' Death ' Bands: Subfraction LDL-IVb Strongest Predictor of CAD

Modified and Courtesy of a FDA.gov website

Let's review some subfractionation techniques. On the market 3 main methods exist. They all work. Dr. Davis prefers NMR. Superko and Krauss are affiliated with Berkeley HeartLab which uses GGE. Density gradient ultracentrifugation is also very popular (VAP-II). Recently, Krauss also appears to be introducing a new technology based on ion-mobility.

Basically, the denser the particle, the faster and mobile (like sp*rm *haa*) the particle moves through a gel (GGE). The denser the particle, the smaller the diameter (Angstroms or nanometers) as determined via electromagnetic resonance (NMR) or absorbance via density ultracentrifugation (VAP, which are indirectly compared to known sizes).

Pattern 'A' is good (all nice large buoyant fluffy particles).

Pattern 'B' is clearly BAD. Dense small stupid cr*ppy stuff. Guess what causes it? Excessive dietary carbs and/or fruit. Lack of omega-3 fats. Excessive omega-6 refined veggie oxidized refined fats not meant for human or animal consumption. Lack of saturated fatty acids. Lack of antioxidants. Lack of hormones.

The medical literature is rife with studies demonstrating that the conversion of small dense LDL to buoyant LDL is associated with regression of coronary artery disease.



Measuring LDL-Cholesterol Alone is Faulty and a Farce

Why is subfractionation via NMR/gel electrophoresis/UC of lipoproteins the most accurate way to assess cholesterol ? In doing so, the density and particle counts can be determined.

Only the marketing ploy of the statin/fibrate/zetia industries want to measure LDL-C alone without particle sizing. Yes. It is not cheap -- $99 via different labs. Some insurances cover it. Most don't at this time.

LDL-C alone tells nothing. It is like looking at someone's debt. Is it good debt (student loans, low fixed interest)? Or is it all bad debt (variable ARM, no down, several high interest boat/car/house loans)??!? Or No Debt? Or a mix (no debt on car boat house but low good student + low fixed vacation house debt)?

Do you have a good accountant? Do you have a good investor (eg, YOU)? Would you trust your money with a loser? With someone who has no money in the bank? With your statinator cardio-idiot? How many coronary events did he/she avert? Using 'tracking' EBCT/MDCT technology and targeted strategies to raise HDL2 and lower small dense LDL and Lp(a), both Drs. Davis and Blanchett (in Colorado, our colleague) have ancedotally seen single-digit events in their practices that span almost 10 years. HeartHawk likes to refer to this phenomenon as 'no event, no matter what score.' Even if the coronary calcification score is 4-digit, literally no events are seen. The failures they do see are related to noncompliance with the program and calcification scores consistently increasing 10+% or 20+%, respectively.

Well, when you trust your local neighborhood statinator, eg local General Practitioner, internal med LDL-centric drug-rep-pimped-up doc, cardiologist with lipidology credentials and certifications, what do they have in the bank? You must ask them. If they don't provide a good enough answer, seek new advice I would heartily suggest.

What do I look for?

No debt. High safe investments. High money in the B A N K . Demonstrated portofolio performance.

...EBCT regression or no EBCT score at all.

Personally I believe non-physician individuals like Richard Nikoley or Dr. Stephan Guyenet PhD or Dr. Dr. Petro Dobromylskyj (vet) or elite athlete Mark Sisson or Robb Wolf MS (Paleo/Xfit protege) know far more than your local GP statinator ninnyhead who are only focused on NCEPIII-LDL-centric guidelines. Quality of lipoproteins trumps quantity alone. Holds true for economic debt too. Does your statinator know that?!?




Lowering LDL-C Alone Does Not Reverse Heart Disease

Remember Cardio Controversies and Dr. Superko? LDL-C reduction alone was no better than placebo. Event rates barely were improved when Superko look at the whole picture comparing statin trials v. niacin trials. Yes, he made a variety of inferences. Yes, Niacin trumps all statin trials. Niacin in alone or in combo trumps ALL STATIN TRIALS in all-cause mortality, cardiac-death, and cardiac events. Superko makes educated, non-biased, medical-literature-based inferences.

So what? He is correct.

Statins raise %-sdLDL. sdLDL is oxLDL. See below. Statins create and sustain Pattern B which is predominance of small dense LDL. On statin therapy, often the LDL are 50-100% all small dense particles. sdLDL cr*p. OxLDL. On our TYP forum, the same phenomenon does appear to occur. Statins appear to prevent regression. What?? I think Superko is super-right.

On statins, the EBCT progression fails to halt despite niacin, omega-3 fish oil ULTRA high dose, 10-20+ lb fat loss, body recomposition, Lp(a) reduction, HDL2 increases... despite all TYP-directed efforts... EBCT scores increase 10-25+% annualized. Why?

Statins s*ck.

They maintain a high oxLDL concentration which the body cannot escape. It is not unlike bad revolving debt.

This is worse in those with Lp(a) -- anything greater than 3 mg/dl.

Yes. It doesn't matter how much Lp(a) one exhibits. Any amount jacks up the picture. Dr. Hecht, Superko's partner in cardio controversies, has shown that. Hecht, like Drs. Davis and Blanchett, is one of the earliest, most vocal proponents of using CT technology for screening of subclinical coronary atherosclerosis. I'll be going over later how he thrashes the retarded Heart Protection Study which marketing ploys by statin companies attempted to lower the LDL-C health standards. *urrg*

It is a good thing at TrackYourPlaque that we no longer rely on this useless drug class. (BTW fibrates s*ck. BTW zetia s*cks too.)



Niacin and n-3 fatty acids trump them all.

Statins Increase OxLDL
For oxLDL to 'transform' to Large fluffy healthy LDL, CETP needs to deposit cholesterol esters into the particles. How can it if statins block cholesterol synthesis? Or if worse Zetia blocks dietary cholesterol uptake from the gut. Frankly the lipoproteins are f*cked. They never seem to attain the large, fluffy particle size associated with regressive Pattern A in the niacin regression trials (70% converted to Pattern A compared with Placebo, HATS trial NEJM 2001).



Statins Raise %-sdLDL, Lp(a) OxLDL (or OxLDL/apoB)

Mechanism? Lp(a) 'tracks' inversely with analogously with growing and increasing Large LDL and HDL2. Statins s*ck. Statins lower all LDL species, including the good stuff, the buoyant LDL which are necessary for regression. A new marker is the oxLDL/apoB ratio and several trials found an increase in oxLDL proportions related to apoB. Yet another adverse finding was an increase in oxPL (oxidized phospholipids) which bind Lp(a). Does oxPL increase toxicity of Lp(a)? I don't know but it probably does not help and likely explains many of the increases in EBCT scores in statinators. How long are these effects in place? I wish I knew.

Increases in Lp(a) were found with every statin tested.

--COMPELL
--PROVE-IT
--lipitor and zocor
--MIRACL
--REVERSAL



Krauss and Superko: Only the Densiest Particles Predict CAD

Superko and Krauss found evidence in 2001 that the small dense LDL-III a+b subspecies tracked the best with CAD. However more recently Krauss made note that the smallest, densest fraction out of 7 subspecies actually tracked the most predictable with progression of subclinical and clinical coronary artery disease. I call this band on gel electrophoresis the 'death band'. No, I'm not talking about a rock 'n roll band. The LDL-IVb fraction is the 'death band'. The goal at Berkeley Heartlab is to achieve < 2.5% based on one trial (when angiogram stenosis > 30%). However, this goal is not low enough. We see EBCT and MDCT progression even at > 1.5%. Likely stenosis is < 30% as the trials demonstrate continued progression.

Other researchers have found similar correlations with small dense LDL being superior in predicting CAD (Koba S et al. J Atherothromb 2008).

Berkeley Heart Lab in fact advise for Pattern B a 'high 40% fat diet.' That is pretty progressive! But they fail to specify the components of the fat: monounsaturated, polyunsaturated, n-3 v. n-6 and saturated. Are they afraid of liability? Are they afraid of success? Are they afraid of regression? I dunno.

They do fail to address the carb intake therefore it probably would be fair to say that they can not broach diet unless carbohydrate intake is fairly accurately laid out.



























Only two studies exist that I can find that implicate Large LDL in coronary artery disease risk. Krauss wrote the first one in 1995, then re-clarified oh just last month. I briefly discussed HERE. In the clarification, he and other researchers retrospectively analyzed 3 large seminal trials and found no independent correlation between Large LDL and coronary atherosclerosis. One trial included in the review was the Quebec Cardiovascular trial.








TITLE: Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Québec Cardiovascular Study.
Lamarche B et al. Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):553-9.

CONCLUSIONS: These results indicated that estimated cholesterol levels in the large LDL subfraction were not associated with an increased risk of IHD in men and that the cardiovascular risk attributable to variations in the LDL size phenotype was largely related to markers of a preferential accumulation of small dense LDL particles.
PMID: 15618542

Insulin: Chronic Kidney Disease and Atherosclerosis

Health from a paleolithic standpoint...

Please click below:

Insulin: Chronic Kidney Disease and Atherosclerosis

Case: 45 yo Female, Perfect Framingham, Perfect Cholesterol, Perfect PLAQUE PROGRESSION

When I see a female with Peripheral Vascular Disease (plaque in the legs) or angina/CAD (heart disease: plaque in the coronary arteries) or Chronic Kidney Disease (plaque in the kidney arteries)... invariably Lp(a) and low HDL2b are the PRIME factors for plaque buildup.

Another factor is a positive family history of a coronary event in the father prior to age 60 yo.



Review: Goals for Regression

Dr. Hecht has ten case studies which I will review one by one here. Earlier (Cardio Controversies: Dr. Hecht) we reviewed the success case study of the the young male with strong family CAD history, high Lp(a) and 15% EBCT regression after only 15 months on niacin 4000mg daily (and low low dose weak statin). This gentleman had regression after doubling the HDL2b from 12% to 24% and the small LDL shifted to buoyant Pattern 'A' LDL subspecies. Most notably, his Trigs started in the 200s then reduced to only 30s. O-u-t-s-t-a-n-d-i-n-g. Drugs alone? No. He must have lost weight, changed the diet, gained some body recomposition and started a good exercise program. Drugs alone cannot lower to Final Trigs 30s from the 200s. TYP goal for Trigs is 60 mg/dl however this is typically exceeded by most members especially those who are able to shift to Pattern 'A' and reach the other TYP goals. Trigs are an expression of our carbohydrates in our diet (starchy and sweet foods/beverages), saturated fats, and omega-3 fatty acids (ALA flaxseed; EPA DHA fish oil). As Trigs drop, buoyancy goes to the particles, both LDL and the HDLs. HDL-2b, the regression particle is the most buoyant, largest HDL subspecies. HDL-2b is associated with extreme longevity in centenarians, cancer-protection in remission cases and vascular regression of plaque in heart trials and at TYP.

HDL-2b are like good, loyal friends who watch out for you and your family.

Can you ever have too much?




Case Study: Perfect Scores, Perfect P L A Q U E

Dr. Hecht presents a case of a young female, no symptoms, with perfect plaque progression. She has a double-digit coronary calcification score of 95 which takes her to the top 98th percent for her age for plaque. Normal heart disease stratification at this time in conventional medicine uses the Framingham score. With her perfect baseline lipids, her score is quite good.
The Framingham 10-year risk is calculated to be < 1%.

Translation: 0-10% = 'low risk'. (10-20%=mod; >20%=high)

Her risk, in fact, is estimated to be insignificant, negligible risk.

No worries???

Yes, worry.

Alarmingly, she has the highest heart calcifications and the 'real age' of a 98 year old female.



Real Age, Real Baloney: Coronary Calcification Tells Age

Some experts Dr. Hecht discusses want to use EBCT or MDCT percentile scores as the 'real age'. This makes sense to me. It is the internal metabolic milieu, chaos and entropy which reflect our longevity and status.

Just as well, the internal metabolic calm reflect our regression and control of lifespan.



Advanced Metabolic Testing
Her results for the metabolic testing show perfect CRP (C-reactive protein). CRP is bunk. It could be elevated if you sneeze. If it is chronically elevated, then you have issues but it is no more telling of plaque than the traditional, conventional lipid panel.

On further examination, the metabolic testing which is identical to what we look at TYP program shows:
--elevated apoB (goal < 60-70)
--mildly elevated homocysteine (goal < 8.0)

Both of these indicators are related to inflammation and high carbohydrate intake. Inflammation may stem from excessive omega-6 and/or fructose, deficiencies (n-3 omegas, vitamins ADEK, B-vitamins B3 B6 B1 folate B12, minerals Magnesium Selenium Zinc Chromium Iodine Iodine, vitamin C, vitamin "O" optimism *haa*, carotenoids, mitochondrial components Carnosine CoQ10 ALCAR Carnitine; hormones adiponectin T E2 E2 P preg DHEA, etc), food allergies (wheat, gluten, A1 casein, nuts, etc), heavy metal and environmental toxicity (mercury from seafood, estrogenic pesticides, etc).





Ultimate Testing Lipoprotein Subfractionation:


The 'death band' is evident.

Recall according to Krauss, goal LDL IVb is less than zero. Just kidding, the goal is to get this subfraction which is the most dense, most lethal to as low as possible. In patients with large amounts of plaque where stenosis was > 30%, Krauss found < 2.5% of LDL-IVb was highly statistically significant for regression on angiogram. For those with 'less' plaque (read: less stable), LDL-IVb of 2.5% was still too high for regression to occur. What is good? I believe as low as possible. We see at TYP even when LDL-IVb is 1.5%, EBCT progression still occurs at 10-25%.

I don't find this acceptable.

The death band should be as low as possible. Or none.

Ultimate goal: Shift the LDL from dense to buoyant (known as LDL1 + LDL2a+b on BHL) and annihilate the 'death band'. Stop stuffing the face with fructose (fruit). Cut back olive oil and replace with some saturated fats.




Major Risk Factors for CAD: Low HDL2b, Lp(a)



Diagnosis: This young lady has extensive 98th-percentile plaque. Dense LDL, the death band LDLIVb, low HDL2b, and Lp(a).

Conventional Prognosis: No action on her doctor's part until she comes in with throbbing, painful legs or shortness of breath, back ache, jaw pain, heartburn (extensive plaque leads to vague, non-specific anginal symptoms in females). Worse case scenarios: tries to run a half-marathon or marathon and has a coronary event and is resuscitated with brain damage. Or SCD (sudden coronary death) where the first sign of heart disease is silent and fatal.
Unconventional TYP Prognosis: Longevity and shifting 98th-percentile calcifications to 15-50th-percentile less each year. Shortly... her real age will be 17 years old.

Yes, shaving YEARS off of her real age, coronary calcification percentile rank.


Hecht-Treatment: Hecht discusses niacin 4 grams per day and some statin (why? I dunno why because he contradicts himself when it comes to bashing LDL and LDL-goals; I sense some 'cognitive dissonance' on his part). Most cardiologists and physicians don't know a lick about diet, nutrition, what organs/hearts require, and basic micro- macronutrients. Didn't the father of medicine, once say 'let food be thy medicine'? We in the Paleo/Primal and TYP communities already know food can be poison (e.g. gluten, wheat, grains, legumes).

Is Hecht's therapeutic strategies enough? No. Some cases are 'treatment failures' which we'll later breakdown why.




Optimal Longevity Treatment To Reverse Vascular Dysfunction:

(1) Statin-less (statins increase Lp(a), OxLDL, OxLDL/apoB, %-dense LDL and prevent shifting from pattern B to A+++; causes autoimmunity and auto-antibodies, cellular level mitochondrial and myocyte damage, depletes antioxidants ubiquinols and coenzyme Q10; Crestor is associated with higher incidences of diabetes and kidney problems (proteinuria) in clinical trials)

(2) Niacin

(3) Omega-3 fish oil 6000++ mg EPA DHA daily for Lp(a), low HDL2b, high dense LDL, shift to pattern A, optimize n-6:3 ratio (goal ~1.5-2.0 per Dr. Barry Sears PhD and medical literature involving CKD patients)

(4) Correct Vitamin D deficiency (goal [25OHD] 60-80 ng/ml)

(5) Correct Saturated Fatty Acid Deficiency: Stop the AHA-low-fat-low-cholesterol-diet. Obtain Saturated Fats 15-20+% daily to increase HDL-2b, lower the death band LDLIVb, shift to Pattern 'A', and lower the atherogenicity of Lp(a)

(6) Correct Vitamin K2 deficiency (Sources: fermented cod liver oil, casein-free butter, hard cheeses if not allergic, natto, vitamin K2 100mcg daily MK7)

(7) Correct thyroid and adrenals by initially supporting (egg yolks, vitamins ADEK K2 Bs C; tocopherols, tocotrienols, minerals: Magnesium Selenium Zinc Chromium Iodine Iodide; saturated fatty acids, omega-3 fats ALA EPA DHA, carotenoids, avoidance of n-6 PUFAs) and if not sufficient then thyroid replacement (Armour +/- T4) and adrenal support (read HERE and HERE) to achieve optimal metabolism and stable core body temperatures 98.2 - 98.6 degrees F.

(8) Correct insulin disparities (exercise, C-A-R-B RESTRICTION, stress reduction, SLEEP, yoga, resistance train, weight loss, ketosis (diet, intermittent fasting), insulin-sensitizers: R-alpha lipoic acid, L-carnitine, Chromium, Leucine, Taurine, Glutamine, whey protein, flaxseed and fish oil, bittermelon, celery, pycnogenol, krill oil, astaxanthin, other antioxidants and proanthocyanidins, etc)

(9) Correct other calcified organ dysfunction: pineal (melatonin), hypothalamus (yoga, relaxation, breathing ex, etc), thyroid (see above), pancreas (see insulin above + digestive enzymes), gallbladder (digestive enzymes), colon (probiotics)

(10) No w-o-r-r-i-e-s ! *winky*



What about 4 grams per day of vitamin B3, niacin?

Does overdosing on niacin aid the above? Unfortunately 'no'. The mechanism of action is that niacin mimics all of the above (increases hGH, testosterone, steroids, ketosis, fasting and exercise). Adverse effects of niacin include: gout, diabetes and liver test elevations. Again I like niacin b/c it works but I don't love it. It doesn't appear to work on everyone in the year 2008-2009 and likely the future. Numerous nutritional and environmental toxicities apparently have shifted the cardiology and endocrinology playing field since the niacin trials were published, including the HATS 2001 NEJM publication by BG Brown et al.



Dr. Davis' Nutritional Wisdom and Recent TYP Topics (Members) to Reverse Vascular Dysfunction:

o Fructose: Dangerous at Any Level?
o Anthocyanidins: Eat Purple
o S-L-E-E-P -- Quality and Quantity
o Iodine Deficiency -- Importance for Heart Health
o Thermoregulation -- Thyroid and Adrenal Dysfunction
o TYP Part 3 Diet: 40% Fat Diet for Lp(a) and read more HERE

Cardio Controversies: Dr. Harvey Hecht MD

Figure 1: Correlation of metabolic factors and calcium percentile

in asymptomatic patients with EBT showed calcified plaque

(Hecht HS. Prog Cardiovasc Dis. 2003 Sep-Oct;46(2):149-70.)

Dr. Davis has known for years that assessing and treating based on the LDL-Cholesterol alone is bunk. Just as simply visually inspecting someone's physical appearance to determine their heart status is bunk. The healthiest appearing athletes may in fact have the most profound coronary artery obstructions. Similarly an asymptomatic menopausal female with exceptionally 'high' HDLs, 'low' LDL and low Trigs may also have the highest Lp(a) and peripheral vascular obstructions in the lower extremities. Heart disease is still the #1 killer of Americans and across the globe in adults. Is it a wonder why? We are not even correctly identifying asymptomatic heart disease in moderate risk individuals ((+) family history of atherosclerosis disease (heart, kidney, peripheral, cerebral, aneurysm), Lp(a), low HDL, high Trigs, Metabolic Syndrome, high fasting or post-prandial insulin, etc).

The current protocol that physicians use to score heart disease risk is called 10-year Framingham risk scoring. Recent observational studies are elucidating the complete lack of correlation between this scoring method and detection of moderate to very severe asymptomatic subclinical disease.

Framingham scoring for low or moderate risk indivuals is bunk (Nasir et al. Int J Cardiol. 2006 Mar 22;108(1):68-75.)

Complete. Utter. BUNK.

According to Nasir et al asymptomatic Brazilian men (avg age=47) who were considered low or moderate risk according to Framingham scoring, moderate to very high risk coronary calcifications were found on an EBCT scan. "...Nearly half of individuals with CACS > or = 100 (45%) and CACS > or = 75th percentile (48%) missed eligibility..." for aggressive therapy for risk reduction. CACS = coronary artery calcium scoring.




Cardio Controversies: Dr. Harvey Hecht MD

Dr. Hecht was one of the cardiologists who has worked closely with Superko and Krauss over the last 10-20 yrs on statin trials, subfractionation of lipoproteins and more recently interventional radiology involving EBCT and MDCT. Like Callister (recall, Cardio Controversies HERE), Hecht originally saw a decline in EBTC coronary calcifications with statin monotherapy in one single study, however he could not be replicated the results at later dates. Like Krauss and Callister, he has questioned why this is the case. In a 2003 publication, he reviews the importance of many concepts that characterize our TYP program (Hecht HS. Prog Cardiovasc Dis. 2003 Sep-Oct;46(2):149-70. Free PDF HERE). Obviously, our TYP program embraces a program that is far and beyond conventional statin+niacin-centric therapy: diet, lifestyles, exercise, nutraceuticals, and no pharmaceuticals (excluding niacin and fish oil). Hecht's approach is basically mega doses of niacin niacin and more niacin (+low dose weak statin), which is quite fine but not very targeted or tolerable to most and fails to address the metabolic origins of heart disease, obesity, MetSyn, diabetes and inflammation.



LDL-Cholesterol Alone Tells Nothing

One of Dr. Hecht's first assertions is that LDL-C is completely, fully, unrelated to subclinical and clinical coronary calcifications. See above diagram, Figure 1. The R correlation quotient between LDL-C and positive coronary calcification was 0.0006 (p=0.90). To quote my favorite THINCer, Peter, 'count the ZEROES.' *ha*

Utterly. Unrelated.



Metabolic Parameters Matter

The highest correlations between overall plaque burden and measurable lipoprotein parameters were LDL peak particle diameter in angstroms, R = 0.14, P = .02 and high-density lipoprotein cholesterol, R = 0.11, P = .02). Of course these R values are not great since optimal statistically is 0.80 but this is the closest relationship determined from countless EBCT scans and patient datasets. In other words, Pattern 'A' versus Pattern 'B' makes a big difference, even a little more than how much HDL there is.

Figure 8. Correlation of annualized progression
of calcium score and change in metabolic factors.

C h a n g e in Plaque Burden Correlates Best With Small Dense LDL Changes

Hecht continued to examine how changes in the metabolic parameters related to change in coronary calcifications as visualized and quantitified by EBCT. The best relationship was found between percent change in Small Dense LDL (IIIa+b subfractions). Not HDL improvements (he apparently didn't look at HDL2b). Not Trig improvements. Definitely not LDL-C improvements (again, don't forget to count the zeroes,
R = 0.009, P=0.91). Not even the TC/HDL ratio improvements.

Regression or progression in coronary calcifications was highly associated with changes in sd-LDL out of ALL the parameters tested (R=0.46, p=0.71). See above. We see these correlations at TYP as well. Regression is highly associated with
--control of sd-LDL to < 10-30%
--annihilation of the 'death band' LDL-IVb from > 5% to as low as possible < 1-2 %
--solid Pattern 'A'
--increasing HDL-2b to as high as possible 60-200%


Our members do regression with DIET. LIFESTYLES. Supplements (omega-3, phosphatidylcholine, vitamin D, etc). LOW DOSE niacin 1-2 grams per day. STATIN-LESS... or on the way to statin-less.





High-Saturated Fat Diet Improves ALL Metabolic Metrics

These metabolic metrics -- sdLDL and HDL2b -- according to Krauss' research on lipoproteins are related mostly to (1) dietary saturated fatty acid intake (2) dietary carb loads.

Let's summarize Dr. Krauss' high fat study once more and then see how it compares in the context of CACS regression in an extremely high risk CAD patient whose father had an MI at age 46 (Case study #8; Figure 16). The carb intake again in Krauss' study is considered high by many standards at 39% and not as effective in lower small dense LDL or raising HDL-2b as lower carb or very low carb (VLCD) diets in insulin resistant individuals. Interesting comparisons can still be made.

Summary of Heart-Healthy Improvements with a High-Saturated Fat (18%) Diet in only Six Weeks:

(1) Increased total HDL-Cholesterol 18% (baseline 42 mg/dl)
(2) Increased Regression subspecies HDL-2 of 50%(3) Reduced Triglyercides by 30% (baseline 141 mg/dl)
(4) Increased total LDL-Cholesterol by 13% (good thing b/c LDL-diameter incr)
(4) Decreased LDL-IIIa+b from 27% to 18%(5) Decrease LDL-IV from 6.0% to 3.4%

Figure 16. Case 8. Metabolic data and EBT images

before and after 14 months of statin and niacin

combination therapy in a 47-year-old man with a

baseline calcium score of 442 in the 97th percentile.

Regression Case Study in a High CAD RISK Individual:
EBCT CAC Reduction 15% Annualized

This 47 yo patient's (see above) therapy included ultra high dose niacin (equivalent to 8 tablets of OTC Slo-Niacin 500mg) which was a dose similarly used in the HATS regression trial, plus low dose weak potency statin. His CAC score put him at the highest 97-percentile of extremely high coronary risk. His father had suffered an acute myocardial infarction at age 46.

What is quite notable with this regression case is the rapid changes in multiple metabolic parameters esp Lp(a) with niacin. Niacin is one of the few therapies that successfully lowers Lp(a). In the HATS trial ~20% of men and ~30% of women had elevations of Lp(a). High dose niacin worked for this gentleman with the tremendous plaque burden. In the EBCT scan, the reduction in LAD was obvious the author stated. See above.

Recall what does niacin mimic? Niacin binds the ketone body receptors which are activated during many of the strategies employed by TrackYourPlaque members:
--intermittent fasting ('fastest way to control plaque')
--carbohydrate restriction
--mod-high protein diet (Primal, Protein Power, phases 1-2 of South Beach)
--mod-high fat diet (TYP Diet Part 3, Primal, Protein Power, low carb high fat Paleo)









Metabolic Parameters Improved

Can we achieve similar multiple metabolic parameter improvements with diet + lifestyles alone?

Faster?

Without drug or ultra high dose niacin side effects?

How would ultra high dose 15 months of Niacin 4000 mg + statin daily in a 47 yo asymptomatic male compare with 6 weeks DR. Krauss' high fat diet in n=103 healthy men (46% fat, 18% sat fat when compared with AHA-Walter-Willet-low fat 8% sat fat)? Granted it is hard to make comparisons between Krauss' healthy study participants and this asymptomatic CAD Case Study, the baseline values for lipoproteins were not that significantly dissimilar from this Case Study (Low HDL, higher TG).

Very similar endpoints in fact can be achieved V E R Y rapidly!

The primary parameters to compare are:

High Fat x 1.5 months:
** Increased Regression subspecies HDL-2 of 50%
** Decreased LDL-IIIa+b from 27% to 18%
** Pattern 'A' to 'A+++' (LDL diameter from 25.9 to 26.5nm)

Pharmacotherapy x 15 months:
** Increased Regression subspecies HDL-2b of 71%** Decreased LDL-IIIa+b from 34.1% to 18.6%
** Pattern 'B' to 'A+++' (LDL diameter from 24.9 to 26.6nm)

Lp(a) Reduced By Saturated Fatty Acids and Raised by Low-Sat-Fat Diets
Benefits of Krauss high-saturated fat diet cannot be overstated. Saturated fats control CETP and thus control the amount of Lp(a) individuals produce. In fact, when an experiment group was put on a low fat, high veggie diet, Lp(a) increased significantly by as much as 9% (Silaste ML et al Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):498-503. Free PDF HERE .)

Additionally, the low fat diet produced HIGHER oxidized LDL (OxLDL) by 27%. Recall the small dense LDL are less resistant to oxidation than buoyant large LDL and transform to OxLDL rapidly.

Not good.

For. Plaque. Burden.

OxLDL causes fatty/calcified organs: arteries (atherosclerosis); endothelium (hypertension); liver (NASH); pancreas (diabetes, MetSyn); thyroid (Hashimoto's), visceral fat (obesity); etc.


Saturated fat lowers and controls Lp(a) and coconut oil is one great example (Muller H et al . J Nutr. 2003 Nov;133(11):3422-7. Free PDF HERE). In this study by Muller et al women with elevated Lp(a) in the 30s mg/dl were provided a coconut oil-rich diet (22.7% sat fat; 3.9% PUFA) was compared with a high PUFA-diet (15.6% PUFA !!yikes). Lp(a) was reduced 5.1% compared to baseline habitual diets with the high saturated fat diet whereas in the high PUFA diet, Lp(a) increased a whooping 7.5%. The difference between Lp(a) on the high sat fat compared to the high PUFA diet was 13.3%.

[Coconut oil is great unless one is allergic. I am aware of a friend allergic to both olives + oil and coconuts + oil. Dr. Hyman discusses food allergies and how to determine what they are via an elimination diet HERE to control inflammation and reduce autoimmunity.]



References

Hecht HS, Superko HR. Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women. J Am Coll Cardiol. 2001 May;37(6):1506-11.

Nasir K, Santos RD, Roguin A, Carvalho JA, Meneghello R, Blumenthal RS. Relationship of subclinical coronary atherosclerosis and National Cholesterol Education Panel guidelines in asymptomatic Brazilian men. Int J Cardiol. 2006 Mar 22;108(1):68-75.

Santos RD, Nasir K, Tufail K, Meneghelo RS, Carvalho JA, Blumenthal RS. Metabolic syndrome is associated with coronary artery calcium in asymptomatic white Brazilian men considered low-risk by Framingham risk score. Prev Cardiol. 2007 Summer;10(3):141-6.

Campbell CY, Nasir K, Carvalho JA, Blumenthal RS, Santos RD. The metabolic syndrome adds incremental value to the Framingham risk score in identifying asymptomatic individuals with higher degrees of inflammation. J Cardiometab Syndr. 2008 Winter;3(1):7-11.

Superko HR. Small, dense, low-density lipoprotein and atherosclerosis. Curr Atheroscler Rep. 2000 May;2(3):226-31.

Superko HR, Hecht HS. Metabolic disorders contribute to subclinical coronary atherosclerosis in patients with coronary calcification. Am J Cardiol. 2001 Aug 1;88(3):260-4.

Hecht HS, Superko HR, Smith LK, McColgan BP. Relation of coronary artery calcium identified by electron beam tomography to serum lipoprotein levels and implications for treatment. Am J Cardiol. 2001 Feb 15;87(4):406-12.

Anand DV, Lim E, Raval U, Lipkin D, Lahiri A. Prevalence of silent myocardial ischemia in asymptomatic individuals with subclinical atherosclerosis detected by electron beam tomography. J Nucl Cardiol. 2004 Jul-Aug;11(4):450-7.

Rumberger JA. Cost effectiveness of coronary calcification scanning using electron beam tomography in intermediate and high risk asymptomatic individuals. J Cardiovasc Risk. 2000 Apr;7(2):113-9. Review.

Coylewright M, Blumenthal RS, Post W. Placing COURAGE in context: review of the recent literature on managing stable coronary artery disease. Mayo Clin Proc. 2008 Jul;83(7):799-805.

Grundy SM. Coronary calcium as a risk factor: role in global risk assessment. J Am Coll Cardiol. 2001 May;37(6):1512-5. Review.

Hoff JA, Daviglus ML, Chomka EV, Krainik AJ, Sevrukov A, Kondos GT. Conventional coronary artery disease risk factors and coronary artery calcium detected by electron beam tomography in 30,908 healthy individuals. Ann Epidemiol. 2003 Mar;13(3):163-9.

Budoff MJ, Gul KM. Expert review on coronary calcium. Vasc Health Risk Manag. 2008;4(2):315-24.

Shifting to Pattern ' A ' for Longevity

Increasing Saturated Fat Intake Shifts to Pattern 'A'

Krauss has shown that increasing saturated fat intake and reducing carbohydrates lowers sd-LDL and shifts to Pattern 'A' (Influence of dietary carbohydrate and fat on LDL and HDL particle distributions. Siri PW, Krauss RM. Curr Atheroscler Rep. 2005 Nov;7(6):455-9.).

Undeniably Pattern A with a dominance of Large-LDL is desired for regression, longevity and cancer protection. Again, Krauss has spelled out in seminal articles that Large-LDL-Particles are not associated independently with atherosclerosis (JAMA rebuttal: Is the size of low-density lipoprotein particles related to the risk of coronary heart disease? Krauss RM. JAMA. 2002 Feb 13;287(6):712-3.; Ion Mobility Analysis of Lipoprotein Subfractions Identifies Three Independent Axes of Cardiovascular Risk. Krauss RM et al. ATVB. 2009 Sep 3.)




What is independently associated with CAD???

(1) Small Dense LDL, particularly the 'death band' LDL-IVb produced by dietary deficiencies of saturated fatty acid and/or ketones and/or excessive dietary carb loads

(2) Low HDL-2 (ditto)


No individual at TYP with subclinical or post-CAD event fails to demonstrate the above two characteristics. Without a doubt, these 2 metabolic parameters describes all atherosclerotic processes that lead to obstructive disease, clinical events, morbidity and mortality. Some individuals with 2-4 stents or bypasses, exhibit zero HDL-2 at the start of our program and 100% sd-LDL.

No joke.

Of course it immediately changes on the TrackYourPlaque program (faster when it is STATIN-LESS).



Krauss and Pattern 'A'
Of all the literature I have reviewed on Pattern A, Krauss has performed nearly all the seminal, landmark research. He has explored a variety of manners to shift to Pattern 'A' (sans statins, sans niacin).

Lots of Fat. 46% minimum.

Saturated Fat. 18% saturated minimum.

Carb restriction. See first diagram, at top.



Can we obtain zero% Pattern B:100% Pattern A in individuals? Minimal and near-zero 'death bands' of LDL-IVb? It sure would be nice.

When the line breaks 'zero' fat intake is ~ 65% and carb intake 20%. Is 20% still too high for some inviduals? I believe so.

I consume about 20-50 grams daily when I am insulin resistant (around my mense when my body thinks I'm getting ready for a baby; during the year of synthetic hormone h*ll). How do I know when carbs are excessive for me (eg, eating a whole dark chocolate candy carb = 30-40grams)?? I ck my blood glucose on a meter 10-20min afterwards (because I peak fast on high GI foods) and it may be > 110-120 g/dl. After rice/sushi, the BG may peak to 180 g/dl for like... 5 min. I can tell the damaging high glucoses are followed by damaging high insulin (and a reduction in adiponectin, the hormone related to body fat loss) because I may have heart palpitations, rapid/racing heart rate, a little anxious (?? or is it the I.V. Caffeine), not relaxed, (HUNGER for 24-72hrs afterwards) and basically feel like... CR*P.

I weigh about 125 lbs now and consume about 1-2 g per kilo of protein daily (somedays more with more exercise, somedays less with IF) which is approx 45-56 grams daily (= approx 2 chicken breasts) which makes up about ~15% of energy (or more).

If I estimate I obtain about 1000-1600 cal/day and calculate 20% would be allocated to carbs as an example, then that would be equivalent to ~50-80 grams of carbs daily. WOW. That is a lot more than my current consumption and my experience is that I would gain weight on that dietary intake (esp during insulin resistant periods), even if I consumed 65% fat and 15% protein (or even 50% fat and 30% protein).

Perhaps if carbs were restricted further, more individuals would have achieved Pattern 'A'?

10% Carbs?

5% Carbs?

See below, same graph, I've extrapolated into Pattern A territory by extending the Fat%/Carb% x-axis.



Saturated Fat Intake Lowers LDL-IVa+b

In a trial in n=103 men, low-fat versus high-fat diet were compared. Krauss yet demonstrates again that increased dietary fat and specifically the saturated fat portion are statistically related with reducing small dense LDLs LDL-III and LDL-IV and shifting lipoproteins toward Pattern A. (Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Dreon DM, Krauss RM et al. Am J Clin Nutr. 1998 May;67(5):828-36.)

In summary, the present study showed that changes in dietary saturated fat are associated with changes in LDL subclasses in healthy men. An increase in saturated fat, and in particular, myristic acid, was associated with increases in larger LDL particles (and decreases in smaller LDL particles). LDL particle diameter and peak flotation rate were also positively associated with saturated fat, indicating shifts in LDL-particle distribution toward larger, cholesterol-enriched LDL. This study also showed that increases in dietary saturated fat were associated with decreases in HL activity. This finding, together with our previous cross-sectional analyses that revealed significant inverse relations of HL activity with LDL peak flotation rate (15), suggests an inverse association of HL activity with concentrations of buoyant LDL particles.

Diet Compositions

Low fat diet:
--24% of energy as fat (6% saturated, 12% monounsaturated, and 4% polyunsaturated)
--59% as carbohydrate, with equal amounts of simple and complex
carbohydrates.

High fat diet:
--46% of energy as fat (18% saturated, 13% monounsaturated, and 12% polyunsaturated)
--39% as carbohydrate. TOO HIGH!!

The main fat as described by the authors was "Palmitic acid (16:0) ... the primary dietary saturated fatty acid in both diets, followed bystearic (18:0) and myristic (14:0) acids, which are representative of the major saturated fatty acids in most human diets (3)." The carbohydrates would be considered high and associated with a higher incidence of Pattern B according to the first Krauss trial described earlier in the post. Nonetheless the results were quite fascinating. Only saturated fatty acids corresponded statistically with improvements in shifting to Pattern A, increased LDL diameter size and to reductions in small dense LDL (both LDL-III and LDL-IV). Please see below stats.




Reduction of LDL-IV by 39% With Increased Saturated Fat
The amount of dietary saturated fat tripled up from 6% to 18% of total energy. This change statistically correlated to reductions in LDL-IV by a total of 39%. The 'death band' which would have corresponded to LDL-IVb was not determined in this trial but definitely some proportion was significantly decreased. Between LDL-IVa and LDL-IVb, we do not know the precise proportional changes.



3X Increase in Saturated Fat Increased HDL-2 by 50%

Recall in the HATS regression trial (NEJM, 2001) where 90% reduction in death and events were observed, the niacin arm was associated with a 70% shift to large buoyant LDL and HDL-2 increase of 60%. With an increase in saturated fats of from 6% to 18% daily, the HDL-2 subfraction increased 50%.


'Death Band': Percent-LDL-IV Changed from 6.0% to Only 3.4%
Examing the relative amount of the 'death band' LDL-IV, Percent of LDL-IV changed from 6.0% in the low-fat group to only 3.4% in the high-fat group. Recall in the previous post Krauss observed that regression (where stenosis is > 30%) was highly associated with quartiles of LDL-IVb less than 2.5%.




Summary of Heart-Healthy Improvements with a High-Saturated Fat (18%) Diet in only Six Weeks:

(1) Increased total HDL-Cholesterol 18% and the improvements were in vast increases of the regression subspecies HDL-2 of 50%

(2) Reduced Triglyercides by 30%

(3) Increased total LDL-Cholesterol by 13% which is a good indicator that large buoyant LDL are starting to prevail because this change is accompanied by increases in HDL-Cholesterol. An increase in LDL-C is a good thing and associated with regression when the HDL-C is increasing concomitantly. This is not the case in Metabolic Syndrome. Increasing LDL-C in MetSyn are ONLY associated with higher small dense LDL-C which translates to Pattern B (for extremely BBBBAAADD).

(4) Decreased small dense LDL (LDL-III) from 27% on the low fat diet to 18% on high saturated fat. Not bad. The TYP is goal is < 10-30%. For our TYP members who restrict dietary carbohydrates (eg, grains, fruit/berries, etc) and add significant amounts of saturated fat, in 4-6wks they observe basically eradication of small dense LDL to ZERO. These members may have struggled with dense LDL of even 70-80% for years.

(5) Decrease in the deadliest, smallest LDL (LDL-IV) from 6.0% to 3.4% with high saturated fat intakes.




Longevity: Small Dense LDL and HDL-2
We learn so many lessons from the regression trials with niacin, vitamin D (Dr. Davis publication, CKD hemodialysis patients HERE) and the omega-3 trials. The longevity observations in centenarians fascinate me to no end. I enjoy reading them since they conceptualize the same principal components that Krauss, Superko, Callister, Davis and other forward-thinking, visionary cardiologists and physicians advocate for heart health:
(a) achieve low small dense LDL
(b) bank on high HDL-2

The centenarian study that we reviewed earlier HERE is worth another mention at this time (Unique lipoprotein phenotype and genotype associated with exceptional longevity. Barzilai N et al. JAMA. 2003 Oct 15;290(15):2030-40.).




Centenarians Exhibit Pattern 'A+' With sd-LDL << 10%

The Ashkenazi Jewish study compared centenarians, their offspring and population controls (both short-living Ashkenzi Jewish as well as Framingham). Corollaries exist between the long-living (probrand) centenarians and the CAD regression pattern in the trials that we have reviewed here. The long-living typically have resistance against hypertension, diabetes, cancer and coronary artery disease. Uncannily, these centenarians have Pattern A and an extremely low percentage of small dense LDL subparticles, not unlike our Paleo (low carb, high fat) friends and Paleo/ TYP members who achieve all of Dr. Davis TYP goals.



Figure 1. Frequency Distribution of Lipoprotein Properties in Female Probands, Offspring, and Controls. The frequency distribution of plasma high-density lipoprotein (HDL) oncentration levels and particle sizes, and low-density lipoprotein (LDL) particle sizes in female probands, their offspring, and an Ashkenazi control population. [To convert HDL oncentration to mmol/L, multiply by 0.0259. The solid lines represent the mean and the dotted lines represent 1 SD of control.]


What strikes me is that the centenarians (probrands) exhibit generous quantities of large buoyant LDL (60-70+%), only < 10% sd-LDL, Pattern 'A' lipoproteins and an inordinate amount of large-sized HDL-2. Even with modern eating (refined processed foods), their children also similarly exhibit a prevalence of high HDL-2 and high buoyant LDLs. Like good wine, the centenarians' HDL-2 and buoyant LDL appear to have gotten better with age!



Maximize Genetic Expression
Burst your genetic ceilings and boundaries! With the appropriate diet low in carbohydrates, wheat/gluten-free, containing sufficient saturated fatty acids, we can achieve similar longevity-associated lipoproteins. Many are doing it and it's not that hard. Clinical studies support the validity of the benefits of high-saturated fat diets for achieving regression, shifting to Pattern ' A ', controlling small dense LDL, and raising HDL-2.

'Death Band' = sdLDL on Lipoprotein Subfractionation

Diagrams #1, 2

Modified and Courtesy of some FDA.gov website

Subfractionation of Lipoproteins 101

Let's review some subfractionation techniques. On the market 3 main methods exist. They all work. Dr. Davis highly prefers NMR for its subtleties, scope, and particle counts. Superko and Krauss are affiliated with Berkeley HeartLab which uses GGE (BHL). Density gradient ultracentrifugation is very popular among our members (VAP-II and VAP). Recently, Krauss appears to be introducing a new technology based on ion-mobility.

Basically, the denser the particle, the faster and more mobile the particle moves through a gel (GGE). The denser the particle, the smaller the diameter (Angstroms or nanometers) as determined via electromagnetic resonance (NMR) or absorbance via density ultracentrifugation (VAP, which are indirectly compared to known sizes).



Pattern A = Large LDL-C Predominance

Pattern 'A' is good (all nice large buoyant fluffy particles). LDL particles are not perfectly spherical; they can appear even flat like red blood cells. Large LDL however fit 'perfectly' into LDL receptors on cholesterol-requiring tissues like our sex organs (which produce testosterone and estrogen from cholesterol) and the all-important adrenal glands, tiny triangularlike-walnuts sitting on the kidneys which regulate our blood pressure, tension in the endothelium/smooth vasculature, and minute-to-minute brain functions by issuing cortisol, another cholesterol-based derivative that is mandatory for life.

Pattern 'A' is desirable and highly asscociated with regressive patterns for calcification in the vasculature whether the plaque build up (scar-tissue) is in the renal (kidney) arteries, carotid (neck) arteries, peripheral (legs), coronary (heart), or inner lining of the entire arterial tree (hypertension).

Hypertension? This is just extensive calcium deposition occurring at the smooth muscle, endothelium and vessel wall fibroblast level in the vascular tree. HERE and HERE discuss the role of oxLDL on increasing MMP-9 and arterial stiffening.



What is easier to regress? Dr. D and I agree that the carotids are the easiest (plaque there comes and goes based on full moons or voodoo medicine... no joke, it's so easy). Since the brain is the most important organ... (again, yes, debatable...arguably it might be the... liver...*haa*) the carotids provide blood flow to this GINORMOUS organ. Consequently these arteries are 7-8mm, titanic-sized bilateral highways.

Distribution of blood flow at rest and during flight-fight-fright correlates well with artery lumen sizes IMHO (courtesy of a Rutgers anatomy phys student w/concise pictures HERE).

At rest:a. Brain: 13% (7-8mm)b. Heart 4% (2mm distal LAD; 3-4mm LAD; 4-5mm RCA) (Brown BG et al. Circulation 1992;86;232-246.)
c. Kidney: 20% (5-6mm)d. Abdominal organs (incl liver): 24% (5-6mm)

During exercise:
a. Skin, muscles and heart increase
b. Remaining tissues either remain same or decrease

Renal is the hardest. I think Dr. T at Nephropal will agree. These are relatively narrow yet receive the greatest majority of tissue perfusion, and have less possibility of collateral growths/angiogenesis than other arterial vasculature. Renal stents notoriously ALL 100% fail. Bypasses are currently unconceivable. Peripheral is not good either (but again, also reversible).

No matter where the plaque is, however, it is ALL potentially reversible.

A L L .

A good 'indicator' of regression is blood pressure normalization < 110/70. Everyone at TYP on the program who maximizes expression of Pattern 'A' with sdLDL as low as possible and HDL2b as high as possible (200-400% increases) notice dramatic reductions in blood pressure. Of course !

In the HATS trial, again where events were prevented by 90% and angiographic regression observed, reductions in blood pressure occurred. We see this in ALL of our successful TYP members as well. Pattern A for A+++ (blood pressure, Large-LDL, HDL2b and sexy hot elastic unstiffened unobstructed vasculature).




Pattern B = Small Dense LDL-C Predominance

Pattern 'B' is clearly BAD.

Dense small stupid cr*ppy stuff.

Small dense LDL quickly and rapidly become oxidized LDL (OxLDL) which do NOT fit into traditional LDL Receptors. They instead are attracted to many non-LDL receptor surfaces and tissues (Galeano NF et al, J Lipid Res. 1998;39:1263-1273). These sites include the endothelium to initiate 'stiffened'/calcified arteries (eg, hypertension), atherosclerosis (plaque burden: CAD ED CVD PVD RAS) or liver to initiate NASH/fatty liver or even our pancreatic islet cells that are highly related to hastening T2DM pathogenesis (Cnop M et al. Endocrinology. 2002 Sep;143(9):3449-53.).

Yes.

sdLDL is sad news. Especially if one has 50 to 100% sdLDL. Yeah, that is kinda f*cked up and highly associated with prevention of regression. This explains the sad results and outcomes from all statin trials compared with the niacin trials (HATS, FATS, CDP, etc). Recall: Cardio Controversies and Dr. Superko. Pattern ' B ' perpetrated by statins also explains the lack of regression in nearly all EBCT and MDCT clinical trials. Ten out of about 12 to 13 trials that I have reviewed for statins and CT coronary calcifications show no difference between statin and placebo arms.... Or.... even worsening (one lipitor study). Why?
Statins s*ck. (And zetia is worse, eg SEAS, ENHANCE trials... more %-sdLDL... more HDL-3... more cancer... more plaque progression)



Small dense LDL and OxLDL penetrate deeply through several tissue layers.

Tissues involved: any tissue. You name it.






CAD is Autoimmune
OxLDL attract auto-antibodies.

Auto-antibodies are like the 'cleaners' (you know... in Mob terms). Auto-antibodies can go CRAZY.

O-U-T-T-A . . . C-O-N-T-R-O-L . . . (Baby Bash Feat. PITBULL OOOhh... Yeah).

Yes, CAD is an autoimmune process not unlike Hashimoto's/thyroid-insufficiency or NASH/calcified-liver or T1DM or T2DM/pancreatic-insufficiency or Addison's/adrenal-insufficiency







What Promotes Pattern ' B ' ?

Guess what?

Silent and overt celiac disease (gluten intolerances: wheat barley rye) and other food allergies (A1-casein, egg whites, nightshades, nuts, etc)

Excessive dietary carbs (grains, potatoes, peas, corn and fruit). Candy/sweets. Artificial sweetners. Lack of omega-3 fats. Excessive omega-6 refined veggie oxidized refined fats not meant for human or animal consumption.

Lack of s a t u r a t e d fatty acids.

Lack of antioxidants.

Lack of hormones (thyroid, estrogen, testosterone, adiponectin, vitamin D, melatonin, etc).

Synthetic vitamins, hormones or drugs (Lurotin/fake-beta-carotene (used in the HATS AO-arm; ATBC: 7% higher death rate; CARET: 28% higher cancer+mortality); levonorgestrel, Provera/medroxy-progesterone, Premarin/horsey-hormones, oral contraceptives).

Zetia.

S-T-A-T-I-N-S . . . and thus statins +/- Zetia s*ck...





Role of Large LDL in Pattern 'A'

LDL-5 (on VAP) and LDL-6 (on VAPII) are the densest smallest LDL subspecies (devoid of cholesterol content). See below diagram #2. These subparticles oxidize to OxLDL in the metabolic pathway of lipoproteins quickly in the bloodstream, studies show. LDL1 and LDL2 are the Large LDL subspecies which are rich in cholesterol content and extremely resistant to oxidation. Additionally, these magnificently-sized particles are the carriers of antioxidants which provide protection from oxidation, ROS and free radicals, to peripheral tissues after digestion from food. Large LDL transport the great majority of our important fat-soluble antioxidants: coenzyme Q10 (idebenone, etc), carotenoids, vitamin E (tocopherols, tocotrienols), vitamin K1 K2 (menaquinones 4 - 9 chain lengths), et cetera.








Conversion of Pattern 'B' to Pattern 'A' Associated with Regression

The medical literature is rife with studies demonstrating that the conversion of small dense LDL to buoyant LDL is associated with regression of coronary artery disease. In the HATS trial where 90% of cardiac death and events were COMPLETELY AVERTED after 3 yrs of niacin ultra-high-dose of 3-4 grams daily (and low low dose of weak-statin 10-40mg/d), conversion to Pattern A occurred in an astounding 70% of the treatment arm. Even niacin alone produces similar outcomes of 60-70% relative risk reduction, compared with statins 17-25%. In other words, niacin alone or in combo is 300-400% better than statins relatively speaking.

What mimics niacin? What binds 'niacin'-receptors?

Ketone bodies.

Generated from intermittent fasting, physical prolonged exercise (low intensity) or... a ketotic diet, eg high protein or high fat and no carbs.





Large LDL Not Associated with Heart Disease

Only 2 studies show Large LDL are remotely associated with heart disease (that I can find) and definitive CAD progression. In each case, the presence of the 'death band', a high peak of LDL-IVb and LDL-IIIa+b (sdLDLs) and an absence of the 'regression peak' HDL-2 occurred (Campos H, Krauss RM, et al. 1995 ATVB. 15;1043-1048.; Campos H et al. 2001 JAMA 286:1468-1474). In 1995, only 3 LDL subspecies were determined. The more infinitely denser, heaveir sub-species -- LDL-IIIb, LDL-IVa, LDL-IVb -- hadn't yet been 'discovered'. 'LDL-III' from Campos/Krauss' article is actually LDL-IIIa.




The 'Death Band' = sdLDL Highly Associated With CAD

See below. LDL-III is considered dense particles. Dense like bullets. In the below graph the 'densest' of the LDL-III is circled. This is not a rock band... I refer to it as the 'death band' since it is associated with coronary events. Peaks corresponding the heaviest, smallest of the LDL-III particles (far left 2 lines at ~1.4%; red) in the CAD group was significantly higher than the control ones (1 line at ~0.5%; pink). If I do some retardo-calculus, then the 'circled' tiny death-band peak is ~2.8% versus ~0.5%. 5.6 times greater in area under the curve.

So, this 'circled' sd-LDL subfraction contained 560% more of the smallest densest 'death-band' particles in the CAD group than compared to control (no CAD).

HDL2 in the CAD group was statistically lower at 10 mg/dl (out of 38 mg/dl, 26%) whereas the control was 50% higher, 15 mg/dl (out of 42 mg/dl, 36%).

Controls (no CAD)... had HDL-2 fifty-percent HIGHER. (Recall, HDL2 increased 60% in the HATS trial in the niacin arm).

In a 'response' to the second Campos study, Krauss wrote an articulate rebuttal to Campos et al discussing the relevance of high sdLDL-Particles and low HDL2-Particles in CAD progression, not Large-LDL-Particles. HERE (sorry, not free yet).





The Denser, The More D A N G E R O U S

How dense is Campos?? How deep do LDL-centric-zealot-statinator-idiots dig?





The Densest Bullet of Them All: LDL-IVb

The bands I circled above were dense. Even denser LDL subparticles exist. These smaller, more atherogenic particles contain even less antioxidants, less transportable-cholesterol and are tremendously prone to oxidation. On NMR these are identified as subclass LDL-IVb and on VAP LDL-5 (VAP-II, LDL-6).

Eight years later after these newer LDL subparticles were identified, Superko and Krauss demonstrated that the mere presence of the SMALLEST, DENSEST LDL sub-species (IV-b) was MOST associated with fastest plaque progression (Superko, Krauss et al. ATVB 2003 Feb 1;23(2):314-21.) Japanese researchers have arrived at the same conclusions as well (Koba S et al. J Atheroscl Thromb 2008,15(5):250-260. Free PDF HERE)

As to be expected, Superko and Krauss, also showed that reduction of the SMALLEST, DENSEST LDL sub-species (IV-b) was highly associated with fastest plaque regression. Therefore, when sdLDL were controlled and reduced to the point where the smallest denset LDL (IVb) were less than 2.5%, a decrease in plaque burden and regression of atherosclerosis was observed. However this observation did not hold true for those with less extensive angiographic plaques where stenosis < 30% (?soft plaque still progressing? yet lower appears better). Diagram from Superko and Krauss 2003.




What Ultimately Lowers 'Death Bands' LDL-IVb The Best?

Saturated fatty acids (all of them: short-chain, medium-chain, long-chain) (Noakes M et al. Nutr Metab Cardiovasc Dis. 2009 Aug 17.; Krauss RM et al. Curr Atheroscler Rep. 2005 Nov;7(6):455-9.; Noakes M et al. Am J Clin Nutr. 2009 Jul;90(1):23-32.)

High-protein, Low Carb Diets (Clifton P, Krauss RM, et al. Am J Clin Nutr. 2008 May;87(5):1571S-1575S.)

Carb restriction (Volek JS et al. J Nutr. 2009 Sep;139(9):1667-76.)

Ketotic Diets (Clifton P et al. Obes Rev. 2006 Feb;7(1):49-58.)

Paleo Diets (Frasetto LA et al. Eur J Clin Nutr. 2009 Aug;63(8):947-55. Hays JH, Editorial 2004. )

Niacin (ultra high dose) (HATS trial, NEJM 2001)

Omega-3 PUFAs: DHA EPA ALA (Schaefer EJ et al. Atherosclerosis. 2008 Mar;197(1):12-24.; Mozzafarian D. J Cardiovasc Med (Hagerstown). 2007 Sep;8 Suppl 1:S23-6.)






What Lowers Blood Pressures Concomitantly Whilst Annihilating 'Death Bands' and Raising HDL2b?

ALL THE ABOVE (see above citations)

(Except for Niacin, A-L-L the above are additionally associated with weight control, body fat loss, improvement in Metabolic Syndrome, T1DM, T2DM, insulin control, hyperinsulinemia)





What Does Not:
--olive oil (monounsaturated fatty acid)
--omega-6 veg/seed/bean oils
--mercury, cadium, heavy metal toxicity; selenium-deficiency (Houston MC. Altern Ther Health Med. 2007 Mar-Apr;13(2):S128-33.)
--low fat/high carb AHA diet
--low fat diets
--low cholesterol diets
--low saturated fat diets
--statins
--zetia

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