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Heart Disease II – Beyond LDL

by Alex Boersma

In Part I of this series we dispelled some of the mythology promoted by conventional wisdom on heart disease.  We learned that  dietary cholesterol and saturated fat are, at best, only weakly associated with cardiovascular events.  We learned that this weak association is decidedly distinct from any causality.  We learned that LDL and total cholesterol levels are not particularly effective in predicting heart attacks.  And we learned that statins are not the medical panacea the pharmaceutical companies would have us think they are.

In this installment we will go beyond the short sighted diet-heart hypothesis and examine a number of variables and blood markers which actually do correlate significantly with heart disease.  Although there is still much work to be done, science has come a long way in unravelling the complexity of a disease which remains the #1 killer of North Americans – despite the hundreds of billions of dollars spent on attempting to find a cure.  If we can understand a bit of that science, we can take some of the simple steps necessary to make sure we never need a cure.  Because, make no mistake about it, for most people, heart disease is entirely preventable.  And, at least for me, preventing a disease is always a superior option to attempting to cure it and there are groups that support this position and help in anything they can with this, going online at sites like Inspire help people understand this and get help.

 

WHAT WE KNOW NOW

 

Forewarning:  This gets a little bit technical.  I don’t usually use a lot of referances because I understand clearly that writers can cherry pick referances to prove just about any point…I see it all the time.  Usually, when I use them, it is to support an idea which is contrary to conventional wisdom…sort of an “I’m not just making this stuff up” statement.  This article, unfortunately, is mostly about stuff that is contrary to conventional wisdom.  I do acknowledge that there is opposing evidence out there…inferior evidence, in my opinion, but still evidence.  Let’s be clear.  The search for truth requires slogging through mountains of contradictory evidence…I’ve done it and the words you see on these pages are my conclusions.  I fully believe that if some of the people who dispense conventional widsom (doctors and dieticians) went through the same process, they might start preventing disease instead of just trying to treat it all the time.  Having said all that, if the technicalities are not of interest to you, feel free to skip down to the bottom for the partial summary.  The summary is all you need to prepare for part III, which will be the part that teaches you, quite simply, how to prevent and even reverse heart disease.

The pre-occupation with blood cholesterol and dietary saturated fat stems from old science.  When researchers were only capable of measuring total cholesterol, they theorized that dietary and blood cholesterol were responsible for heart disease.  When this theory was proven to be untenable, they discovered LDL and the fact that dietary saturated fat increased its level in the blood.  So they theorized that blood LDL and saturated fat were responsible for heart disease.  This theory has also proven to be untenable, and many scientists have moved on again.  Unfortunately, mainstream medicine (with the support of pharmaceutical companies for whom the LDL theory has turned out to be enormously profitable – to the tune of tens of billions of dollars a year) remains mired in the 30 year old science.

 

SMALL DENSE LDL AND OXIDIZED LDL

So what do we know now that we didn’t know 30 years ago?  We know that there are many different sizes of LDL.  We know that the smaller and denser the LDL, the more likely it is to cause heart disease.  In fact, we know that people with a preponderance of small dense LDL are at least 3 times as likely to have heart disease as those with a preponderance of large and fluffy LDL.   We know that the small dense LDL is much more likely to penetrate the epithelial cells lining the inside of your arteries and begin the process of atherosclerosis.  http://www.johnshopkinshealthalerts.com/reports/heart_health/1886-1.html

 We know that LDL needs to be oxidized to begin the process of atherosclerosis.  http://www.ncbi.nlm.nih.gov/pubmed/12029985

We know that small dense LDL is much more likely to become oxidized than larger, fluffier LDL and that this variation is due mostly to differences in levels of anti-oxidants, particularly CoQ10 and vitamin E.   http://www.ncbi.nlm.nih.gov/pmc/articles/instance/521478/.  

We know that small dense LDL is intimately associated with high triglyceride levels and low HDL levels. http://www.ncbi.nlm.nih.gov/pubmed/10208494

We know that small dense LDL is highly prone to interacting with glucose (glycation), which makes it even more likely to become oxidized.  http://www.lipidsonline.org/news/article.cfm?aid=6319 

From a testing perspective, we now know that there are much better ways of predicting heart disease than merely by measuring LDL.  Non invasive measures of determining the prevalence and/or progression of plaque (CT scans and electron beam tomography) in coronary arteries have put the lie to mainstream LDL testing.  http://www.medical-hypotheses.com/article/S0306-9877(09)00398-3/abstract

Arthur Hecht recently did a study http://www.newportbodyscan.com/Downloads/translating_plaque_to_lipid_intervention.pdf  in which he found that the correlation between plaque in people’s arteries and LDL was 0.0006.  That’s a lot of zeros.  In contrast, the correlation between arterial plaque and small dense LDL  was 0.14 while for HDL it was 0.11.  Similarly, Johnston et al found that after subjecting 1653 men and women without history of coronary heart disease to CT angiography:

“26% of the patients on statins had no detectable plaque. CONCLUSION: Coronary risk stratification using a risk factor only-based scheme (i.e. the way almost all doctors do it – my italics) is a weak discriminator of the overall atherosclerotic plaque burden in individualal patients. Patients with little or no plaque might be subjected to lifelong drug therapy, whereas many others with substantialal plaque might be under-treated or not treated at all”  http://www.ncbi.nlm.nih.gov/pubmed/19098205

Heart scan:  the arrow points to a seriously calcified coronary artery.  Good to know, but your regular blood test may not tell you about it!

For those of us without ready access to CT scans or electron beam tomography, there is still much to be learned from old fashioned blood testing.  One of the most useful things we can find out from blood work is the total LDL particle number   http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/87930.  NMR (Nuclear Magnetic Resonance) and VAP (Vertical Auto Profile) testing are two commonly used tests for detemining particle size and number

As you can see from the picture below, blood with the same cholesterol content can differ significantly in the number of LDL particles present.  When the particles are smaller there are clearly more particles even though the total cholesterol content remains the same.  So the fact that there is a high number of LDL particles lets us know that the LDL is small, dense and, consequently, atherogenic.  Alternatively, if the same amount of total cholesterol has significantly fewer LDL particles, we know that these particles are large, buoyant and, in this case, non-atherogenic.  In other words, knowing the particle number can help us to know whether any given LDL measurement is truly indicative of heart disease or relatively benign.  NMR (Nuclear Magnetic Resonance) and VAP (Vertical Auto Profile) testing are two commonly used tests for detemining particle size and number.

There is still much debate in the medical community about the usefulness of particle number as a diagnostic tool.  Although many professionals mistakenly believe that such debate negates the validity of particle number testing, nothing could be further from the truth.  The origin of the debate lies not in the validity of the testing, but in the possible superfluous nature of the results.  In most cases, the predominance of small dense particals  can readily be estimated from the results of standard lipid blood testing.  As mentioned above, high triglycerides and low HDL are indicative of small dense LDL predominance…this is clearly shown in the graphic below.   The debate is really over whether expensive particle number testing is really necessary when HDL and triglycerides already tell most of the story.

Well, maybe it wouldn’t be if the medical establishment discontinued its preoccupation with LDL and began to focus on HDL and triglycerides instead!

 

AND WHAT ABOUT INFLAMMATION

 

The newest kid on the block for cardiovascular risk factors is something called C-Reactive Protein (CRP).  In the Time article pictured above, the authors discuss CRP as a measure of chronic inflammation which can be used to more effectively assess a person’s risk of having a heart attack.  They focus particularly on the fact that chronic inflammation seems to make a difference in whether an individual’s atherosclerotic plaques remain stable or burst and create a blood clot which eventually blocks an artery and causes a heart attack or stroke.  It seems that high levels of CRP are associated with a threefold increase in the likelihood of athersclerotic rupture.  Chronic inflammation, then, could be the reason why some people with advanced atherosclerosis have heart attacks while others never do.

What the Time article overlooks, however, is the fact that chronic inflammation probably plays an important role in the formation of atherosclerotic plaques in the first place.  An article in the journal Circulation http://circ.ahajournals.org/cgi/content/full/105/9/1135 clearly outlines the encompassing role of inflammation in all stages of atherosclerosis.  A quick pub-med search reveals dozens of papers in support of this theory.  Interestingly enough, many of these same papers suggest that new research on inflammation should over-ride the existing bias of cholesterol as the cause for heart disease. 

Why isn’t this message getting out to the public?

The diagram above represents current views on the progression of atherosclerosis.  Immune cells such as leukocytes are always travelling around in your blood.  Normally, they aren’t supposed to stick to the walls of your arteries.  But when the walls of your arteries become inflamed, they send out  messenger cells which cause adhesion and subsequent migration of the immune cells into the arterial wall.  The immune cells quickly gobble up any oxidized LDL (which is also attracted to the inflamed arterial wall) and change into foam cells, which then initiate the formation of an atherosclerotic plaque. 

It is not yet clear whether the oxidized LDL in the arterial wall is creating the inflammatory state or whether it is the inflammatory conditions which allow the oxidized LDL into the arterial wall.  Certainly, there is a case to be made for the latter theory, since inflammation generally increases the size of the gaps between endothelial cells.  So if your arterial wall is inflamed, it is easier for LDL to infiltrate it, particularly if it happens to be small dense LDL  Regardless, there are a multitude of factors other than oxidized LDL which can initiate arterial inflammation, including various oxidized lipoproteins, decreased levels of HDL (HDL, besides carrying cholesterol back to the liver, also is a potent anti-inflammatory), elevated angiotensin II levels associated with high blood pressure, toxic chemicals from pollution or cigarette smoking, advance glycation end products (AGE…which we will discuss further below), obesity related cytokines, and a plethora of infectious agents.

Clearly, if there is a role for LDL in the development of arterial inflammation, it is only a small role amongst a variety of other factors.  And, pay attention here, even that small role is being played, not by LDL in general, but by oxidized and small dense LDL. 

So why are all the standard blood tests still focused on LDL?

 

ADVANCED GLYCATION END PRODUCTS

Ever wonder why diabetics are disproportionally susceptible to heart disease?  It’s because of their AGE.  Not age as in the number of years they have been alive.  But AGE as in the number of years they have been accumulating Advanced Glycation End Products! 

Most people have heard of LDL and HDL.  Many have probably also come across the idea that inflammation is related to heart disease.  Some may even have heard of things like oxidized LDL or LDL particle size.  But Advanced Glycation End Products?  What the heck is that?

AGE are the unfortunate byproduct of a dangerous affinity various sugars have for binding with protein or fat molecules.  When they do, they form complex molecules which are unstable and highly reactive….these molecules are called Advanced Glycation End Products.  When AGE attach to LDL particles, they block the uptake of LDL by its cellular receptors. http://www.jbc.org/content/270/18/10828.full  Consequently, the LDL spends more time in the circulation and becomes prone to oxidation.  And, as it turns out, one of the things which oxidizes LDL is, you guessed it, AGE http://www.ncbi.nlm.nih.gov/pubmed/8341651

When AGE make contact with your arterial walls, guess what happens?  http://cardiovascres.oxfordjournals.org/content/63/4/582.full   The spaces between your endothelial cells get bigger, allowing more of those nasty small dense and oxidized LDL particles in.  Immune cells are then attracted to the endothelium to initiate plaque formation.  Can you spell inflammation!

When glucose attaches itself to the protein in your blood, you get something called glycosylated haemoglobin.  This can be measured in a blood test called a HbA1C test.  HbA1C  is an excellent marker for the amount of glycation happening in your system.  It also accurately reflects your average blood sugar over the past 3 months.  Either way, it is a number you want to keep low.

 

PARTIAL SUMMARY

So far so good.  Now we know a little more about scientific advancements in the study of heart disease.  Now we are ready to examine the dietary and lifestyle implications of all this new information.  But before we do, let’s summarize:

  •  Total cholesterol and LDL, while perhaps of some interest, are clearly not effective tools for determining risk of heart disease.  Lowering LDL should certainly not be a primary target for risk reduction in heart disease.
  • HDL and triglycerides are a better measure of cardiovascular risk.  This is particularly true because high HDL and low triglycerides seem to reflect a lower percentage of small dense LDL.  We should try to keep HDL high and triglycerides low.
  • Small dense LDL and oxidized LDL are bad characters.  It would be nice to be able to track them with more advanced blood tests.  Regardless, we should try to implement lifestyle changes which will minimize their expression.
  • Inflammation plays a significant role both in the development of atherosclerosis and in the extent to which it becomes deadly.  Knowing what your C-reactive protein levels are would be useful.  Any effective program geared towards reducing cardiovascular disease should include steps to reduce inflammation.
  • Advanced glycation end products are also bad characters.  They are critically involved both in the development of oxidized LDL and the progression of inflammation.  It would be good to know your HbA1c levels.  Keeping HbA1c levels down should be one of the targets of cardiovascular risk reduction. 

In part III of this series we will go on to look at each of these factors and find out how they can be manipulated by diet and exercise.

 

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