Wednesday, July 30, 2008

Corona and Lime -- UR Mine

Corona and Lime
By Shwayze
video
Courtesy of Youtube.com


Will miss you... RIP

Adieu Amber Ale... So long, farewell, Hefeweizen! Bye-bye Bud Light...

The last wheat products to go...



My phytoestrogens will have to be sourced elsewhere like from barley-only beer -- GO HOP -- **hip-hop** HURRAY...

See below abstract -- Luv our microscopic friends and fauna that reside in our mile-long bowels! Treat them well...

In my former career as a research associate, I worked on barley and calmodulin (yes a target of Vitamin D -- who knew?). A great deal of my time was spent on northern blots (which takes a certain knack b/c RNA deteriorates easily) and southerns (DNA's durable Thank God). Yes, we were partially funded by the USDA (as well as beer companies.... j/k! maybe ??indirectly??). Had to test theories and research qualitative factors... after work beer with the post-docs and grad students was often a job requirement... no joke *hee*.
    • Activation of proestrogens from hops (Humulus lupulus L.) by intestinal microbiota; conversion of isoxanthohumol into 8-prenylnaringenin.
      Possemiers S, et al.
      J Agric Food Chem. 2005 Aug 10;53(16):6281-8.
      Laboratory of Microbial Ecology and Technology (LabMET), Faculty of Bioscience Engineering, Gent University-UGent, Coupure 653, Gent, Belgium.
      Hop, an essential ingredient in most beers, contains a number of prenylflavonoids, among which 8-prenylnaringenin (8-PN) would be the most potent phytoestrogen currently known. Although a number of health effects are attributed to these compounds, only a few reports are available about the bioavailability of prenylflavonoids and the transformation potency of the intestinal microbial community. To test these transformations, four fecal samples were incubated with xanthohumol, isoxanthohumol (IX), and 8-PN. Upon incubation with IX, present in strong ales up to 4 mg/L, 36% was converted into 8-PN in one fecal sample and the estrogenic properties of the sample drastically increased. In an experiment with 12 fecal cultures, this conversion was observed in one-third of the samples, indicating the importance of interindividual variability in the intestinal microbial community. Eubacterium limosum was identified to be capable of this conversion (O-demethylation) of IX into 8-PN, and after strain selection, a conversion efficiency of 90% was achieved. Finally, strain supplementation to a nonconverting fecal sample led to rapid and high 8-PN production at only 1% (v/v) addition. Up to now, the concentration of 8-PN in beer was considered too low to affect human health. However, these results show that the activity of the intestinal microbial community could more than 10-fold increase the exposure concentration. Because prenylflavonoids are present in many beers with IX being the major constituent, the results raise the question whether moderate beer consumption might contribute to increased in vivo levels of 8-PN and even influence human health.
      PMID: 16076107


    Stuff from my old lab below -- flora and fauna -- sometimes not much different. Many hormone actions and metabolic rules are conserved across nature.

      • Nitric oxide acts as an antioxidant and delays programmed cell death in barley aleurone layers. Beligni MV, et al. Plant Physiol. 2002 Aug;129(4):1642-50.
      • Hormonally regulated programmed cell death in barley aleurone cells. Bethke PC, et al. Plant Cell. 1999 Jun;11(6):1033-46.

Thursday, July 24, 2008

Modern Wheat: Staff of Life or... Staff of Cancer? Death?

Admittedly, stopping wheat was the last part of TYP regimen that I embraced. It's also perhaps the H-A-R-D-E-S-T. Wheat is ubiquitious as a convenient and delicious food component (which makes up the largest tier of the USDA food pyramid and a half-tier of the Harvard healthy eating pyramid). Don't we need wheat for life? Well, after nearly one month now of (near) complete wheat cessation (cheated with 1-2 chocolate croissants aaannnnddd... a few beers, irresistible bread pudding and slices of Ezekiel), I have to say, there is life after wheat. No one died. No one had seizures or delirium tremens. No one even puked.

Now my kids are a different story -- they still occasionally whine when they don't get their pizza, PB&J or penne pasta from Pasta Pomodoro, our (former) favorite restaurant. It turns out that potential replacements do exist (on earth)! Whole Foods Market (aka $$$ 'Whole WALLET') does have a gluten-free pizza shell in the frozen gluten-free area that is purportedly tasty. Rice noodles or mung bean noodles just are the same as penne pasta . . . How about a suitable vehicle for peanut butter & jelly. . . ? we're still figuring that out... any thoughts are welcome!

Why are Wheat-grains so filthy and abominable in the Track Your Plaque plan for atherosclerosis stabilization and regression? Sounds so blasphemous doesn't it? Like cursing food of the gods? Wheat helped potentially grow the Roman empire (by supplying their soldier-class with a convenient portable energy source) and build world wonders like the Egyptian pyramids 3rd century BC. In modern times, why does it represent so many chronic diseases and ailments? Wheat is currently linked to all the below conditions. Acute sudden death does not generally occur (nor does anaphylaxis or other fatal reactions like scurvy or beri beri) however the death is chronic, very very slow, mildly painful, taking decades.
--celiac sprue
--'silent' celiac sprue
--autoimmune diseases -- most arthritis syndromes (?even OA/DJD), Type 1 diabetes, Hashimoto's hypothyroidism, Grave's hyperthyroidism, lupus, multiple sclerosis, ?asthma
--infertility
--PCOS
--NASH/NAFLD
--gallbladder disease
--primary biliary
--lymphoma
--colon cancer
--pancreatic cancer, other cancers
--eczema, acne, psoriasis
--systemic inflammation
--et cetera

Can our daily bread be causing cancer? People are in disbelief that the staff of life can be the strongest factor in (!!) infertility and crippling arthritis... 'Don't we need fiber?' as if I've suggested something sacreligious. 'Aren't we supposed have whole grains at every meal?'

I used to feel the same way too until I was witness to testimonials.

I'm more of a true believer now for complete wheat cessation after hearing not only amazing stories that Dr. Davis has frequently blogged about at HEARTSCANBLOG but witnessing some personal amazing stories from people who have stopped wheat completely in their lives for only 2 to 4 weeks.
  • decrease or elimination of 30-50 units insulin daily
  • reduction in pain from arthritis
  • decrease or cessation of pain and arthritis medications
  • improvement in vitality, energy and youthfulness
  • acne improvement or resolution
  • skin showing glowing clarity and smoothness, eczema-free
  • easy weight loss 10-15 lbs (women) or 20-30 lbs (men who typically start with more lean tissue mass than women)
  • chronic pain syndromes
  • improvement in neuropathic pain syndromes
  • hypertension decrease or normalization


Many parts of the TYP plan promote heart protection as well as cancer prevention. Wheat cessation is just one part of this ultimate optimum health guarantee. Other critical components which clinical studies have shown to promote prevention and regression of cancer include:
--fish oil omega-3 PUFAs EPA + DHA (high dose and ultra high dose)
--elimination of pro-inflammatory omega-6 polyunsaturated fatty acids (cheap industrial veggie oils like safflower, sunflower, cottonseed, canola, etc)
--excessive fructose (the carb in fruit and starches like corn)
--elimination of trans fats and fructose/high-fructose-corn-syrup
--normalization and optimization of steroid hormones: vitamins A/D/E/K2, B-complex, C, micronutrients (Zn, MAGNESIUM, Se, Cu, etc), Estrogen, Progesterone, Testosterone, DHEA, Thyroid, et cetera
--daily exercise/movement/play + occasional intensive bursts ('sex' counts!)
--OPTIMISM

Wheat, the staff of slow painful death... and cancer. Stop wheat products now for elite health and fitness.

Consider trying wheat cessation for 1-2 wks -- you may be surprised by the results just as I was!

Thursday, July 17, 2008

Hearts of Stone, Arteries of Glass



A recent Wall Street Journal article "Defending Against Disease -- With Vitamin D New Studies Suggest It Isn't Just Bones That Might Benefit" by the wonderful Melinda Beck highlights benefits of Vitamin D3. In TYP, we've known the benefits for years :) but it's nice to see the rest of the world catching up.

The benefits of Vitamin D3 are potent, powerful immunomodulation -- to the point where autoimmune diseases, viral and bacterial infections and cancer are effectively reduced. What is the value for heart disease and diabetes prevention? In hemodialysis patients, great lessons are can be learned. Nephrologists often describe patients with severe (stage 5) chronic kidney disease (CKD) patients on hemodialysis as having 'hearts of stone, blood vessels of glass.' Unfortunately over 70% of chronic hemodialysis patients have coronary artery disease (and Lp(a)). What medical science shows is that Agatston coronary calcification scores can be dramatically reduced when vitamin D is replenished and calcium is restricted. Sevelamer (Renagel) is a calcium-free, metal-free polymer phosphate binder. In 52-weeks, calcium restriction, a phosphate-binder and vitamin D resulted in one individual in a 21% reduction in Agatston CAC score (from 968 to 756; see Figure 2).

Average reduction in CAC at 6-mos in the Sevalamer group was 8% CAC score reduction/regression, whereas the Calcium-binder group exhibited an increase of CAC score of 10%. Interestingly, the study protocol encouraged discontinuation of Vitamin D once PTH was 150 therefore regression does not appear to be achieved further in the Sevelamer group between the 6-12 month period.

With chronic kidney disease, impaired activation of Vitamin D occurs which leads to degeneration of bones (renal osteodystrophy) and subsequent release of calcium and phosphate into the blood stream (ie, the building blocks of bone). To normalize phosphate and prevent precipitation of bony matrix in soft tissues (including the heart), phosphate binders are used. In the past, calcium carbonate was used -- cheap and effective. The problem was that calcium added to the mix created higher CAC scores and vascular calcification. Higher rates of mortality secondary to coronary artery disease, peripheral vascular disease and strokes were witnessed in the past. However now with newer calcium-free phosphate binders and Vitamin D (real and fake) as standard of medical care, vascular calcifications, aortic, valvular and coronary calcifications can be halted. In fact... even dramatically REDUCED. Wow... Dr. Davis, you R-O-C-K !

He's right about wheat toxicity... and he's right about the powers of vitamin D!
Why did these UCSF and Tulane researchers use EBT calcium scanning to 'track plaque'? There reasoning was 'The purpose of EBT imaging in our study was to investigate whether the treatments would contribute differently to calcium deposition in the arterial wall. Since the Agatston score is very sensitive to density, and is directly related to the calcium content of the plaque, this was considered the primary EBT end-point. The volumetric scoring method does not apply a scalar density factor but rather estimates the bulk of atherosclerosis [16], and was calculated for completeness. The median inter-scan variability is 8 to 10% for the Agatston score [17, 18] and 6 to 8% for the volume score [16].' Kidney specialists have known the value of EBT scanning (non-invasive, cheap, low-radiation) for YEARS because diagnostic tests which utilize iodine contrast dyes are harmful to kidneys. EBT requires no dyes and therefore maintains protection against kidneys. Additionally, clinical events track well with EBT and vascular calcifications.





Vitamin D used in the trial was one of the below per the investigator:
  • 1,25-dihydroxy vitamin D3
  • Synthetic analog, IV
  • Synthetic analog, PO


EBT scoring measures up and predicts events in coronary disease patients with CKD:
Huybrechts KF, Caro JJ, London GM.
Modeling the implications of changes in vascular calcification in patients on hemodialysis.
Kidney Int. 2005 Apr;67(4):1532-8. PMID: 15780108


METHODS: Data on 179 patients on hemodialysis treated at one center in France included biochemical values during the year prior to study entry, patient characteristics, and cardiovascular events over an average of 4 years. As arterial calcification was evaluated ultrasonographically and quantified using a 0 to 4 score, an equation relating this to the electron-beam tomography (EBT)-based calcification score used in the trial was developed and applied to all patients. The estimated scores were then used in survival and Cox proportional hazards analyses of cardiovascular events in relation to the degree of calcification, controlling for other characteristics.

RESULTS: Mean age at inclusion was 54 years, dialysis vintage 70 months, average follow-up 49 months; 32% suffered an event. The calcification score, diabetes, C-reactive protein (CRP), diastolic blood pressure, gender, smoking and hypertension are independent predictors of cardiovascular risk. The resulting equation indicates that, relative to a calcification score below 400, the risk of an initial event increases 44% for a score of 600, and more than doubles for a score of 1000.




Heart protection has been demonstrated with Vitamin D in this CAD hemodialysis subgroup. Reduced clinical events and mortality are demonstrated and discussed below:



We also know that Vitamin D in just a single dose (100,000 IU D2... which is dose-equivalent to 33,333 IU natural D3) administered to elderly Scotland residents with Type 2 Diabetes significantly improves endothelial function with testing flow-mediated vasodilatation (FMD):


Great reference for Vitamin D:
THE CLINICAL IMPORTANCE OF VITAMIN D (CHOLECALCIFEROL): A PARADIGM SHIFT WITH IMPLICATIONS FOR ALL HEALTHCARE PROVIDERS (CME)
By Alex Vasquez, DC, ND, Gilbert Manso, MD, John Cannell, MD

Monday, July 14, 2008

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

Tuesday, July 8, 2008

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

Monday, July 7, 2008

Eden: Liver = Heart


HOOVERPHONIC: Eden
Which Samurai with his spunky
spiky haired-side kick deftly defeats PLAQUE?
video
Courtesy of Youtube.com



Eating is definitely a sensory activity that starts with the brain-- have you heard that saying 'eating with your eyes'? Have you ever given your liver much thought while you consuming your meals or snacks? Ever wonder where does the food go before it hits the bloodstream?

In fact, the human liver is the largest internal organ comprising of 3 lobes and receives all the blood after a meal from the stomach and intestines via the portal vein. How does the body sense abundance in the environment?

Through the eyes? No... ye ol' LIVER...

If food (quantity and quality and composition) serves as one of the cues from our external physical environment, then the liver and the PPAR receptors located there there are the sensors of the degree of energy abundance/scarcity. What elements are essential for life outside of air? Food -- water -- light.... Similarly, what senses light? It is likely that VDR (vitamin D receptor) plays an equally important and parallel role. Abundant sunlight for most countries near the equator typically signals abundant food/energy. Vitamin D does rev up energy, productivity, and *hey* fertility! Naturally it follows that the skeletal muscles are the sensor for muscle movement and certainly the PPAR receptors in skeletal muscle do a great deal to command the balance of energy demand and supply/thermogenesis.

What might the holy trinity of human energy look like? mTOR--PPAR--VDR ? How might it have been shaped in our 'evolutionary heritage'...??? (thanks for the term Grey Whale!)

Well, we certainly know a lot of about what contribute's to this trinity's dysregulation...

  1. Lean-muscle-and movement-deficiency

  2. Wheat/grains consumption (including excessive fruit/FRUCTOSE too)

  3. Vitamin D3/sunlight deficiency



Even statins improve this trinity... by activating (!!) PPAR ... This special anti-inflammatory and MMP-stabilizing effect occurs specifically at the macrophage level and for plaque, this translates directly to the surface, volume and core of plaque atheroma. The pleiotropic benefits of statins can now be attributed to a direct activation of PPAR on macrophages via the MAPK pathway.



Paumelle R, Staels B. Peroxisome proliferator-activated receptors mediate pleiotropic actions of statins.Circ Res. 2007 May 25;100(10):1394-5. No abstract available. (see Diagram: Cross-talk of statins/ PPARs in the antiatherogenic properties of statins -- PDF here) PMID: 17525375

Yano M, Matsumura T, et al. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res. 2007 May 25;100(10):1442-51. PMID: 17463321

Paumelle R, Staels B, et al. Acute antiinflammatory properties of statins involve peroxisome proliferator-activated receptor-alpha via inhibition of the protein kinase C signaling pathway.
Circ Res. 2006 Feb 17;98(3):361-9. PMID: 16397146


Landrier JF, Thomas C, et al. Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.
J Biol Chem. 2004 Oct 29;279(44):45512-8. PMID: 15337740


Verreth W, De Keyzer D, et al. Rosuvastatin (INCREASES mRNA of PPAR-GAMMA AND) restores superoxide dismutase expression and inhibits accumulation of oxidized LDL in the aortic arch of obese dyslipidemic mice. Br J Pharmacol. 2007 Jun;151(3):347-55. PMID: 17384667

Roglans N, Sanguino E, et al. Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats. J Pharmacol Exp Ther. 2002 Jul;302(1):232-9. PMID: 12065722

Sanguino E, Roglans N, et al. Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4. Br J Pharmacol. 2005 Aug;145(7):853-61. PMID: 15912134



In historical texts (ie, the Bible), the liver was actually considered 'the heart.' And, in the ancient days, harm to the liver was actually worse than to the heart. How were they so wise (without high tech ALT/AST tests or abdominal u/s) ??! For warriors, the liver was an easier, bigger target to hit than the smaller heart. We often neglect this fantastic vital organ. Interestingly, when the trinity is disrupted, this organ becomes metabolically deranged even before the heart.


Here are the liver's awesome functions and roles:
  • first pass effect = all blood during digestion is maximized to flow through the liver. Perhaps this is the role after meal apertifs, Greek grappe or (!!YUM)aged port have -- they relax, increase Vagal communications to the GI system to further shunt blood flow to the stomach and intestines for digestion

  • cytochrome P450 -- detox's, purifies everything we eat including plant toxins and exogenous chemicals like drugs (explains why oral estrogen can worsen HDLs whereas topical/transdermal estrogen improves and RAISES HDLs by bypassing the liver route)

  • cytochrome P450 activates and processes everything we eat including all food components and neutraceuticals (vitamin D3, essential fatty acids, protein)

  • energy sensor (carbs, fats, proteins, alcohol, caffeine, etc -- all my favorite food groups)

  • ultimate CONTROLLER in the financial as well as airtraffic sense because the liver contains the highest concentration of PPAR receptors: alpha, gamma, and D-E-L-T-A (aka beta)

  • producer of lipoproteins which are the energy 'traffickers' for the immune system, skeletal muscles and even brain (which relies on ketones/fatty acids when blood glucose (BG) is naturally lower)

  • producer of TGs -- the lipoprotein fraction where carbohydrate-energy (dietary carb +/- fat) is bundled into for transport to the rest of the body (including clogging up the heart tissues and arteries). Recall that TGs is the second RISK FACTOR most highly associated with plaque. First is... fasting insulin levels.




















  • regulates and synthesizes cholesterol which is the template of EVERY nuclear steroid (and some aromatases, desaturases, and cyt P450 are under the control of VitaminD3) -- steroids like testosterone, estrogen, cortisol -- and composes the structural backbone/shell of every cell in our body and in particular the brain/nervous system which is comprised nearly entirely of cholesterol and fats (should pregnant moms eat 'low fat'? do pregnant moms want brain-deficient, cognitively-challenged children?)

  • vitally crucial for producing mannose-binding lectin (MBL) which is an activator of our host defenses in the innate broad-spectrum non-specific immune system (which fights virus, bacteria, and other foreign invaders including FRUCTOSE attached to our own cells) ; 'fruct-osylated-cells' aint good... sounds pretty bad eh? indeed VERY BAD

  • first organ to become unhappy when carbohydrates are excessive ('fatty liver', NAFLD, NASH, etc); see diagram above

  • one of the most prized organ meats and delicacy (in indigenous cultures and our household with a little soy sauce and honey) highly valued for its nutritional content of metabolically-active and heart protective Vitamins K2, D3, A, E and other essential nutrients and minerals.





In a recent Circulation article, researchers are elucidating the important role of Von Willebrand factor (VWF) in acute coronary syndromes (ACS).

"von Willebrand factor (VWF) plays a pivotal role in platelet adhesion and aggregation at sites of high shear rates (eg, in coronary arteries that have stenotic or ruptured atherosclerotic plaque lesions). Numerous studies have investigated the relationship between VWF plasma levels and thromboembolic cardiovascular events. In contrast to the rather weak association in the general population, in patients with preexisting vascular disease, VWF is significantly predictive for adverse cardiac events, including death. Likewise, VWF typically rises during the course of acute coronary syndrome, and the extent of this VWF release is an independent predictor of adverse clinical outcome in these patients. Various lines of evidence indicate that VWF is not only a marker but also actually an important effector in the pathogenesis of myocardial infarction. This central role of VWF in thrombogenesis has made it a promising target for research into new antiplatelet therapies that specifically inhibit VWF (AND BLAH BLAH BLAH... DRUGS)..."


How is VWF related to the thrombosis and clotting effects in our blood vessels? Obviously there is a healthy balance. Those with VWF deficiency have bleeding gums, mucus membranes and bleeding under the skin.

Is the liver involved? It appears the liver is involved in everything!

Platelets require the intervention of a blood protein known as Von Willebrand factor (vWF), which facilitates platelet adhesion to the sub-endothelial matrix of damaged, exposed endothelium. When the liver is aged, i.e. metabolically/oxidatively affected, a corresponding increase in vWF occurs intrahepatically (see below). Can this also occur systemically? To the coronary arteries? Or carotids? If we keep the endothelium of one of our most vital organs, the liver, happy... clear and uncongested, then endothelium elsewhere is likely to be protected as well. Prevent hardening of the liver, and you'll prevent hardening of the arteries. Reverse liver damage, and you'll reverse artery damage.

Timing as usual makes a difference. Even young-obese children are displaying NASH/NAFLD and early changes in myocardial structure such as diastolic dysfunction/heart failure.

The below changes including the increase in vWF from the endothelium in the liver blood circulation sounds a lot like instigation of arteriosclerosis of the liver...


Love your liver... and both hearts will appreciate it...

Ways to maximize liver function and productivity:
** Movement, play, movement, work, intervals of intensity, play, grow your muscles... especially with our children. 'The family that plays together, stays together...and doesn't have heart attacks together,' quoted by a member at my CF gym
** Complete Wheat/Grain avoidance and minimal fruit
** Adequate vitamin D3 (achieve: 25(OH)D 60-70 ng/ml)


Old age and the hepatic sinusoid.

Anat Rec (Hoboken). 2008 Jun;291(6):672-83. Le Couteur DG, et al.

Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial cell, sporadic deposition of collagen and basal lamina in the extracellular space of Disse, and increased numbers of fat engorged, nonactivated stellate cells. In addition, there is endothelial up-regulation of von Willebrand factor and ICAM-1 with reduced expression of caveolin-1. These changes have been termed age-related pseudocapillarization (SOUNDS TO ME LIKE CALCIFICATIONS AND ARTERIOSCLEROSIS). The effects of old age on Kupffer cells are inconsistent, but impaired responsiveness is likely. There are functional implications of these aging changes in the hepatic sinusoid. There is reduced sinusoidal perfusion, which will impair the hepatic clearance of highly extracted substrates. Blood clearance of a variety of waste macromolecules takes place in liver sinusoidal endothelial cells (LSECs). Previous studies indicated either that aging had no effect, or reduced the endocytic capacity of LSECs. However, a recent study in mice showed reduced endocytosis in pericentral regions of the liver lobules. Reduced endocytosis may increase systemic exposure to potential harmful waste macromolecules such as advanced glycation end products. Loss of fenestrations leads to impaired transfer of lipoproteins from blood to hepatocytes. This provides a mechanism for impaired chylomicron remnant clearance and postprandial hyperlipidemia associated with old age. Given the extensive range of substrates metabolized by the liver, age-related (I.E. METABOLIC DEREGULATION) changes in the hepatic sinusoid and microcirculation have important systemic implications for aging and age-related diseases.
PMID: 18484614