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)
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.).
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 ' ?
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).
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?
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