patients still at risk for cardiovascular events."

Statins and LDL reduction... 'This is not enough.'

Niacin . . . m a y b e .

Diet is definitely the best. Trumps them all.




At TrackYourPlaque we agree with Superko and have taken it further.





Grasp the 'Basics' for Regression (TYP Goals):
1. No statins
2. Vitamin D > 60
3. Trig < 60
4. HDL > 60
5. Small LDL less than 10% or none (LDL-IVb as low as possible and diet works well, again, very VERY well)
6. Large LDL > 60%
7. Large HDL (2b) > 50%


Regression is associated with Large HDL (Krauss RM et al, ATVB 1996).
Progression is associated with Small LDL, notably LDL-IVb (Superko HR, Krauss RM et al, ATVB 2003).


Answer: Niacin (which mimics ketotic diets, coming up in Benefits of High-Saturated Fat Diets, Parts VI and VII)

Benefits of High-Saturated Fat Diets (Part IV): REGRESSION IN HEART PATIENTS

Few studies review the benefits of high-saturated fat diets in actual heart disease patients. Perhaps, researchers worry about... M A L P R A C T I C E . . . ?

Like urban myths, do such studies exist?

Indeed studies of high saturated fat diets in heart disease patients IN FACT do EXIST.

LA...la la la... I feel on top of the world... (LMFAO)


The diagram exemplifies a normal coronary artery, with a large.. wide diameter... spacious... flexible.. lumen (Courtesy: medicinenet.org). The diameter of the artery can be measured accurately down to fractions of a millimeter via angiography.

It was observed that in post-menopausal women with documented heart disease from the Estrogen Replacement and Atherosclerosis (ERA) trial, a multicenter clinical trial evaluating the effects of hormone replacement therapy on atherosclerotic progression, in the group consuming the highest-saturated dietary fat diet (12.0% Sat Fat), an enlargement in coronary diameter of 0.01 mm and a 0.1% regression in coronary artery stenosis.

Quoted to Men's Health, "In the nutrition field, it's very difficult to get something published that goes against established dogma," said Dr. Dariush Mozaffarian MD MPH, assistant professor, Harvard. "The dogma says that saturated fat is harmful, but that is not based, to me, on unequivocal evidence." Mozaffarian says he believes it's critical that scientists remain open minded. "Our finding was surprising to us. And when there's a discovery that goes against what's established, it shouldn't be suppressed but rather disseminated and explored as much as possible."

In a year during my pharmacy student training at Stanford, I worked with Dariush on an internal med rotation for 4wks. I think I learned more about drugs and how to use them than some of my preceptors combined. His teaching approaches were usually articulate, concise and patiently provided. Gosh, can I say, I've had serendipity with many mentors in my little drug journey so far. *haa*

• Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women. PDF click HERE. Mozaffarian D, Rimm EB, Herrington DM. Am J Clin Nutr. 2004 Nov;80(5):1175-84. EDITORIAL. Figure 1 below.
  

Dividing the saturated fat intake into quartiles, the individuals at the highest quartile (dietary saturated fat intake: 12.0%) demonstrated the least progression on angiogram of coronary diameter. In fact, this was the only group that exhibited REGRESSION.

This group was also characterized as having the:
--least medications, including lipid-lowering medications
--the least medications and the higher the saturated fat, the more coronary artery widening in coronary artery diameter
--highest LDL (low density lipoprotein) measurements
--highest HDL (high density lipoprotein 'good cholesterol)
--highest HDL2 (the regressive particle)
--lowest Trigs
--MOST PAST AND CURRENT SMOKERS
--highest dietary fat intake (32%)
--highest monounsaturated fat intake
--lowest dietary carbohydrate intake (47.1% v. (!!) 69%)



Improved Anti-Atherogenic Lipoproteins
"A higher saturated fat intake was associated with a more favorable lipoprotein profile, including higher HDL,HDL2, and HDL3 cholesterol; higher apoprotein A-I; lower triacylglycerolc oncentrations; and a lower ratio of total cholesterol(TC) to HDL cholesterol (TC:HDL cholesterol). Women who consumed more saturated fat consumed less carbohydrate and dietary fiber and more total fat, protein, cholesterol, polyunsaturated fat, trans fatty acids, and monounsaturated fat."



Lipid-Lowering Drugs: The Less, The More Regression
The researchers astutely noticed that "among the women not taking lipid-lowering medication at baseline or during follow-up, there was 0.22 mm less progression for each 5% greater energy intake from saturated fat, compared with 0.09 mm less progression for each 5% greater energy intake from saturated fat among women taking lipid-lowering medication (P = for interaction 0.008)."


Omega-6 PUFAs: Highly Associated with Progression
After the Lyon-Diet Heart trial was completed and showed a dramatic reduction in all-cause mortality, cardiac death and events with simple reductions in omega-6 PUFAs and increase omega-3 from fish and ALA sources like olive oil, I think this trial hits it home again that any increase in dietary PUFAs are extremely pro-inflammatory leading to progression of coronary artery diameter reductions. The lowest quartile consumed less than 3.9% PUFA which was positively (see above) associated with less of a decline of average minimal coronary artery diameter (P for trend =0.04) compared with other quartiles. Clearly, a dietary PUFA concentration greater than 3.9% was highly statistically correlated to angiogram progression. The highest quartile that consumed 7.5% PUFA in the diet this was shown to produce the second highest amount of artery diameter constriction in this trial.

FIGURE 1 (divided, above, below). Mean (SE) change in minimal coronary artery diameter according to intake of different nutrients, with adjustments as in Table 2 (see footnote 1), except that total fat was not adjusted for carbohydrate, and carbohydrate and protein were also adjusted for polyunsaturated fat. These models estimate the effect of saturated fat replacing other fats (monounsaturated or polyunsaturated),monounsaturated fat replacing other fats (saturated or polyunsaturated), polyunsaturated fat replacing other fats (saturated or monounsaturated), total fat replacing carbohydrate, carbohydrate replacing saturated or monounsaturated fat, and protein replacingsaturated or monounsaturated fat.

Median intakes(% of energy) for quartiles 1–4 were as follows:
saturated fat*** (6.1, 7.8, 9.5, and 12.0),
monounsaturated fat (6.9, 8.6, 10.7, and 13.0),
polyunsaturated fat** (3.9, 5.2, 6.1, and 7.5),

total fat (17.6, 21.7, 27.0, and 31.9),
carbohydrate* (47.1, 55.6, 60.5, and 68.9)
protein (12.7, 15.8, 18.0, and 21.2).

P for trend = 0.001 (**saturated fat), 0.40(monounsaturated fat), 0.04 (**polyunsaturated fat), 0.48 (total fat), 0.20 (protein), and 0.001 (*carbohydrate).

High Carbohydrate Intake: Associated with Coronary Plaque Progression
The authors also found that "Carbohydrate intake (see above) was strongly positively associated with progression, with a 19-mm greater decline in mean minimal coronary artery diameter in a comparisonof extreme quartiles of intake (P for trend = 0.001)."


Overview
The design of this particular study was novel in examining multiple dietary components against a validated heart disease marker for progression. Obviously, prospective RCTs utilizing high-saturated fat, low carb, low PUFA diets would constitute the best scenarios to show unequivocal heart disease reversal. Am I going to hold my breath?



R e g r e s s i o n
With a high-saturated fat diet in documented heart disease patients... coronary artery stenosis regression occurred shockingly in individuals who took less lipid-lower drugs, smoked more, and basically were hedonistic beyond a conventional cardiologist's belief. Should we live life a little dangerously... disobey the 'rules'?

Benefits of High-Saturated Fat Diets (Part II): Centenarians, CETP, TYP Diet Part 3

We've been talking a lot of about increasing dietary saturated fatty acids (SFAs) at TYP. The Part 3 Track Your Plaque Diet was published approximately half a year ago and I've been remiss in not promoting it more sooner.

The NEW Track Your Plaque Diet:
Part 3 Special Issues
-- Lp(a)
-- Apo E
-- Diabetes
-- Pre-diabetes
-- Metabolic Syndrome (MetSyn)

Key Summary from Dr. Davis:
--Liberal fat intake of some saturated fats from eggs, meats (non-cured and processed), dairy; monounsaturated; fish oil
--Completely avoid hydrogenated, “trans,” fats
--Wheat and cornstarch reduction or elimination
[Edit: I don't agree with Davis' remaining 'edicts' because they do not appear to work and raise inflammation per clinical trials... =< 200mg cholesterol per day, =< 20 grams saturated fat per day and 15+% omega-6 vegetable PUFAs daily and LDL =< 60 mg/dl]

The Track Your Plaque Basic Diet Principles

Diet Principle #1: Eliminate wheat and cornstarch, limited dairy
Diet Principle #2: Don’t limit fats, but choose the right fats
Diet Principle #3: Unlimited vegetables, some fruits
Diet Principle #4: Unlimited raw nuts and seeds
Diet Principle #5: Unlimited healthy oils
Diet Principle #6: Foods should be unprocessed

Regression or Stabilization

Pioneering the field of cardiovascular research, regression and plaque tracking, Dr. Davis has been promoting (the below) seven TYP goals for Y E A R S . . . light years ahead of the common conventionalist/ interventionalist. New recent observations made by both researchers investigating atherogenic dyslipidemias and by those conducting long-lived healthy centenarian research are, in fact, aligned with several of these seven TYP goals. Maximixation of plaque control and regression have been observed when these seven goals are optimized (TYP 2.0).

For carotid arteries, achievement of any of the below factors will likely induce entire resolution of atherosclerotic plaque. However for the coronary arteries, regression is slightly tougher for a variety of reasons and achievement of all or nearly all seven will support dramatic coronary calcification regression.

Coronary arteries are thinner and more affected by systemic inflammation and the shearing forces secondary to high blood pressure (whether during physical exertion or at rest).

On the other hand, for stabilization and complete elimination of coronary events (angioplasty, stent, MI, bypass or death), gaining control of only three out seven is right on the money... imo.

We define stabilization as EBT CAC score progression of less than 10-20% annual increase.

The average American increase is 30-60% annually (of course faster in Lp(a), apo E4, diabetes and MetSyn).

Wouldn't you like your investment portfolio to grow as fast as American plaque?



So...Easy. To gain control.

Choose any 3.



1) Small-Dense-LDL =< 10% of total LDL particles (imo irregardless of total LDL on NMR or VAP) (Dr. Davis' TYP Goal)

2) HDL > 60 mg/dl (Dr. Davis' TYP Goal)

3) HDL2 (Large-HDL) > 50% of total HDL particles (Dr. Davis' TYP Goal)

4) Large-LDL > 60% total LDL particles (soft goal)

5) vitamin D = 60-80 ng/ml (Dr. Davis' TYP Goal)


6) Sufficient omega-3 ALA and EPA DHA (fatty acid profile, AA:EPA ratio of 1.5-2.0:1; if we flip the ratio around to EPA:AA, in other words omega-3 to omega-6 ratio of 1:1.5, then we're talking 60% of our RBC/cellular membranes being enriched with omega-3 PUFAs content versus omega-6 PUFAs. We really like 60% for some reason at TYP...go figure.)

7) control of inflammation (unfortunately few 'markers' to TRACK):

• dietary (avoidance of gluten, food allergens, casein, etc; adequate ADE K1 K2 MK4-9 vit C B-vits the right ones and minerals Iodine Mg Zn Se, fiber (if tolerated), saturated fatty acids, CLA, GLA, cholesterol, CoQ10/quinones, plant sterols (esp stigmasterol), etc)
• environmental (stay away from plastics/bisphenols/ heavy metal exposure/ pollution/ pesticides, etc)
• mental /psychosocial (stress, excessive physical training, etc)
• hormonal (optimization of thyroid, vit ADEK1K2, omega-3, SFAs, E T P DHEA preg, insulin, cortisol, melatonin, etc)
• pharmaceutical/xenobiotic (adequate intake of antioxidants/ omega-3/ phytochemicals/ FOOD to thwart toxins; avoidance of synthetic hormones, certain drugs (excessive statins), synthetic vitamins (eg, Lurotin, D2/Ergocalciferol, etc), omega-6-PUFA seed/legume oils, etc))
  

Original TYP Goals for Regression: 60-60-60

HDL = 60 mg/dl or higher
TG = 60 mg/dl or lower (#9)
Vitamin D [25OHD] = 60 ng/ml or higher

Am I a *haa* h e r e t i c . . . ?

(LDL = 60 mg/dl is #8 and IMO optional -- this is the easiest with synthetic drugs but unfortunately it prevents #1-4 for some low chol/low fat folks)




VLCD + Cholesterol + SFAs Support 'Super-TYP' Goals #1 through 4

Dr.Volek has published numerous articles on nutrition and metabolism in regards to the benefits of VLCD (very low carb diets) and ketogenic diets in controlling insulin and other hormones. He has shown in various studies how very low carb diets shift small dense LDL particles (atherogenic) to large, fluffy, buoyant LDL particles (regressive). Cholesterol and SFAs (saturated fatty acids) from eggs were demonstrated by Volek to be particularly effective at promoting larger HDL particles, the 'good' cholesterol associated with plaque regression, longevity and cancer protection.

Below is a diagram illustrating the proposal how low carb diets reduce insulin and how high fat/cholesterol diets increase Large-HDL (HDL-2) particles and increase LDL-receptors on adipose cells (and presumably the 'cholesterol core' of atherosclerotic plaque in diseased coronary, carotid, renal and peripheral arteries).

Again, obtaining the lowest proportion of small dense LDL is the holy grail of plaque victims (eg, anyone with a positive (+) EBT coronary calcification score).

Modification of lipoproteins by very low-carbohydrate diets.
Volek JS, Sharman MJ, Forsythe CE.
J Nutr. 2005 Jun;135(6):1339-42. PDF here.

Eggs distinctly modulate plasma carotenoid and lipoprotein subclasses in adult men following a carbohydrate-restricted diet. Mutungi G, Volek JS, et al. J Nutr Biochem. 2009 Apr 13.

Dietary cholesterol from eggs increases plasma HDL cholesterol in overweight men consuming a carbohydrate-restricted diet. Mutungi G, Volek JS, et al. J Nutr. 2008 Feb;138(2):272-6.








Healthy Centenarians Attain ~4 of 7 TYP Goals

Long-lived centenarians, also known as probands, had lipoprotein analyses performed via NMR. Of the markers tracked, four out of seven TYP goals were achieved. Interestingly, centenarian data shows that they still display vitamin D deficiency like the rest of us.

See picture (top)

Figure 2 displaying the Percentage of Large and Small HDL and LDL Particle Sizes in Long-Lived Probands, Offspring, and Ashkenazi and Framingham Controls HDL indicates high-density lipoprotein; LDL, low-density lipoprotein. *P less than .001 for probands vs Ashkenazi and Framingham controls and P less than .001 for offspring vs Ashkenazi and Framingham controls for both large and small HDL and LDL particle sizes.

1) Small-Dense-LDL =< 10% of total LDL particles (irregardless of total LDL on NMR or VAP) (TYP Goal)

2) HDL ~ 60 mg/dl (Table 1: women HDL=56 (SD 15); men HDL=50 (SD 17)) (TYP Goal)

3) HDL2 (Large-HDL) > 50% of total HDL particles (TYP Goal)

4) Large-LDL > 60% total LDL particles (soft goal)


Barzilai N et al. JAMA 2003. Oct 15;290(15):2030-40. Unique lipoprotein phenotype and genotype associated with exceptional longevity.


Apparently this sub-population of Ashkenazi Jewish have a genotype variation on the CETP gene which regulates and controls HDL-particle sizes. HDL-cholesterol is an antioxidant and they have the genetic ability to upregulate Large-HDL particles more than the rest of us. Their offspring may have version as well. The offspring (and controls, who were the spouse of the offspring) who were free of any chronic conditions (no hypertension, no metabolic syndrome, no cardiovascular disease) incidentally displayed similar high HDL particle counts, large HDL and LDL particle sizing and buoyancy, and reached the TYP goals of greater 60% Large-LDL and greater than 50% Large-HDL. Their counterparts with chronic conditions failed to meet these goals.



Polymorphism in CETP Gene and Phenotype of Exceptional Longevity

Can we exert control on our gene expression? We already know by altering omega-3 and vitamin D blood levels, we can alter gene expression of the various components of our immunity and cardiovascular health (Weaver KL J. Biol. Chem 284: 15400-15407; Biocarta; DeLuca HF PNAS 1993 90(20):9257-9260).

Volek et al have demonstrated how one can achieve control of small dense LDL via inhibition of CETP activity by a very low carb diet/HIGH-FAT DIET with additions of dietary eggs/cholesterol/SFAs.

Can we obtain similar sd-LDL less than of 10% lipoprotein profiles as long-lived heart-disease-free, cancer-free centenarians? We may not have the genetic programming/genotype but I certainly believe with our current understanding and technology, achievement of the centenarian phenotype is a definable undertaking.


Previous animal pharm posts:

• Saturated Fats as Potent Anti-Atherogenic Drugs: Lauric Acid Diets Decrease CETP, Increase PLTP
• Lauric Acid Diets (Sat Fat) Reduce Small Dense LDL (atherogenic) MORE THAN Oleic Acid Diets (Olive Oil)

Physiologic Actions and Benefits of Vitamin D: CARDIOVASCULAR

Dr. Schwalfenberg MD has written a wonderful review about the wide range implications of vitamin D insufficiency and the potential adverse impact on Canadian citizens. The above figure delineates how vitamin D affects all organ systems in humans. He however failed to list (1) the benefits for vascular atherosclerotic plaque remodeling which Dr. Davis has deep experience with, (2) Thyroid (he does discuss Parathyroid -- which the 2 are intimately related), and (3) modulation of the cholesterol/steroid/testosterone/estrogen reserves. Otherwise, I believe this is one the best comprehensive reviews done on the studies so far generated regarding vitamin D. Dr. Schwalfenberg has even included a brief mention about how medical residents were deficient due to long hours working indoors (Haney EM, Stadler D, Bliziotes MM. Vitamin D insufficiency in internal medicine residents. Calcif Tissue Int 2005;76(1):11-6.20). I liked that one.


Who is Vitamin D deficient?

He implies that nearly EVERYONE (greater than 50%) in Canada is either insufficient or deficient in Vitamin D due to the northern location of Canada relative to the equator. In Table 1, he cites a succint list (2 pages long) of the clinical trials and epidemiological studies on various subpopulations (including the medical residents). Below is Table 5 which lists Risk Factors for Low Serum Vitamin D levels.



The definition of 'insufficient' however begs a little argument. Less than 25 nmol/L (U.S.: 10 ng/ml) is considered clinically deficient at this time and less than 80 nmol/L (32 ng/ml) is clinically insufficient. Fortunately, the tides are changing and the awareness of the populace is increasingly demanding for this sunlight hormone. Costco warehouse carries the 1000 IU tablets and Long's and CVS pharmacies carry it as well; Oprah recently discussed vitamin D in reference to her recent-onset Hypothyroidism -- Oprah, honey, are you still consuming W-H-E-A-T ?? Oprah's magazine has a piece HERE about how various Maternal/fetal Vitamin D Deficiencies may determine our astrological zodiac behavior, characteristics and traits. Interesting, huh?? Science meets popular wisdom *hee* and it lights up Oprah's community board HERE.


At Track Your Plaque (and other expert communities), the optimal target goal for Vitamin D blood levels is 25(OH)D = 70 ng/ml (translates to: 70 * 2.5 = 175 nmol/L).




Cardiovascular Actions and Benefits of Vitamin D

With the addition of Vitamin D to the arteriosclerosis reversal program, Dr. Davis witnessed countless cases of regression of CAC/plaque (coronary artery calcium score) and improved benefits of many organ systems. For the LEF mag, he wrote a fantastic, complete review about the basics of Vitamin D and its role in cardiovascular health. HERE is the PDF for September 2007 Vitamin D’s Crucial Role in Cardiovascular Protection.

He writes about Vitamin D so frequently on HEARTSCANBLOG, it's a topic that certainly becomes hard to ignore, right? Assessing serum Vitamin D was actually my first introduction to the TrackYourPlaque program and why it is so effective in initiating and maintaining longevity and optimal health. Is the medical science and the establishment still millenium behind us? Or...suddenly are they starting to play catch up with Dr. Davis -- our favorite interventionalist and humble icon? The latest title from JACC: Holick MF. STATE-OF-THE-ART PAPER: Vitamin D Deficiency -- An Important, Common, and Easily Treatable Cardiovascular Risk Factor? J Am Coll Cardiol, 2008; 52:1949-1956. Wow, he finally got into JACC.


Let's review what the medical science so far says:

• Low Vitamin D = Predicts All-Cause and Coronary Mortality (Maerz W. Arch Intern Med. 2008 Jun 23;168(12):1340-9.)


• Low Vitamin D = Predicts Strokes (Maerz W Stroke. 2008 Sep;39(9):2611-3.)


• Solar Radiation (not the Mediterranean diet) = Lower Coronary Heart Disease Mortality Rates in Europe (Wong A Eur J Epidemiol. 2008;23(9):609-14.)


• Statins = Vitamin D Increases (Grimes Lancet 2006)


• Statins = Improved Bone Mineral Density if 25(OH)D greater than 12 ng/ml (=30 nmol/L) (Duenas A Eur Rev Med Pharmacol Sci 2008)


• Statins = (Increased HDL 5-9% and) LDL-reduction less than 120 mg/dl are related to Regressive Coronary Volume Scores (CVS) assessed by EBT (electron beam tomography) (Russo DJ NEJM 1998 -- see below Figure)


• Calcium Begets Calcium = Kaiser Hawaii study: the higher the CAC, the faster the progression and obstruction (Golden JG Radiology 2002)


• Deteriorated Bone Mineral Density = Aortic Calcifications over 25 year Framingham study (Wilson PW Calcif Tissue Int 2001)


• High CAC = High Coronary Mortality and hard events (Raggi P JACC 2002: 39(2) 225-30.)


• Vitamin D = Regression of Coronary Plaque and Atherosclerosis assessed by EBT. The single human prospective (non-randomized) trial by Dr. Davis presented at the April San Diego FASEB meeting (Progression and Regression of Coronary Calcium Score FASEB J. 2008 22:1092.15.)

My Personal Experience with the Physiologic Actions and Benefits of Vitamin D

I never would've suspected that I had Vitamin D Deficiency -- I'm a tan Asian female who spends significant time in the sun esp in the summer Cali season when my children swam nearly everyday. I'm into skin cancer prevention so naturally in the past I lathered our bodies up with sunscreen (though as a kid my parents NEVER did b/c sunscreen did not exist, but then again we didn't wear seatbelts either). I didn't have an autoimmune disease I thought (although later I found out my asthma has autoimmune components -- oops -- I didn't learn that in school during the Pathophysiology of Diseases classes). After diligently reading the blog, PubMed (which confirmed what Dr. Davis and other experts like Holick, Heaney, Vieth, Cannell and others try to publicize), and some internet sources (ie, WAPF) for several weeks, I decided to get my 25(OH)D vitamin D blood level evaluated. In October 2007 my 25(OH)D was only ~20 ng/ml. The TYP recommendation at the time was 50-60 ng/ml. The current target by Dr. Davis is now 60-70 ng/ml. I started on 2000 IU daily for 4 weeks however my level didn't reach 50 and I didn't notice any benefits. I finally upped the level to 4000 IU daily in the AM (outside of the recommendation of the Endocrinologist that I -- against better judgement -- consulted individually with) and achieved > 60 ng/ml by December 2007.


The benefits I noticed were myriad and echo the things Dr. Davis talks about on his blog and other writings:
--better energy, mood, endurance
--more muscle growth
--resistance to colds and infections
--MY ASTHMA COMPLETELY WENT AWAY and I stopped having bronchitis every year (coughing for 4-8 wks at a time where antiobiotics and inhalers were useless and futile)
--my children's asthma resolved (no more inhalers for us) with supplementation 1000 IU daily in the AM (in addition to cod liver oil (CLO) + fish oil)
--20% increase in HDL (from 70 to 84 mg/dl)
--40% drop in TGs (from 50s to 30s)
--improvement in mild insulin resistance
--calmer and more regular heart rhythms
--improvement in my estrogen (despite the contraceptive suppressing most of it)
--resolution of SAD (seasonal affective disorder, 'winter blues')
--resolution of Reynaudy-type symptoms (cold extremities, poor circulation)
--reversal of periodontal gum disease
--reversal of the other plaque hopefully *fingers crossed*
--improvement in thyroid (my TSH has always been 1.3-1.9 and finally in Dec 07 TSH=1.0 perfect)
--faster growth of hair, skin, nails (I'm constantly clipping my nails in winter -- whereas before they essentially stopped growing during these months)
--more alertness
--more mental acuity and communication skills (*shock* I'm bloggin?)
--more IQ points *ha haa* (the fish oil also plays an adjunctive role as my brain's 'high speed internet' connection!!)
--better sense of smell (less allergies)
--better sense of balance (I trip around and fall far less now)
--better reflexes
--better hearing...NOT... according to the hubby
--better vision...NOT (d/t occupational + extracurricular hazards)
--better in bed *chortle* (I mean I sleep better)


-G

Luminations: Coronary Luminology, Lipids, Laughs

Nakashima et al admit that "Despite the fact that millions of dollars have been spent over the last 50 years on atherosclerosis research, little is known about the development of early human atherosclerosis. There are several reasons why the research on early human atherosclerosis has not advanced. First, human atherosclerosis develops very slowly and at different rates from individual to individual, and it is difficult to distinguish between lesion initiation and progression. Second, a thickened intima is present in human arteries before atherosclerosis develops, but whether this intima forms the precursor for the later more advanced lesion is not fully understood. Third, the relationship between extracellular lipids and macrophages has not been clarified (UUUMMM... yeah hyper-reduction of human cholesterol may indeed lead to cancer -- see the SEAS trial... or J-Litt or IMPROVE-IT or hey...very SHARP mono-statinators...). It is generally believed that extracellular lipids are derived from foam cell death, but there are several examples that show that extracellular lipid occurs independently of macrophage cell death. Finally, there are no good animal models for the study of early atherogenesis. The morphological features of early atherosclerosis are different between humans and laboratory animal models, and it may be somewhat misleading to extrapolate the results obtained from animal models, to humans." (though rabbits are very cute and so are indeed are we, we aren't evolved exactly like herbivores) Thus...more Animal Pharm facts!


What we are certain of though is that HDL2 -- the large puffy HDLs -- are strongly associated with plaque regression, centenarian-lives/longevity, and cancer reduction (Michalaki et al Mol Cell Biochem. 2005 Jan;268(1-2):19-24).

How can we achieve higher HDL2, these wonderfully big ghetto-fab puff-daddies?




Cholesterol Intake on HDL2 and Reduction of Small Dense LDL

Olson et al researchers examined the effects of (!!)Cholesterol and (!!)Saturated fats on HDL2 (good) and HDL3 (bad) particle sizes.

Schonfeld G, Patsch W, Rudel LL, Nelson C, Epstein M, Olson RE.
Effects of dietary cholesterol and fatty acids on plasma lipoproteins.
J Clin Invest. 1982 May;69(5):1072-80.
PMID: 7068846

ABSTRACT..... The effects of dietary cholesterol and fatty acids on low density and high density lipoproteins (LDL and HDL) were studied in 20 young men. After 2-3 wk of evaluations on ad lib. diets (Latin for eating without controls), basal diets, which consisted of 15% protein, 45% carbohydrates, 40% fat, and 300 mg/day of cholesterol, were given for 4-5 wk (Basal). The ratio of dietary polyunsaturated to saturated fatty acids (P/S) for different groups of subjects were 0.25, 0.4, 0.8, or 2.5. 750 and 1,500 mg/d of cholesterol were added to the basal diets as 3 and 6 eggs, respectively.

RESULTS Total cholesterol and LDL cholesterol (READ: MORE SMALL DENSE LDL -- 'BAD') were lower in all subjects on the basal diets than on the ad lib. diets... Thus, both the cholesterol contents and P/S ratios of diets were important in determining LDL levels...

On the diet with low P/S ratio (this means lowest PUFA proportion, highest S-A-T-U-R-A-T-E-D FATS), HDL2 rose (good), whereas this effect was absent on diets with high P/S ratios.

CONCLUSION The response of LDL to dietary manipulations is consonant with epidemiologic data relating diets high in cholesterol and saturated fat to atherogenesis (NO... NOT TRUE. Mono-statinators rot...substitute the words 'carbohydrates' and 'carbohydrates' respectively...cholesterol does not kill... Carbs/whole-grains do).

The response of HDL2, however, is opposite to that of its putative role as a negative risk factor. Further work is needed to clarify this interesting paradox (THE EDITORS LIKELY MADE THE AUTHORS PUT THIS IN... TRANSLATION, WE'RE COMPLETELY BEFUDDLED BY THESE RESULTS).





Highest Sat Fats and Cholesterol Promote HDL2 Concordant with Regression



In addition to showing the HIGHEST INCREASE in HDL2 and the DEEPEST DROP in HDL3, Olson et al also discovered that the highest sat-fat ratios (4:1) produced the LOWEST apo B, HIGHEST apoA-I/apoA-II and LIGHTEST FLUFFIEST LDL-CHOL (see table III, IV, V). WOW. All good things. Sounds regressive to me. Quite (accidentally) awesome for these scientists from Washington and St Louis Med Schools out in Misery. Dr. Olson also authored a quite profoundly articulate paper entitled "Is it wise to restrict fat in the diets of children?" a few years after the above sat-fat discoveries.

Brave scientist.



Differences Between Moderate vs. High Cholesterol Intake

Did the authors find a clinical difference between Cholesterol intake of 750 mg/day vs. 1500 mg/day? Of course! 1500mg per day (6 eggs) of cholesterol yielded lower apo B (bad) (102 mg/dl vs. 92 mg/dl) and VLDL (very bad stuff)(68 mg/dl vs. 48 mg/dl). The best total HDLs for any of the subgroups studied was: highest sat fats and highest cholesterol 1500mg/day -- 52 mg/dl vs. 50 mg/dl (3 eggs/750mg/d). Without a doubt, the most optimal HDL2/HDL3 ratio was achieved with the highest sat fat ratio and the highest cholesterol intake 1500mg/d 6 eggs daily (see Table).


So...

How do we achieve higher HDL2?

Like a little piggy, I'm laughing all the way to the market to buy cholesterol/eggs *grin*

If we take lessons learned from these 20 young men...If our diet consists of 40% fats and our caloric intake is ~2000 cal/day -- fats could comprise approximately (0.40 x 2000) = 800 cal/day. Fats are 9 cal/g -- this amount is equivalent to about 88 grams fat total.

(Protein 15% 75 grams; Carbs 45% 225 grams OMG -- too much carbs)

A portion of the fat would be MUFA (monounsaturated) and small amounts PUFA (olive oil, fish oil, GLA, chocolate, nuts, nut butters, veggies, etc) and a certain ratio of saturated fats. Add also the cholesterol equivalent of 6 eggs = 1500 mg cholesterol daily. One Tablespoon of Fat contains approx 13-15 grams fat. SATURATED SFA include butter, butter oil, ghee, virgin coconut oil, MCTs, lard, egg yolks, grass-fed meat, seafood, fish, mollusks, etc.

(using omega-3 eggs adds in lutein 8x more per egg and fabulous DHA!)
One large AA omega-3 egg contains about 4.5 grams fat of which 1.5 grams saturated




Individual Genetic Variations

The Missouri authors did point out that increases in LDL varied significantly among the male subjects. Like responses to Lp(a) reduction, it appears genetics and diet-gene interaction may play a large part. In the above trial, carb intake was extremely high and as we aware carbs modulate apo B and sdLDL (and HDL2). The meat used in the trial were from a 'local meat processor' in Missouri. Perhaps back then in the 1980s, the EPA + DHA content was already depleted from common meat sources. Many factors (high carbs high carbs high carbs, no EPA DHA, Cholesterol insufficiency) exist that may explain how the baseline HDLs of these young healthy robust mid-western study participants was only in the mid-40s.

Curiously, apo E polymorphisms and other genetic influences (like PPAR-d a g) may be major players for the optimum diet for regression and fat intake. Pang et al studied apo E patterns in Hong Kong and noticed that carriers of E2 had the best highest apo E levels compared with homozygous apo E3. Other observations were that "Apolipoprotein E (apo E) allele frequencies were: epsilon2 8.7%, epsilon3 80.4% and epsilon4 10.9% with the genotype having a significant effect on plasma apo E concentration (p less than 0.001). Lipoprotein(a) levels were higher in women than men (geometric mean 15.2 versus 10.2 mg/dL, p less than 0.05) and in women with FSH above versus below 40 IU/L (185 versus 136 mg/L, p less than 0.05)." It's not clear to me yet how to discern our apo E polymorphisms without genetic testing and what is the precise diet-gene interaction because optimally the studies would consider the effects of a no-grains/Paleo diet, and unfortunately few take this stance in the medical literature.


Eggs on the other hand appear great! Perhaps the fox know best...

• Effect of egg yolk feeding on the concentration and composition of serum lipoproteins in man. Beynen AC, Katan MB. Atherosclerosis. 1985 Feb;54(2):157-66.
• The effect of egg yolk consumption on the composition of LDL and on the concentration of HDL subclasses was studied in healthy subjects.
• Six volunteers consumed a diet low in cholesterol for 10 days and then daily added 6 egg yolks to their diet for another 10 days; the experiment was repeated 1 year later with the same subjects. Egg yolk consumption caused the cholesterol intake to increase by 1600 mg/day, and the fat intake by 7 energy % at the expense of carbohydrates; this increase was due almost exclusively to monounsaturated fatty acids.
• RESULTS: Upon egg yolk feeding the mean level of serum total cholesterol rose by 13%; the bulk of this rise was due to LDL cholesterol, which increased by 21% (READ: REDUCTION IN sdLDL).
• VLDL and IDL cholesterol decreased by 19 and 11% (good), and serum total triglycerides by 17% (great).
• Marked relative increases of 35 (very good) and 36% (very very good) were seen in the cholesterol level of the HDL subfractions with densities of 1.055-1.075 g/ml (HDL1) and 1.075-1.100 g/ml (HDL2), respectively.
• The HDL2/LDL cholesterol ratio increased by 16% (VERY VERY GOOD).
• No change in cholesterol in HDL3 (d greater than 1.100 g/ml) was observed (GOOD!).
• The increase in cholesterol in HDL isolated by density gradient ultracentrifugation significantly exceeded the increase in cholesterol in heparin-Mn2+ soluble HDL. This suggests the formation of apo E-containing HDL, i.e. HDLc, which has HDL density but is not soluble in heparin-Mn2+. (?translation please?...Is Krauss in the house?)
• The composition of the LDL particles was significantly altered; the core became enriched in esterified cholesterol at the expense of triglycerides, and the ratio of core components to surface components increased by 7%. (read again: elimination of sdLDL and rise in round, puffy fluffy LDL particles *cheers!*)
  PMID: 3986015

Cute...*laugh* I love eggs video

TYPs: Success To Regress

Sometimes it does not hurt to hear the fundamentals repeated because we can be bogged down by advanced discussions on treatment, sophisticated lab testing or diagnostics.


Boiled down Track-Your-Plaque tips for success:

1. BMI -- achieve normal BMI. Advantages -- loss of toxic belly fat and increased metabolism. May take 3-6mos depending on degree of toxic belly fat.

2. Vitamin D3 -- obtain blood 25(OH)D to 60-70 ng/ml -- and Vitamin B3 Niacin (Slo-Niacin or NIASPAN) to raise HDLs. Clinical event reduction and plaque regression with these 2 powerful 'vitamins' cannot be overemphasized. The importance of raising HDL is reviewed here: TYP HDL Report. And we reviewed already here (at the end of the post).

3. Eliminate wheat, cornstarch and grains; Paleo diet RULES

4. Exercise/play/move -- increases metabolism, reduces inflammation, reduces mental stress, and prevents diastolic heart failure -- very common in people with NASH/NALFD and insulin resistance (like Metabolic Syndrome) and Type 2 Diabetes.

5. Do you exhibit elevated Lp(a) (or ultra low HDL)? If so, consider ultra high dose fish oil 8.5 g EPA+DHA daily (studies show only works when combined with moderate exercise/weight loss). Use high potency caps or liquid.

6. Strength training + Intermittent Fasting -- accelerates loss of toxic belly fat.
(However, if you have diabetic retinopathy, please avoid and discuss with your doctor. Extra cerebral pressures (like straining, Valsava, heavy weight lifting) can increase risk of retinal tears and subsequent vision changes/loss.)

7. For the first 1-2yrs of the TYP program, consider L-arginine. Benefits incl increasing NO in the vasculature which lower BP (goal (WSJ Joe Morgenstern's movie review 7/11/2008)? Do you need a trainer? As Wesley bluntly puts it at the end...after his 6 week-long life transformation toward purposeful, elite living... 'so wtf have you done lately...?'

-BG

Atheroma Regression 101 -- Focus on HDL

Dr. Steve Nissen certainly deserves some respect. Not only does (a) he stick his neck out for the heart protection of Americans and (b) endorses CAC scoring/EBT for plaque/atheroma validation, he supports regression data in alignment with the Track Your Plaque goals for regression 60-60-60-60 already established by Dr. William Davis MD FACC. In a recent post-hoc analysis he reviewed data pooled from 4 major trials (ASTEROID, CAMELOT, REVERSAL, ACTIVATE) where plaque was diagnosed with angiography and tracked via IVUS over ~18 months (n=1455). The plaque volume % (PAV) decrements tracked well with i-n-c-r-e-a-s-i-n-g HDLs. And even more substantial reductions in total atheroma volume (TAV) were seen with more dramatic increases in HDLs.

The average 'regression' lead to an average 0.5 increase in PAV (2% increase and wide SD=15.7%) and a total atheroma volume reduction of 2.4 mm3 (only -0.2%; wide SD=17.4%). The authors note that in the ACTIVATE trial nearly 90% of patients were already on a statin and in fact their LDLs were less than 100 at baseline. Benefits for plaque stabilization and regression may have already been reaped prior to initiation for this sub-group which makes up 1/4 of the study. The duration of statin therapy was unknown.

These changes (avg plaque change: + 0.5)) were observed with the combination:
(1) LDL reduction (study avg=87.5 mg/dl final)
(2) increased HDL changes (the 'higher the better' with avg change=7.5% --the greatest regression was associated with HDL increases of 40% and HIGHER)
(3) lower LDL/HDL ratio (study ratio=2.1)

Average apo B was also significantly reduced from 131 mg/dl to 95 mg/dl (36% reduction) which was statistically correlated to changes in both PAV and total atheroma volume (p less than 0.001). The regression graph (see Figure and graph areas where PAV change is less than zero) lines up with TYP standard goals 60-60 for LDL and HDL.

TYP Goals (standard):
-LDL-C =60 mg/ml (see above arrow; higher?? see hard cardiac events)
-HDL-C = 40% increase to 60 mg/ml (study baseline avg = ~43 mg/dl; sorry--arrow wrong!)
-LDL/HDL ratio = 60/60 = 1.0


This regression data certainly emulates TYP to me!! The results truly seem to demonstrate the '60/60' vision...of a regressionist!! Like our beloved Dr. Davis :)



Often Dr. D achieves lipoproteins even beyond his standard goals. Many who follow TYP obtain LDLs lower than 60 and HDLs far higher than 60. Of course TGs fall far lower than 60 as well (often 40s) and of course apo B naturally drop as well (I'd conjecture less than 60).

So perhaps standard goals may be revised for those with 'stubborn' plaque.... based on this new information.

Who might benefit? The analysis showed that independent predictors of change in PAV were baseline PAV, the presence of diabetes and/or hypertension. For total atheroma volume, independent predictors of change were baseline TAV and BMI.

Refer to the L-sided endpoints of each graph in the Figure. The regression data certainly supports substantial size reductions of plaque occur with further improvements in LDL and HDL. HHHhhhhmmm..... Therefore, based on reported values of TYP'ers who experience regression/stabilization, the below standards may apply. At TYP, we are not LDL-centric. Small-LDLp centric extremely so, but never accuse us of LDL-mania...

Ultimate TYP (hypothetical) for Ultimate Regression:

-LDL-C = 60 mg/dl
-HDL-C = 60-80s mg/dl
-TG = 40-50 mg/dl
-TG/HDL ratio = ~50/83 = 48/80 = ~40/67 = 0.60
-LDL/HDL ratio = 60/80 = 0.75

-(? 60-60-60-0.60 ===> LDL-25(OH)D-apoB-TG/HDL-ratio)


The most significant contribution that Nissen made I believe was actually not mentioned in his comments or conclusions. In fact his conclusions from the data differed from mine regarding reduction of clinical events at 18 months and less than 18months after starting a Statin (or for ACTIVATE subjects, statin duration prior to the study longer than the rest of the test subjects). If you review Dr. Nissen's Table 6 below, you'll notice an interesting phenomenon. The best reduction of clinical events outcomes (obstructed events or events requiring re-vasc) supports actually a higher LDL-C (calculated) v. lower LDL-C at time 18 months for the group with a 'good' healthy HDL increase and LDL surprisingly g-r-e-a-t-e-r than average LDL=87.5 mg/dl.... hhhmmm... what could be going on here...? May stabilization (which translates best to reduced revasculariazations) require a little increase in % atheroma volume (though total plaque mass show decreases)?? The data may suggest this (see below 2 duplicated Table 6's).


Dividing out the study pop into 4 subgroups compared responses related to HDLs (and apo B) which appear to exhibit the highest association with clinical events. Perhaps when LDL is less than 87.5 mg/dl, the presence of small LDL still plays a HUGE role? Perhaps those individuals who experienced the most substantial INITIAL improvement in HDLs also had the greatest shift from Pattern B to Pattern A? Perhaps this shift explains the reduction in revascularizations (p=0.07) since these occur at higher frequency 6-12 months after a previous PTCA/stent. Rates of prior percutaneous intervention were in fact high in the study groups (71%, 30%, 81%, n/a). Could the first sub-group have had some plaque shrinkage but were still in the early stages of plaque-remodelling? Perhaps the first sub-group contained two distinct stages of regression -- one early (not stabilizied yet) and one late (stabilization + regression). Of course, the unstabilized will increase clinical events, especially if the presence of small LDL has not been addressed (ie, fish oil deficiency, vitamin D3 deficiency, carb-overloading). It only takes a few events or revascularizations to affect the data. Maybe there is a period of even 'fluffiness' of plaque (surface, core/internal) right before it stabilizes and regresses... synonymous with the changes occuring in the arteries where small LDL is shifting toward buoyant, more benevolent particles? Perhaps it's a phase... and we only have part of the snapshot...

What an amazing picture to behold though... Regression t-r-a-c-k-e-d in such a large population!

Let's thinc again... Perhaps the LDL-calculated based conclusions are bunk? Is LDL-calcuated really the 'lousy' cholesterol???

It's too bad the large trials failed to VAP or NMR the lipoproteins (or at least failed to report smLDL-particles).




Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, Wolski K, Crowe T, Desai MY, Hazen SL, Kapadia SR, Nissen SE. (Full PDF here)
Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.
JAMA. 2007 Feb 7;297(5):499-508.
PMID: 17284700

The conclusions that I draw from the data (though apparently non-statistically significant; who the heck was the statistician) is that human clinical events data support an approximately 50%+ decrease in revascularization-events in the group with higher LDL-C (read: lower small-LDLp) when compared with those with lower LDL-C (read: still high small-LDL in a subset of patients which may have contributed to higher clinical events requiring revascularization).

When plaque stabilizes, the echogenicity increases on ultrasound. Does this also contribute to mildly increased plaque volume? Perhaps? When you get a scab on a traumatic wound, does the scab appear thicker and heavier (esp if you're swimming!) before subsequently falling off after new pink epithelium grows?

Dr. Nissen notes:

"Greater percentage increases in HDL and lower levels of LDL (NOT) and LDL/HDL ratio in patients during treatment with a statin resulted in atheroma regression (BUT NOT HUMAN CLINICAL CAD/CVD EVENTS)...

...This is, to our knowledge the first time that increases in HDL levels have been shown to be an independent predictor of beneficial outcome with statin therapy."

Now Nissen is erudite.

He also looked at 'substantial' responders, meaning those with massive regression (b/c the above data otherwise makes little sense -- to statinators). And HDL-cholesterol undoubtedly must be raised for regression. Could Crestor have higher affinity for PPAR receptors or indirectly affect PPAR more?

His results when looking from a different perspective comparing Non-Responders v. Responders is even more intriguing than the above data. And holds more answers to the key to SUBSTANTIAL REGRESSION. Additionally this data is in direct compliance with TYP principles 60-60-60. Responders were assigned if significant volume/PAV% relative reduction of 5% or greater regression occurred (?about twice or more the average amount?).

Responders comprised 34% of the study population (n=370 were they all Crestor/ASTEROID??). Looking at this data (see Table 5 in the PDF), you'll notice immediately that huge increases in HDL and apo B occurred and likely lead to the dramatic PAV reductions in responders. In fact the difference between HDL improvements between Non-regression subjects and Substantial-Regression subjects was nearly 58% (6.5% v. 10.3%; wide SD 17.2%)) Remember average HDL change was 7.5%. Wow. I bet some of these individuals with massive plaque regression hit the TYP goals of 40% increase to HDL=60 mg/dl (perhaps combined with exercise/diet changes) and TG=60 mg/dl. For apo B, there was also wide variation apparently among the subjects, but also apo B dropped substantially by 40.9 mg/dl to an average of 90.1 mg/dl in the Regression group (almost close to TYP less than 60-70 mg/dl goals!). The median change was 34.8% (SD wide 25.0%) whereas the Non-regression median apoB change was only 25.7% (SD 24.8%).

Wouldn't it have been interesting to see if the Responders had reduced clinical events? Instead of just breaking down LDL-subsets?


Does Nissen know that Statins substantially affect PPAR???! And the regression benefits for regression may be attributed more strongly to PPAR than LDL? Evidently not... though he mentions VA-HIT and Helsinki Heart (he forgot DAIS) which are primary and secondary prevention trials that demonstrated reduced mortality and events with fibrates (PPAR-alpha agonists) especially in the diabetes subsets (ie, high insulin).

We discussed how statins both bind and indirectly affect plaque-mac PPAR earlier here.

The many pleiotropic benefits of statins are related to reduction in inflammation via Macrophage's PPAR activation at the plaque level in damaged endothelium:
--reduction in CRP
--plaque stabilization
--reduced oxLDL in plaque
--atheroma regression


Does this suggest that PPARs regress plaque...?

I do believe so


How do statins causes lipoprotein benefits via activation of Mac PPAR a and PPAR g ?

Nissen saw no significant contribution of statins on TGs on changes in PAV but TGs were statistically associated with improvement. The regression was attributed most strongly to vast HDL increases he reports (and to dramatic apoB and small-LDLp reductions which he didn't really address in the text) .

PPAR activation leads to these lipoprotein benefits:
--reduction in small-LDLp
--reduction in apoB
--reduction in TGs
--INCREASES IN HDL-C


So statins are like PPAR agonists? So statins work like food and food sensors?

What food item works the best as a PPAR agonist? What's my favorite supplement?




Bays et al nicely describes the benefits, MOA, and clinical implications of omega-3 fatty acids. Next to the NIACIN-king... fish oil R-O-C-K-S. Fish oil raises HDLs by an impressive 11-14% in clinical trials. The benefits are dose related, the higher the dose, the higher the HDLs. The lower the baseline HDL, the higher the potential increases.

Fish oils benefits for regression are three-fold:
(a) reduced systemic inflammation via PPAR
(b) increase HDLs via PPAR
(c) reduce apoB and insulin via PPAR

Another dimension of fish oil CAD benefits is its electro-stabilizing effects on cardiac conduction and prevention of arrhythmias.

Bays HE, Tighe AP, Sadovsky R, Davidson MH.
Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications.
Expert Rev Cardiovasc Ther. 2008 Mar;6(3):391-409. Review. (Full PDF here)
PMID: 18327998


Synergistically, Statins and Fish oil can work together to stabilize and regress plaque. The authors eloquently review how both have separate mechanisms which complement and accelerate the conversion of small-LDLp to IDL than to large non-atherogenic LDL.

Synergism... I like that...

What are other mechanisms to raise and maximize HDL?

Depending on the degree of plaque, the more the below are achieved, the greater the increase in HDLs...
--stop all wheat
--stop all grains
--minimize all fruit
--stop all HFCS garbage
--consume adequate high-quality protein 1 g/kg
--consume Hg-free seafood
--consume EPA+DHA
--consume nuts/seeds
--intermittently fast
--exercise, some HIT (high intensity training -- only after medical clearance -- of course)
--get lean muscle mass
--abdominal fat loss
--decrease IR (see above)
--tobacco cessation
--maintain good sleep

-BG

Control Insulin (Part Two)

Briefly, the history of insulin and its relationship to atherosclerosis:

Stout RW. Insulin and atheroma. 20-yr perspective. Diabetes Care. 1990 Jun;13(6):631-54. Review. PMID: 2192848 Department of Geriatric Medicine, Queen's University of Belfast, Northern Ireland.
Many clinical studies have shown an increased insulin response to oral glucose in patients with ischemia of the heart, lower limbs, or brain. Hyperinsulinemia also occurs in patients with angiographically proved atherosclerosis without ischemia and thus appears to be related to arterial disease and not to be a nonspecific response to tissue injury. Fasting insulin levels and insulin responses to intravenous stimuli, including glucose, tolbutamide, and arginine, are normal, suggesting a gastrointestinal factor may be involved in the increased insulin response to oral glucose. In patients with atherosclerosis, insulin sensitivity appears to be normal or enhanced with respect to both glucose and lipid metabolism. Five population studies have shown that insulin responses to glucose are higher in populations at greater risk of cardiovascular disease. Many of the hyperinsulinemic populations also had upper-body obesity, hypertriglyceridemia, lower high-density lipoprotein (HDL) levels, and hypertension. These prospective studies support an independent association between hyperinsulinemia and ischemic heart disease, although their results differ in detail. Hyperinsulinemia is associated with raised triglyceride and decreased HDL cholesterol levels. Total and low-density lipoprotein (LDL) cholesterol is less closely related to hyperinsulinemia. Upper-body adiposity is associated (in separate studies) with coronary heart disease, diabetes, hyperinsulinemia, and hypertriglyceridemia. Insulin and blood pressure are closely related in both normotensive and hypertensive people. Although obesity and diabetes are often found in hypertensive people, hyperinsulinemia also occurs in nonobese nondiabetic hypertensive people. Thus, hyperinsulinemia is closely associated with a cluster of cardiovascular risk factors, i.e., hypertriglyceridemia, low HDL levels, hypertension, hyperglycemia, and upper-body obesity. There is a possibility that insulin has a role in the sex differences in ischemic heart disease incidence and their absence in diabetes, but additional work is required for its clarification. Long-term treatment with insulin results in lipid-containing lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions. Insulin stimulates lipid synthesis in arterial tissue; the effect of insulin is influenced by hemodynamic factors and may be localized to certain parts of the artery. In physiological concentrations, insulin stimulates proliferation and migration of cultured arterial smooth muscle cells but has no effort on endothelial cells cultured from large vessels. Insulin also stimulates cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte macrophages.

Despres JP et al showed in the below study how elevated fasting insulin blood levels was closely associated to the presence of ischemic heart disease. The higher the concentration of insulin, the greater the odds ratio. And additionally they found other factors compounded the risk of heart disease:

--High Triglyercides

--High Total/HDL ratio (in other words, low HDL)

--High Apolipoprotein B

Després JP, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ.Hyperinsulinemia as an independent risk factor for ischemic heart disease.N Engl J Med. 1996 Apr 11;334(15):952-7. PMID: 8596596

Figure. Odds Ratios for Ischemic Heart Disease according to Plasma Insulin and Triglyeride Concentrations, Total:HDL Cholesterol Ratios, and Apolipoprotein B Concentrations. Insulin was measured after subjects had fasted for 12 hours. The median TG concentration (150 mg/dl [1.7mmol/L]), total:HDL ratio (6.0), and apoplipoprotein B concentration (119 mg/dl) were used to define men with either low levels (below the 50th percentile) or high levels (at or above the 50th percentile) for these variables. The results of tests of multiplicative interactions did not reach signficance at the 0.05 level for any of the combinations. P values are for comparisons with the reference group, which was assigned an addos ratio of 1.0. To convert values for insulin to picomoles per liter, multiply by 6.

The researchers Lemarche et al have done a great deal of research examining 'non-traditional risk factors '(see Table 2) and also showed the same link between insulin and associated ischemic heart disease.
Lamarche B, Tchernof A, Mauriège P, Cantin B, Dagenais GR, Lupien PJ, Després JP. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA. 1998 Jun 24;279(24):1955-61. (Full PDF here) PMID: 9643858

In fact, their results uncovered the fact that the largest odds ratio between traditional (LDL, TG, HDL) and nontraditional (small dense LDL, apo B and fasting insulin) fell to the Hyperinsulinemia risk factor. So high fasting insulin correlated stronger with the presence of evidence of coronary artery disease than than LDL-cholesterol. Triglyericides (TGs) even associated to a higher degree than LDL-cholesterol. HHmmmm?

Why do we always call LDL the 'bad' cholesterol? It appears that TGs is a bad character, indeed it appears TGs are the worse cholesterol out of all the traditional risk factors! Dr. Davis has pursued a lower TG goal lower than 'traditional' guidelines for many years. Current 'conventional' cardiovascular advice aims for TGs less than 150 however the Track Your Plaque program advocates an aggressive TG goal of 'normal' less than 60.

Is the 'LDL-cholesterol hypothesis' completely bunk?

Shouldn't Triglyerides be known as the 'lousy/bad' cholesterol?

Is this why statin-monotherapy fail to prevent signficant mortality and morbidity caused by plaque in heart disease and strokes?

The TYP goals for regression of ischemic heart disease are 60-60-60-60 (TG-HDL-LDL-25(OH)D). Many achieve this and beyond -- HDLs 80-90s and TGs 25-50s in the program!

And Elevated Fasting Insulin goal is not just less than 12 mU/L as discussed in the 2nd study above but at TYP the goal for regression is normal fasting insulin levels less than 5-10 mU/mL (30-60 pmol/L).

Is this why the Track Your Plaque program controls plaque comprehensively and trumps all 'conventional' cardiology programs by controlling triglycerides and insulin by a multifaceted strategy?

--Vitamin D3

--Wheat and grain cessation

--Exercise

--Weight loss to achieve normal BMI

--High/ultra-high dose fish oil EPA+DHA

--Hormone optimization (estrogen, testosterone, DHEA, etc)

--Vitamins K2/E/A

--Et cetera

Conclusions by the above authors Lamarche, et al:
'Beyond the mechanisms underlying the atherogenicity of hyperinsulinemia, hyperapobetalipoproteinemia, and small, dense LDL, and irrespective of whether these mechanisms share common paths, results of the present study suggest that the risk of IHD is increased substantially when these metabolic abnormalities cluster. The synergistic contribution of the nontraditional cluster of risk factors to IHD risk and the fact that almost 1 of every 2 IHD cases had these abnormalities simultaneously reflect the multifactorial etiology of IHD. It also emphasizes the importance of defining the risk of IHD based on more than 1 risk factor.
There are a number of critical issues that have to be considered before any decision can be made toward the measurement of these nontraditional risk factors on a routine basis. Among others, results of this prospective case-control study will have to be confirmed through larger population-based studies, as the relatively low number of IHD cases allowed only a gross assessment of risk. The relatively large CIs associated with the estimated risk in some of the subgroups reflect this phenomenon. Population reference values such as those used for LDL-C, triglycerides, and HDL-C also will be needed before critical levels of fasting insulin, apolipoprotein B levels, and LDL particle size or density at which a person becomes at greater risk for IHD are identified. Means to achieve effective treatment of the nontraditional risk factors is also a critical issue that deserves a great deal of scrutiny before decisions can be made toward use of these variables in the risk management of IHD. There are data to suggest that LDL particle size can be modulated by changes in plasma triglyceride levels.41 Studies have shown that triglyceride-lowering therapy with fibric acid derivatives can lead to a significant increase in LDL particle size.42-43 There is also a large body of evidence demonstrating that LDL particle size, apolipoprotein B level, and insulin resistance and/or hyperinsulinemia can be effectively altered by diet and exercise-induced weight loss.44-45 Thus, the ability to favorably modify the nontraditional risk factors by diet, exercise, and appropriate pharmacotherapy provides further support for the use of these risk factors in the management of IHD risk...'

Lawlor DA, Fraser A, Ebrahim S, Smith GD. Independent associations of fasting insulin, glucose, and glycated haemoglobin with stroke and coronary heart disease in older women. PLoS Med. 2007 Aug;4(8):e263. PMID: 17760500

Full PDF here:

Editor's Summary

Background: Narrowing of the vessels that take blood to the heart and brain is a common form of cardiovascular disease—i.e., a disorder of the heart and blood vessels. It is a major cause of illness and death. By starving the heart and brain of oxygen, this condition causes coronary heart disease (CHD; heart problems such as angina and heart attacks) and strokes. A major risk factor for CHD and strokes is diabetes, a common chronic disease characterized by high levels of sugar (glucose) in the blood. In people who don't have diabetes, the hormone insulin controls blood-sugar levels. Insulin, which is released by the pancreas after eating, “instructs” insulin-responsive muscle and fat cells to absorb the glucose (released from food) from the bloodstream. In the very early stages of type 2 diabetes (the commonest type of diabetes, also called “adult onset” or “noninsulin-dependent” diabetes”), muscle and fat cells become unresponsive to insulin, so blood-sugar levels increase. This is called “insulin resistance.” The pancreas responds by making more insulin. As a result, people with insulin resistance have high blood levels of both insulin (hyperinsulinemia) and glucose (hyperglycemia). Eventually, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and type 2 diabetes is the result.

Conclusions:

'Our findings indicate that amongst older women without diabetes and with fasting glucose levels in the normal range, fasting insulin is a stronger predictor of CHD and stroke risk than are fasting glucose or HbA1c.'

In addition, the results demonstrated a 'positive linear association between fasting insulin and CHD and stroke events is consistent with findings from the Atherosclerosis Risk in Communities study (SEE LAST CITATION), in which there was a positive linear association with CHD events that remained after adjustment for other CHD risk factors amongst women, but not amongst men [27]. A metaregression analysis of 17 prospective studies, primarily conducted in men and younger age groups than the current study, found a pooled relative risk of CHD per 50 pmol/l of insulin of 1.18 (95% CI 1.08–1.29) [9], which is consistent with our fully adjusted association with CHD (our results equate to 1.13 [95% CI 1.01–1.27] per 50 pmol/l of insulin). Overall the evidence suggests a modest positive association between fasting insulin and CHD events in women and men. Fasting insulin may exert its effect on cardiovascular risk via a direct impact on endothelial function [28,29].'

CRACK DOWN on insulin... CRACK DOWN on plaque (and cancer)...

Hunger will disappear away as well. Part of insulin's purpose is to drive energy into cells for storage. Insulin drives hunger as well. (...and mainly the consumption of carbs drive insulin secretion)

You will realize the benefits of low blood insulin and will often 'forget' to eat without prompting from this powerful hormone. You'll hunger for other things... vitality, movement, effortless-boundless ENERGY.


Importance of controlling triglycerides and insulin:

INSULIN ==> TG/HDL ratio ==> SMALL DENSE LDL

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McNamara JR, Jenner JL, Li Z, Wilson PW, Schaefer EJ. ***
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Folsom AR, Szklo M, Stevens J, Liao F, Smith R, Eckfeldt JH. **
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-G