Saturday, February 9, 2013

Cholesterol and the Structure of Scientific Revolutions

Historiography notwithstanding, there are two distinct, mutually exclusive, irreconcilable, jointly exhaustive paradigms of cholesterol.[1]  These two paradigms can be stated simply as (1) the malevolent cholesterol paradigm and (2) the benevolent cholesterol paradigm.

The malevolent cholesterol paradigm, also known as the lipid hypothesis, declares that there is a positive correlation between blood plasma cholesterol levels and the development of atherosclerosis.  As cholesterol levels go up, the Malevolents say, so too does risk.

The opposite view is articulated in the benevolent cholesterol paradigm.  Benevolents hold that as cholesterol levels go down, risk goes up.

Both paradigms cannot be true; hence, scientists and community are in crisis.

In the remarkable book The Structure of Scientific Revolutions (1962, 1970, 1996, 2012), Thomas S. Kuhn describes paradigms and scientific revolutions.  According to Dr. Kuhn:

Aristotle’s Physica, Ptolemy’s Almagest, Newton’s Principia and Opticks, Franklin’s Electricity, Lavoisier’s Chemistry, and Lyell’s Geology—these and many other works served for a time implicitly to define the legitimate problems and methods of a research field for succeeding generations of practitioners.  They were able to do so because they shared two essential characteristics.  Their achievement was sufficiently unprecedented to attract an enduring group of adherents away from competing modes of scientific activity.  Simultaneously, it was sufficiently open-ended to leave all sorts of problems for the redefined group of practitioners to resolve.[2]

Summarizing, paradigms are unprecedented achievements attracting an enduring group of adherents and they leave subsequent problems open to solve.

The malevolent cholesterol paradigm certainly fits this template.  Some adherents of this model promulgate misinformation, even as the more technically savvy do not intervene.  The two major false edifices: there is “good” and “bad” cholesterol, the latter of which sticks to the interior of arteries causing atherosclerosis.

First, Benevolents argue, cholesterol is a waxy steroid of fat and there is only one type.  No knowledgeable, responsible, sane, unbiased chemist would disagree with that.  But it’s the protein carriers of cholesterol that are the target of the misnomers.  The many carriers are ranked by density—the ratio of protein to lipid—and include many subclasses such as very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), intermediate density lipoprotein (IDL), high-density lipoprotein (HDL), and chylomicron.  Each, as stated, carries cholesterol and fat.  Since low-density lipoprotein carries cholesterol from the liver to body cells it was misnamed “bad cholesterol” by Malevolents.  High-density lipoprotein carries cholesterol from the body back to the liver for recycling or refuse and was misnamed “good cholesterol.”[3]

Although lipoproteins accomplish this task via the blood, cholesterol itself, for the most part, does not come in contact with the blood.  Indeed, it is housed in the lipoprotein particle, with only a negligible amount on the phospholipid outer layer of the lipoprotein.

Which leads to the other false perception.  Atherosclerosis, Benevolents say, is not developed from plaque made up of particles of fat and cholesterol that stick to the artery walls like sewage inside a pipe.  Rather, a plaque is comprised of arterial muscle tissue, blood platelets, calcium, collagen, foam cells, LDL aggregates, oxidized LDL, white blood cells, et al., that get trapped within the first layer of the arterial wall, called the intima, and the second layer, the media.

Misconceptions aside for the moment, once a paradigm is established, normal science proceeds within that framework.

Normal science is research firmly based upon one or more past scientific achievements, achievements that some particular scientific community acknowledges for a time as supplying the foundation for its further practice.[4]

No part of the aim of normal science is to call forth new sorts of phenomena; indeed those that will not fit the box are often not seen at all.  Nor do scientists normally aim to invent new theories, and they are often intolerant of those invented by others.  Instead, normal scientific research is directed to the articulation of those phenomena and theories that the paradigm already supplies.[5]

Normal science, as stated by Kuhn, aims to refine, extend, and articulate a paradigm that is already in existence.   Normal science may lead to the recognition of anomalies and to crises, but not to new paradigms.  In fact, how little normal science aims to produce major novelties, conceptual or phenomenal, is the most striking feature of normal science according to Dr. Kuhn.[6]

It is thus now understandable that Malevolents, beginning with Keys, try to explain away inconsistencies in the paradigm as paradoxes.  If you aren’t familiar with the story, Dr. Ancel Benjamin Keys (1904-2004) proposed that high-fat diets—especially saturated fat—would increase blood cholesterol and lead to atherosclerosis.  Dr. Uffe Ravnskov, a notable Benevolent, tells the story best:

The definition of the “prudent” diet has changed considerably with time.  Initially, it was considered important to reduce dietary fat of all kinds.  This advice was based on a review paper by Ancel Keys, the main designer of the so-called diet-heart idea.  In his review, Keys presented a perfect curvilinear correlation between the mortality from coronary heart disease and the consumption of fat in six countries, but his curve was based on a selection of countries that fit his hypothesis and it has not been confirmed in studies including many more countries.

The prudent diet was redefined a few years later based on a new study by Ancel Keys, ”Seven Countries.”  According to that study the total fat intake was unimportant; heart mortality in these seven countries was best predicted by the intake of saturated fat.  But within each country no association was seen.  In Finland and Greece for instance, heart mortality in two districts varied with a factor five and seven, respectively, despite similar diets and other risk factors. Furthermore, no correlation was found between the diet and the major electrocardiographic findings.  Considering that all electrocardiograms were analyzed in the American study center this finding should carry more weight than the correlation with the clinical diagnosis, settled as it was by local doctors with varying competence and diagnostic habits.

The seven countries were admittedly selected by Keys.  Such selection may be helpful to illustrate an idea at a preliminary stage, but a proof of causality demands random data.  In more recent studies, including many more countries, the association was weak, absent, or inverse.[7]

Keys omitted countries with a low percentage of fat in their diet and a high incidence of death from CHD as well as those with a high-fat diet and low incidence of CHD.  Thus, even today, instead of seriously trying to explain why countries like France that eat a relatively high-fat diet and have a relatively low incidence of CHD, Malevolents merely label it the French Paradox.[8]

Such naming convention, however, simply follows the path of normal science as, remember, no part of the aim of normal science is to call forth new sorts of phenomena.  Indeed, according to Kuhn, those that will not fit the box are often not seen at all.  Kuhn would agree with you that that doesn’t appear to be scientific; in fact, he considered blindness to data that doesn’t fit prevailing theory, and other attributes of normal science, to be defects.[9]

It shouldn’t come as much surprise then when you learn that in addition to the French paradox, the Benevolents point out, there is an African Masai and Rendille paradox, Albanian paradox, Arctic Inuit paradox, Hispanic paradox, Israeli paradox, Italian paradox, Mexican paradox, New Zealand Tokelau paradox, Spanish paradox, Swiss paradox, and many, many more.

The strongest argument that Malevolents put forth is the fact that, by lowering the body’s production of cholesterol, patients already presenting with cardiovascular disease are less likely to suffer a secondary event.  No knowledgeable, responsible, sane, unbiased researcher will deny that.  Benevolents, however, note that said benefit is small, that Malevolents exaggerate it, and that it is offset by non-heart-disease related deaths.

From the first cholesterol lowering trial up to present day studies, Malevolents have quantified benefit utilizing relative risk, versus the absolute risk calculation employed by Benevolents.  Malevolents quantified the benefit in the first cholesterol-lowering trial—the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT),[10] a multi-center, randomized, double-blind study in 3,806 middle-aged men with hypercholesterolemia, performed in 1984—as a 19% reduction in risk compared to the control group, despite the absolute risk according to Benevolents being 1.6%.  That’s the difference between 7% for those that received the drug cholestyramine and passed away of CHD during the seven year study, and 8.6% for those who received the placebo.  Benevolents Sally Fallon and Mary Enig, for example, pointed out—no small observation—that in the LRC-CPPT, non-heart disease deaths, such as deaths from cancer, stroke, violence and suicide increased in the drug-treated group.[11]

Before continuing, perhaps the use of a metaphor would be helpful.  Let’s map our cholesterol paradigms onto, say, the continuing Korean divide.  Under the malevolent Korean paradigm, at least from a pro-democracy viewpoint, there is a good Korea—the Republic of Korea, better known as South Korea—and a bad Korea, the Democratic People’s Republic of Korea, aka North Korea.  The Malevolents would have us believe that today, in the era of nuclear threat, there can be little doubt about the value of decreasing the level of North Koreans.  In fact, “the lower the better” would be the position of many.  Purge the entire Korean Peninsula of Northerners and allow annexation by the South.

Benevolents would argue that you have to understand the problem more fully in order to solve it.  Disregarding the fact that we’re all from one species—the origin of most human conflict—Koreans from any geography cannot understand how one people—the Korean people—can have two different trajectories, two different destinies.  Of the many influences that have resulted in this unfortunate reality, one proximate reason for the split is notable; the decision to geographically separate one people into two on opposite sides of the 38th Parallel was not made by anyone from Korea.  No, leaders from the Soviet Union, United Kingdom and United States made that pragmatic decision at the Potsdam Conference in 1945.

The benevolent Korean paradigm would hold that Koreans in general, like most people, are good, honest, caring, hard-working, contributing members of society.  Benevolents would point out that there are many negative influencers radicalizing—oxidizing—the North Koreans.  Such influencers would include past and present Japanese, Chinese and Russian ideologies and adherents, poverty compounded by lack of opportunity, and, most importantly, an oppressive, parasitic, implacable, nepotistic, dictatorial regime.  Benevolents would hypothesize that since North Koreans are not hostile per se, something must be influencing them to act antagonistically toward South Korean interests, and that the solution lies in strengthening South Korea and/or repressing, suppressing, inhibiting or removing negative influencers.

Geopolitical expansionism aside, recall now that a plaque is not comprised solely of cholesterol.  Far from it.  Instead, plaque consists of arterial muscle tissue, blood platelets, calcium, collagen, foam cells, LDL aggregates, oxidized LDL, white blood cells, and others, that get trapped within the intima and media.  Foam cells, LDL aggregates and oxidized cholesterol constitute the lion’s share of a plaque.[12]

If you have bought into the malevolent cholesterol paradigm, how LDL cholesterol gets into the intima, media or how it becomes oxidized matters very little.  It’s bad, it’s oxidized, it expands the plaque, and we need to control it; more, reduce it.  The lower the better.  It might even be ideal if reduced at the source.  You could then recruit better and brighter scientists to find novel ways to lower cholesterol and its malevolent carriers further, even at the expense of a patient’s memory, personality and other-cause mortality.[13]

If however, one starts from the assumption that cholesterol is beneficial—that it forms and maintains cell walls and structures, insulates nerve cells, helps synthesize critical hormones, bile, vitamin D and more[14]—and that all the carriers serve a critical function—that they likely comprise a secondary, non-specific immune system in addition to shuttling much needed cholesterol to and fro—then it must be that some thing or things are perniciously acting on cholesterol, its carriers and others.

Uffe Ravnskov and Kilmer S. McCully, another notable Benevolent, in their prescient article “Vulnerable Plaque Formation,” discuss such an opportunity:

An unsettled question concerns the nature of the process that converts macrophages into lipid-laden foam cells, one of the main factors in production of atherosclerotic lesions.[15]

The point is moot to Malevolents because of the circular reasoning that they adhere to the malevolent cholesterol paradigm.  All that matters is driving down cholesterol.  But if you’re Benevolent, you’re interested in the whys, the hows, the what ifs.  You think of yourself as a scientist or science enthusiast, and realize that the current model does not represent the observations in a satisfying way.  You’re open to the idea that there may be something new to be learned that may result in medical application, but that it can’t be grasped by looking at the problem under the same old lens.  And that is a central idea in the paradigm debate:

But paradigm debates are not really about relative problem-solving ability, though for good reasons they are usually couched in those terms.  Instead, the issue is which paradigm should in the future guide research on problems many of which neither competitor can yet claim to resolve completely.  A decision between alternate ways of practicing science is called for, and in the circumstances of that decision must be based less on past achievement than future promise.[16]

There’s much precedence that a host’s macrophage can be subverted by other entities.  Macrophages, the very immune system cell differentiated from monocytes to find, eat and thereby destroy—to phagocytize and lyse—inimical microbes, are known to be exploited by many creatures to access and colonize Animalia.  Phagocytosis is a highly localized event requiring the formation of spatially and temporally restricted signals.  Some of the numerous microorganisms that have taken advantage of this property within human hosts include Legionella pneumophila, the pathogenic bacterium that causes Legionnaires’ disease; Coxiella burnetii, one of the most infectious organisms known, causative agent of Q fever; Trypanosoma cruzi, the parasite that causes Chagas disease; Toxoplasma gondii, an obligate intracellular parasite lethal to fetuses; the many Leishmania species, responsible for the misery and death of millions of humans per year; and pathogenic strains in the genus Mycobacterium which include Mycobacterium tuberculosis, responsible for causing tuberculosis, and Mycobacterium leprae, the cause of leprosy.  Macrophage colonization is also an important causal factor in rheumatoid arthritis, fibromyalgia and Sarcoidosis inflammation.  HIV infection is an independent risk factor for atherosclerosis; there are direct effects of HIV and viral proteins on macrophage cholesterol metabolism.[17]

And there are many inorganic constituents that influence plaque buildup such as reactive oxygen species,[18] advanced glycation end products (AGEs),[19] the receptor for advanced glycation end products (RAGEs),[20] and homocysteine.

Kilmer S. McCully, MD, is recognized as the first person to discover and propose the homocysteine theory of heart disease in 1969.  His book, The Heart Revolution: The Extraordinary Discovery That Finally Laid the Cholesterol Myth to Rest, presents an accessible description of that problem and its solution.  According to Dr. McCully:

When there is too much homocysteine in the blood, arteries are damaged and plaques form.  The result is arteriosclerosis and heart disease.  This happens when we don’t get enough of certain vitamins—namely B6, B12, and folic acid.  These B vitamins are missing in our diets because processing and refining foods destroys these sensitive vitamins.[21]

If you adhere to the Malevolent view, you believe that by eating less cholesterol, a high-complex-carbohydrate, medium protein, low-fat diet, you will likely prevent fat or cholesterol from entering your arteries and developing atherosclerosis.

But the Benevolents teach that, while well-adapted individuals may flourish, a diet high in carbohydrates and low in saturated fat and cholesterol may have adverse consequences for the rest of us.  Instead, they proffer a high-fat, medium protein, low-carbohydrate diet.[22][23]  Benevolents have come to realize that eating fat and cholesterol doesn’t contribute to fat gain, raised cholesterol in the blood, or atherosclerosis.[24]

There was a time that H. sapiens didn't know about microbes, “animalcules” as first described by Antonie Philips van Leeuwenhoek (1632-1723).  Today, the average person knows about germs—inimical animalcules—and that, for instance, washing your hands before performing surgery—the Semmelweis protocol—reduces a patient’s risk of infection.  Less people are aware that it took more than a generation for the scientific community to implement that procedure, and it was not fully embraced until long after Ignaz Philipp Semmelweis (1818-1865) had died at the hands of guards in a Viennese insane asylum.

At one time, everyone knew that the bad evening air caused malaria.  It is now common knowledge that mosquitoes and not bad air are malarial vectors, but less people know that there are many different species of the single-celled Plasmodium that use insects, birds, reptiles and mammals as reproductive vesicles and are the actual cause of the disease.  Even less know that of the forty-one genera of 3,500+ mosquito species, only one genus containing a small handful of species serve as vectors of Plasmodium.  Not to mention that only the females inoculate animals with the parasite as only female mosquitos take a blood meal in order to gain nutrients required for oviposition.

Bleeding a patient to health, whether via blood-letting or leeches, e.g., Hirudo medicinalis, had been a common practice for more than two millennia prior to the nineteenth century.  Although the procedure was thought to reduce an overage of one of the four humors—black bile, blood, phlegm, yellow bile—adherents were actually on to something.  Today, leeches are used in micro- and reconstructive surgery and phlebotomies are used to treat metabolic syndrome.[25]

Many people are confident that ulcers are caused by stress, however, very few realize that a bacteria, Helicobacter pylori, is the real culprit in most cases.[26]

Paradigms often shift instantly after years of confident work in the opposite direction.  Analyzing new data or taking a fresh look at the old, and the more simplistic, dualistic, provincial, adolescent views of the world give way to complex, in-depth, global understandings.

I am not a doctor; but, in the optimistic words of Bob Dylan, “You don’t need a weatherman to know which way the wind blows.”  What we have in common is passionate curiosity.  The internet, that last bastion of free speech—at least for now—together with those housed collections of books and articles neatly interspersed with desks and chairs known as libraries, can help satiate that curiosity.  You could also ask your physician questions, about the layers of an artery, where plaques are formed, which species don’t manufacture cholesterol, what substances make up cell membranes, serve as precursors to hormones, bile, vitamin D; about reactive oxygen species, AGEs, RAGEs, homocysteine, foam cells, etc.  If you’re not satisfied with the answers, perform your own independent research.

Moreover, if you’re that once idealistic graduate student who somehow managed to get through medical school only to land in a practice ruled by what seem like irrational clinical practice guidelines and insurance requirements written to best serve insurance providers, realize that guidelines are not laws.  Rewriting guidelines after replacing biased guideline writers may eventually happen.  Until then, know that you may join a growing number of brave physicians whose examination rooms are impervious to infectious bias, false perceptions, political pressure, and pharmaceutical marketing plans.

Perhaps we will find, like the many giants from whose shoulders stood I to write this apprisal, this appeal, that we can learn a lot from Malevolents:

Einstein is somewhere quoted as having said: “The Ununderstandable about nature is that it is understandable.”  I think he should have said: “that it is explainable.”  These are two very different things, for we understand very little about nature.  Even the most exact of our exact sciences float above axiomatic abysses that cannot be explored.  It is true, when one’s reason runs a fever, one believes, as in a dream, that this understanding can be grasped; but when one wakes up and the fever is gone, all one is left with are litanies of shallowness.[27]

[1] For a good review, albeit biased by the malevolent cholesterol paradigm, see “Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part I,” Daniel Steinberg, J. Lipid Res. 2004 45:(9) 1583-1593.  First Published on April 21, 2004, doi:10.1194/jlr.R400003-JLR200.  AbstractFull TextFull Text (PDF).

[2] Kuhn, Thomas S.  The Structure of Scientific Revolutions.  The University of Chicago Press, Chicago, IL, 2012, p. 10-11.

[3] For a particularly good, in-depth, historiographical discussion of VLDLs, HDLs, IDLs, and LDLs, see Taubes, Gary.  Good Calories, Bad Calories.  New York: Anchor Books, 2008, pp. 153-177.

[4] Kuhn, Thomas S.  The Structure of Scientific Revolutions.  The University of Chicago Press, Chicago, IL, 2012, p. 10.

[5] Ibid, p. 24.

[6] Ibid, p. 35.

[7] Ravnskov, Uffe.  The Cholesterol Myths: Exposing the Fallacy that Saturated Fat and Cholesterol Cause Heart Disease.  US: Newtrends Publishing, Inc., 2000.  See the excerpt entitled “Atherosclerosis and coronary heart disease have nothing to do with the diet,” available online.  Article.  For a good analysis of Keys’s six and seven country studies, see “The Truth About Ancel Keys: We’ve All Got It Wrong,” by Denise Minger.  Article.

[8] For a good recent video on saturated fat and cholesterol, see “Enjoy Eating Saturated Fats: They’re Good for You,” by Donald W. Miller, Jr., M.D.  Video.  For a pithy video on the lack of correlation between cholesterol and heart disease, see “Cholesterol and Heart Disease,” by Malcolm Kendrick.  Video.

A good, recent book on cholesterol is Kendrick, Malcolm.  The Great Cholesterol Con: The Truth About What Really Causes Heart Disease and How to Avoid It.  London: John Blake Publishing, Ltd., 2008.  See also Ravnskov, Uffe.  Fat and Cholesterol are Good for You!  What Really Causes Heart Disease.  Sweden: GB Publishing, 2009.  See also Groves, Barry.  Trick and Treat: How ‘Healthy Eating’ is Making us Ill.  London: Hammersmith Press Limited, 2008.  A more recent, accessible paperback is Bowden, Jonny, and Sinatra, Stephen.  The Great Cholesterol Myth: Why Lowering Your Cholesterol Won't Prevent Heart Disease.  Beverly, MA: Fair Winds Press, 2012.

For a brilliant and thorough analysis, see Colpo, Anthony.  The Great Cholesterol Con: Why Everything You’ve Been Told About Cholesterol, Diet and Heart Disease is Wrong!  Lulu, 2006.  Anthony Colpo’s book is particularly interesting because it was written by someone whose only credential is having written a brilliant, thorough book.

On the side of the malevolent cholesterol paradigm, see especially Steinberg, Daniel.  The Cholesterol Wars: The Skeptics vs the Preponderance of Evidence.  New York: Academic Press, 2007.  In addition, there are hundreds of books that promulgate lowering cholesterol as the way to decrease risk of heart disease and stroke.

[9] Kuhn, Thomas S.  The Structure of Scientific Revolutions.  The University of Chicago Press, Chicago, IL, 2012, p. 24.  On point of both blindness to data that doesn’t fit prevailing theory and the two competing cholesterol paradigms, see Ravnskov, Uffe.  Ignore the Awkward: How the Cholesterol Myths Are Kept Alive.  South Carolina: Createspace, 2010.

[10] The Lipid Research Clinics Coronary Primary Prevention Trial Results.  I. Reduction in Incidence of Coronary Heart Disease.  JAMA. 1984;251(3):351-364.  doi:10.1001/jama.1984.03340270029025.   Abstract.

[11] They also analyze the Multiple Risk Factor Intervention Trial (MRFIT), sponsored by the National Heart, Lung and Blood Institute.  It compared mortality rates and eating habits of over 12,000 men.  Those with “good” dietary habits (reduced saturated fat, reduced cholesterol and reduced smoking) showed a marginal reduction in total coronary heart disease, but their overall mortality from all causes was higher.  Similar results have emerged in several other studies.  The few trials that indicate a correlation between fat reduction and a decrease in coronary heart disease mortality also document a concurrent increase in deaths from cancer, brain hemorrhage, suicide, and violent death.  See “Multiple Risk Factor Intervention Trial; Risk Factor Changes and Mortality Results.” Journal of the American Medical Association, September 24, 1982, 248:12:1465.  Abstract.  Op cit. Fallon, Sally, and Enig, Mary.  Nourishing Traditions: The Cookbook that Challenges Politically Correct Nutrition and the Diet Dictocrats.  Washingston, DC: NewTrends Publishing, Inc., 2001. 

See also Ravnskov U, Rosch PJ, Sutter MC, Houston MC, Should we lower cholesterol as much as possible? BMJ 2006;332:1330-2.  Article.  

[12] For an accessible visual representation of plaque formation, see Figure 1 in “Progress and Challenges in Translating the Biology of Atherosclerosis,” Nature 473, 317-325 (19 May, 2011), doi:10.1038/nature10146.  Article.  See also “The Vascular Biology of Atherosclerosis and Imaging Targets,” by Peter Libby, Marcelo DiCarli, and Ralph Weissleder, first published April 15, 2010, doi:10.2967/jnumed.109.069633.  J Nucl Med, May, 2010, vol. 51, no. Supplement 1, 335-375.  Article.

[13] Cholesterol-lowering therapy and cell membranes. Stable plaque at the expense of unstable membranes?  Glyn Wainwright, Luca Mascitelli, Mark R. Goldstein, Arch Med Sci 2009; 5, 3: 289-295.  Full Text (PDF).

[14] See for example, “Cholesterol: The Essential Molecule,” by Stephanie Seneff.  Article.  Dr. Seneff’s Homepage.

[15] Uffe Ravnskov and Kilmer S. McCully, “Vulnerable Plaque Formation from Obstruction of Vasa Vasorum by Homocysteinylated and Oxidized Lipoprotein Aggregates Complexed with Microbial Remnants and LDL Autoantibodies,” Ann. Clin. Lab. Sci., Winter 2009; 39: 3 - 16.  Article

[16] Kuhn, Thomas S.  The Structure of Scientific Revolutions.  The University of Chicago Press, Chicago, IL, 2012, p. 156.

[17] See ”The Macrophage: the Intersection Between HIV Infection and Atherosclerosis,” Crowe, SM, Westhorpe, CLV, Mukhamedova, N, Jaworowski, A, Sviridov, D, and Bukrinsky, M.  April, 2010, Journal of Leukocyte Biology, vol. 87, no. 4, 589-598.  doi:10.1189/jlb.0809580.  Article.

[18] For a good brief overview, see “Reactive Oxygen Species (ROS),” on Kimball’s Biology Page.  See also “The Role of Oxidative Stress in Atherosclerosis,” Vogiatzi, G, et al.  Hellenic J Cardiol 2009; 50: 402-409.  Full Text (PDF).

[19] See for example “Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation.”  Glycobiology (July 2005) 15 (7): 16R-28R.  doi:10.1093/glycob/cwi053.  First published online: March 10, 2005.  Article.  See also “Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes,” Basta G.  Cardiovasc Res (2004) 63(4)582-592.  Doi:10.1016/j.cardiores.2004.05.001.  Full Text.

[20] See for example “Receptor for advanced glycation end products and atherosclerosis: From basic mechanisms to clinical implications,” Basta G.  Atherosclerosis 2008 Jan;196(1):9-21  Epub 2007 Sep 10.  Article.

[21] McCully, Kilmer S.  The Heart Revolution: The Extraordinary Discovery That Finally Laid the Cholesterol Myth to Rest.  New York: Perennial, 1999, pages 10-11. 

[22] Exogenous carbohydrates are non-essential.  See “Is Carbohydrate Essential for Human Nutrition?” Eric C. Westman.  Am J Clin Nutr May 2002 col. 75 no. 5 951-953.  Article.  See also Taubes, Gary.  Good Calories, Bad Calories.  New York: Anchor Books, 2008.

[23] Fiber likely reduces absorption of critically needed zinc, copper and magnesium.  See “Zinc, copper and magnesium absorption from a fibre-rich diet,” Knudsen, E, Sandstrom, B., and Solgaard, P.  J Trace Elem Biol. 1996 Jun;10(2):68-76.  Article.  For a good history of the fiber hypothesis revolving around Denis Parsons Burkitt (1911-1993), see Taubes, Gary.  Good Calories, Bad Calories.  New York: Anchor Books, 2008.

[24] No association between cholesterol and degree of atherosclerosis has been found in postmortem studies of unselected individuals.  High cholesterol is not a risk factor for women, patients with renal failure, diabetic patients, or old people.  Seven of 10 cohort studies found that patients with stroke ate less saturated fat than did healthy controls.  The concentration of short chain fatty acids in adipose tissue, the most reliable reflection of saturated fat intake, is similar or lower in patients with coronary heart disease compared with healthy individuals in five case-control studies.  No clinical or angiographic trial has found exposure-response between individual degree of cholesterol lowering and outcome.  Old people with high cholesterol live longer than those with low cholesterol.  See Ravnskov U. High cholesterol may protect against infections and atherosclerosis. Q J Med 2003;96:927-34.  Article.

In cohorts of people with familial hypercholesterolaemia, cholesterol is not associated with the incidence or prevalence of cardiovascular disease, and their average life span is similar to other peoples’.  No randomised, controlled, unifactorial, dietary, cholesterol lowering trial has ever succeeded in lowering coronary or total mortality.  More than 20 cohort studies found that patients with coronary heart disease ate the same amount of saturated fat as did healthy controls.  See Ravnskov U. The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998;51:443-60.  Article.

For all the above, see Hypercholesterolaemia: Should medical science ignore the past?” by Uffe RavnskovBMJ 2008;337:a1681.  Article.

[25] See “Effects of Phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial,” Houschyar, et al., BMC Medicine, 2012 10:54.  Full Text (PDF).

As an interesting aside, in the second millennium, blood-letting was typically recommended by physicians, but was carried out by barbers.  This division of labor led to the distinction between physicians and surgeons.  The red-and-white-striped pole of a barbershop is derived from this practice.  The red represents blood, the white is the tourniquet used, and the pole itself represents the stick squeezed in the patient’s hand to dilate the veins.

[26] Helicobacter pylori was first discovered in the stomachs of patients with gastritis and stomach ulcers in 1982, by Drs. Barry Marshall and Robin Warren.  At the time, the conventional thinking was that no bacterium can live in the highly acidic human stomach.  Marshall and Warren rewrote the textbooks with reference to what causes gastritis and gastric ulcers.  In recognition of their discovery, they were awarded the 2005 Nobel Prize in Physiology or Medicine.

To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture.  He became ill with nausea and vomiting several days later.  An endoscopy ten days after inoculation revealed signs of gastritis and the presence of H. pylori.  These results suggested H. pylori was the causative agent of gastritis.  See The Nobel Prize in Physiology or Medicine 2005.”  3 Feb, 2013.  Article.

[27] Chargaff, Erwin.  Heraclitean Fire: Sketches from a Life Before Nature.  New York: The Rockefeller University Press, 1978, p. 56.