This is a contribution from members of THINCS,
The International Network of Cholesterol Skeptics



                           Your number is up!

 How cholesterol, homocysteine, and infections conspire to cause heart disease and stroke

Kilmer S. McCully M.D.

  When you are examined by your primary care physician or nurse for an annual health evaluation, a part of the routine examination is analysis of samples of blood and urine.  In this way serious life-threatening conditions like cancer, leukemia, diabetes, high blood pressure, hardening of the arteries, or cirrhosis of the liver can sometimes be detected at an early treatable stage of the disease.   One dreaded result from analysis of your blood or urine involves elevated blood cholesterol and the risk of heart attack or stroke, the number one killer in the USA today.  Another result is elevation of the level of the amino acid homocysteine in the blood, which is also associated with increased risk of vascular disease and many other serious medical conditions. 

Your essayist spent 40 years, the major part of his professional career, pursuing the connection between homocysteine, cancer, arteriosclerosis, and diseases of aging.  The purpose of this essay is to discuss the way in which cholesterol, homocysteine, and infections interact in the cells and tissues of the body to promote these serious diseases.   This essay will focus on how these factors conspire to create the vulnerable plaques of atherosclerosis in the lining of the arteries. When vulnerable plaques rupture, the results are hemorrhage into the plaque and thrombosis (blood clot) causing occlusion of the lumen of the artery. This disastrous complication is the direct cause of heart attack, stroke, and amputation, depending upon which artery is affected.



Cholesterol [chole = bile, and stereos = solid, Greek] is a fatlike alcohol occurring in animal fats and oils, especially gallstones, bile, blood, brain, milk, egg yolk, liver, kidney, nerves, atherosclerotic arteries, and adrenal glands.  Cholesterol is a lipid, a substance extractable from tissues by organic solvents like chloroform-methanol.  When the lipid fraction is treated with alkali, triglycerides, phospholipids, sphingolipids and lipoproteins are converted to substances soluble in water.  Because of its chemical composition, however, cholesterol remains with the lipid fraction after alkali treatment, hence it is a non-saponifiable lipid.  Cholesterol is a fatty alcohol that is a normal constituent of all animal cell membranes and is not present in plant tissues.  In the liver, intestine and other tissues cholesterol is synthesized from acetate in the coenzyme A form, through a complex series of reactions involving several terpene intermediates, as demonstrated by Konrad Bloch and other investigators.

In the mid 19th century the important German pathologist Rudolf Virchow described the process by which arteriosclerosis develops in arteries.  His name for the disease was “endoarteritis chronica deformans nodosa.”  He described inflammatory changes in arterial wall, fatty infiltration of intima, mucoid degeneration of arterial wall, fibrosis, calcification, and atheroma with crystal deposition.  He suggested that altered permeability of arterial intima led to increased filtration of plasma and deposition of plasma fats in association with the degenerative changes of arterial wall.  In 1914 Ludwig Aschoff described deposition of cholesterol crystals in aortic atheromas.

Wladimir Sergius Ignatowsky, an obscure medical investigator in St. Petersburg, became interested in the idea that arteriosclerosis in populations in England was related to consumption of meat, eggs and dairy products by the wealthier classes.  In 1908 he reported the results of feeding these foods to rabbits, a vegetarian species.  He discovered plaques in the arteries of rabbits resembling the plaques found in human arteries with atherosclerosis, including deposition of lipids and cholesterol crystals.  Because of the large amounts of animal protein in the experimental diet, he suggested that the plaques were caused by protein intoxication.  In 1914 another investigator in St. Petersburg, Nicolai Anitschkow, decided to feed purified cholesterol dissolved in plant oils to rabbits, and he discovered deposition of cholesterol in many organs including the arteries of these animals.  He suggested that the plaques in Ignatowsky’s rabbits were caused by the cholesterol of the animal foods in the experimental diet.  These experiments were undoubtedly related to the discovery of cholesterol crystals in human plaques by Aschoff and other investigators.

In America a young investigator in Boston named Harry Newburgh, who was trained in medical research at Massachusetts General Hospital, was recruited by the University of Michigan Medical School in 1919 to become the first full time faculty member in America devoted to research in clinical medicine.  He decided to repeat Ignatowsky’s experiments with rabbits using meat powder as a source of protein in the diet from which all fats and cholesterol had been removed by extraction with organic solvents.  He found that plaques developed in the arteries of his rabbits, even though no fats or cholesterol were present in the experimental diet, effectively disproving Anitschkow’s suggestion that these substances caused the arterial plaques.  Newburgh then started giving individual amino acids one by one to dogs, rabbits and other animals, looking for evidence of arterial plaques.  Although he found no plaques, he discovered toxicity of several amino acids to kidneys, leading to the Newburgh-Marsh diet, an effective treatment for kidney failure in the years before dialysis treatment.  The amino acids methionine and homocysteine had not been discovered when Newburg conducted his experiments, and if they had been available, he would have discovered the ability of these amino acids to cause plaques in animals.

According to Ancel Keys, a professor of physiology and nutrition in Minnesota, the earliest epidemiological investigation relating cholesterol to human atherosclerosis was conducted by the Dutch physician, CD DeLangen, who reported his experience working with patients in Java.  In 1916 DeLangen reported that his patients had low levels of cholesterol in the blood, possibly explaining the rarity of atherosclerosis, phlebothrombosis and gallstones in this Asian population.  In contrast, Javanese stewards on Dutch ships in Java, who consumed the rich Dutch diet, had increased levels of cholesterol in their blood, and DeLangen advocated a low cholesterol diet for prevention of atherosclerosis, based on these observations.

Keys later became the leading advocate of what became to be known as the “diet-heart” hypothesis that related dietary consumption of fats and cholesterol to susceptibility to vascular disease, especially coronary heart disease.   Keys and his colleagues studied mortality rates from countries around the world, reporting an association with dietary fat available for consumption in the “Seven Countries Study.”  However, when similar data from other sources, available to Keys, are considered, the association becomes quite weak.  For example, the mortality rate in Finland was almost 7 times higher than in Mexico, although the fat consumption was identical.  Subsequently authoritative critical review of the Seven Countries Study by statisticians Smith and Pinckney revealed “a massive set of inconsistencies and contradictions,” leading to the conclusion that the “study cannot be taken seriously by the objective and critical scientist.”

The longest running study of cardiovascular disease in a population was initiated in Framingham, Massachusetts in 1948 and continues to this day.  This landmark longitudinal study identified important major risks for disease, especially smoking, lack of exercise, age, male gender, and elevated cholesterol levels in younger men.  In spite of the great emphasis on cholesterol levels, the Framingham study made several critical observations that refute the “diet-heart” hypothesis.  In the first place, dietary cholesterol has no relation to cholesterol levels in the blood, and dietary cholesterol has no relation to the risk of developing cardiovascular disease.  This observation was confirmed by multiple large studies from Chicago, Puerto Rico, Honolulu, Netherlands, Ireland, and the massive Lipid Research Clinics study of US citizens.  The next astounding finding is that elevated cholesterol is not a risk factor for women of any age or for men over age 47.  Furthermore, both total mortality and cardiovascular mortality in Framingham participants increases in those with LOW cholesterol levels.  This finding has been confirmed by multiple studies from Canada, Sweden, Russia, and New Zealand.  These contradictory findings have been ignored, distorted, and incorrectly reported by supporters of the “diet-heart” hypothesis.

The massive Multiple Risk Factor Intervention Trial (MRFIT) screened 360,000 men to find those with the highest risk of developing cardiovascular disease.  Approximately 12,000 overweight, hypertensive, smokers with elevated cholesterol levels were recruited for this 7 year trial, involving consuming a low fat diet, smoking cessation, exercise and anti-hypertensive drugs.  At the end of the trial, blood pressure was down, smoking decreased, and average cholesterol levels were down 7%.  When the results of this $100M trial were analyzed, 115 in the treatment group had died of heart disease, compared with 124 in the control group, an insignificant difference.  Looking at mortality from all causes, there were 265 deaths in the treatment group, compared with 260 in the control group.  In looking at the failure of this massive and expensive $100M trial, the investigators found minor benefits of smoking cessation, no benefit of lowering blood pressure, and no effect of lowering cholesterol levels by 2% compared with the control group. 

In the even more massive Lipid Research Clinics (LRC) trial, 4000 participants with very high cholesterol levels were selected from almost half a million men.  After significant lowering of cholesterol levels for 7 years by the resin cholestyramine, 190 men had suffered nonfatal heart attacks in the treatment group, compared with 212 in the control group.  As for fatal heart attacks, the figures were 1.7% compared with 2.3%, a difference of 0.6%, or 12 individuals.  The investigators expressed these differences as relative risk reductions of 19% and 30% by throwing out the denominators of their fractions. 

In the later trials with statin drugs that lower cholesterol levels more effectively than the unpleasant resin cholestyramine, a similar statistical approach was taken to increasing the apparent effect on reducing cardiovascular mortality and adverse events.  In an analysis of 6 major statin trials (EXCEL, 4S, WOSCOPS, CARE, AFCAPS, LIPID), the reduction of cardiovascular mortality ranged from -19% to -41% when expressed as relative risk reduction, but from –0.12% to -3.5% when expressed as absolute risk reduction.  This statistical manipulation to make the results more impressive illustrates Mark Twain’s aphorism:  “There are lies, damn lies, and statistics.”  Thus a multi-billion dollar drug industry depends upon using misleading interpretations of statistics showing trivial differences between treated and control groups.

Another way of looking at absolute risk reduction is to consider the number needed to treat (NNT) to achieve one positive outcome.  In the case of antibiotic therapy for pneumonia the NNT is 1.1, meaning that 10 of 11 patients treated are cured, or a 90% success rate.  The NNT for a successful medication is generally considered to be 2 to 4, meaning a 25% to 50% success rate.  In the recent ENHANCE trial of Vitorin, a combination of simvistatin and ezetimibe prescribed to lower blood cholesterol, the NNT is 67, meaning that a positive outcome is observed in only one of 67 participants when taken for 5 years.  This number corresponds to a 2% success rate, or a 98% failure rate, a dismal and unacceptable outcome.  In addition, Vitorin failed to prevent intimal-medial thickening, as assessed by ultrasound, contradicting the claim that cholesterol lowering by this medication prevents the early stages of arteriosclerosis.  These results further call into question the claims for a preventive effect of cholesterol lowering on arteriosclerosis.

The gigantic MONICA study, sponsored by the World Health Organization, analyzed the relation between cardiovascular mortality and blood cholesterol in 27 countries, in much the same way as the Seven Countries Study.  The results are similar, showing that countries like Japan and China have low mortality and low cholesterol levels, and countries like Finland have high mortality and high cholesterol levels.  Yet countries like France, Germany, Switzerland, and Luxembourg have a low mortality rate and yet a high blood cholesterol value.  This so-called “French paradox” is not a paradox at all, when examination of the data reveals great disparities in mortality between different regions with the same cholesterol levels.  Similarly the residents of Corfu have a 5 fold greater mortality than residents of Crete, despite identical dietary practices and identical cholesterol levels.  Residents of the North Karelia regions of Finland have mortality rate of 493/100,000 and those in Fribourg France have mortality rate of 102/100,000, yet the cholesterol levels are identical at 245 mg/dl in both regions.

The National Cholesterol Education Program is a quasi-governmental body sponsored by members of the National Institutes of Health, American Heart Association, and other supporters of the “diet-heart” hypothesis.  This body recommends a low fat, high carbohydrate diet to prevent heart disease, in spite of the increasing incidence of diabetes, obesity, and hypertension that is linked to consumers of this diet.  They consistently advocate programs of extreme lowering of cholesterol levels by drug therapy, in spite of evidence of increased risk of mortality from heart failure, cancer, cirrhosis, and other diseases in older subjects with low cholesterol levels.  They also recently recommended lowering the acceptable level of Low Density Lipoprotein (LDL) in the population by statin therapy, in spite of the fact that 8 of the 9 members of the advisory panel had a direct conflict of interest by accepting payments from the drug industry.  This body has popularized the concept that LDL is “bad cholesterol” and HDL is “good cholesterol” in spite of the marginal and sometimes contradictory data distinguishing these fractions from total blood cholesterol.  This body also advocates “aggressive cholesterol lowering” in the population in spite of the fact that no cholesterol lowering trials have demonstrated reduced mortality or sudden death from such treatments in the otherwise normal population.



Homocysteine is an amino acid that is important in sulfur metabolism, as discovered by the prominent American biochemist Vincent DuVigneaud in 1932.  He discovered that this amino acid has one more carbon atom than cysteine, an important constituent of all proteins, and gave it the name “homocysteine” [homo = same in Greek].  An amino acid called “cystic oxide” was discovered by Wollaston in 1810 by isolation from bladder stones, and was later shown to contain nitrogen by Berzelius in 1833, hence the name cystine [kystis = bladder in Greek].  In working with homocysteine and the amino acid methionine, DuVigneaud discovered its importance in supporting growth of animals lacking methionine by chemical transformations in the body called transmethylation.

Little was known about the significance of homocysteine in human disease until 1962, when cases of the new disease homocystinuria were discovered among children with mental retardation, dislocated ocular lenses, accelerated growth, osteoporosis and a tendency to form blood clots in arteries and veins.  Your essayist became interested in the possible connection between homocysteine and arteriosclerosis in 1968 through review of a case of homocystinuria from 1933 that was discovered by pediatricians at Massachusetts General Hospital.  This archival case was the uncle of a 9-year-old girl with mental retardation, dislocated lenses, and abnormal blood vessels of the skin who was diagnosed in 1965 by the new Amino Acid Laboratory directed by Mary Efron and Vivian Shih.  As reported in the New England Journal of Medicine, the boy from 1933 died of thrombosis of the carotid artery and a massive stroke, and the pathologist Tracey Mallory found that the arteries were narrowed by arteriosclerosis “similar to changes found in a very elderly man.” 

Because of an interest in amino acid metabolism and experience with the biochemistry of methionine and homocysteine at the National Institutes of Health, I read the pertinent literature on this new disease, confirmed the presence of arteriosclerosis in slides surviving from the 1933 case, and found plaques scattered through the arteries of this child.  By chance I was able to study the case of a 2-month-old baby boy who had recently died of the new disease, cobalamin C disease, characterized by excretion of homocysteine, cystathionine, and methyl malonic acid in the urine.  Realizing that this case could shed light on the possible connection between homocysteine and arteriosclerosis, I restudied the tissues of this new case and discovered astonishingly advanced changes of rapidly progressive arteriosclerosis.  Since the enzyme deficiency and the pattern of abnormal metabolism were different from the archival case from 1933, I concluded that the amino acid homocysteine produced arteriosclerosis in these children by a direct effect on the cells and tissues of the arteries.  There was no evidence that lipids are deposited in the arteries of these children, and no cholesterol was found in the arterial plaques.

In experiments with rabbits utilizing similar a similar approach to that of Ignatowsky and Anitschkow more than a half century earlier, my research group at Massachusetts General Hospital discovered that administration of the pure amino acid homocysteine to these animals produces arterial plaques and thrombosis of veins and arteries.  Simultaneously giving pyridoxine (vitamin B6) to the animals prevents the plaques and thrombosis.  Although I did not know it at the time these experiments were completed in 1975, Fumio Kuzuya in Japan repeated our experiments and observed essentially the same results in the late 1970s, reporting his reports in Japanese articles.  These results were also observed by Harker and Ross in Seattle, utilizing intravenous homocysteine administration to baboons.  Thus these animal experiments led to the formulation of the homocysteine theory of arteriosclerosis in 1975.  This theory helped to explain several important previous observations of experimental plaques in monkeys deprived of vitamin B6, animals made hypothyroid by thiouracil, and animals deprived of choline and other methyl donor nutrients.

Because the B vitamins folic acid, pyridoxine and cobalamin are all involved in normal metabolism to prevent excessive production of homocysteine, the homocysteine theory of arteriosclerosis implicated deficiencies of these vitamins in human arteriosclerosis, heart attacks, strokes and amputations from vascular disease.  Because the sensitive vitamins folic acid and pyridoxine are destroyed by traditional methods of food processing, such as milling of grains, canning, extraction of sugars and oils from whole foods, and addition of chemical additives to bleach or preserve foods, this theory helped to explain the large increase in vascular disease in the early and mid 20th century.  Similarly, the decline in mortality from cardiovascular disease beginning in the 1950s can be attributed to addition of the synthetic B vitamins to the food supply by fortification of processed foods.  Important support for the homocysteine theory was provided by the Framingham Heart Study, which showed that deficiencies of these B vitamins are widespread in older participants, leading to elevation of homocysteine levels and increased risk of plaques.

Many hundreds of studies by investigators worldwide have now proven that elevated homocysteine levels increase the risk for heart disease, stroke, peripheral vascular disease, and reduce longevity in diverse populations.  In 1998 the US Food and Drug Administration mandated the addition of folic acid to refined flour, rice and other grain foods, the first such action since niacin, thiamin, riboflavin and iron were mandated for addition to refined grain foods in 1941.  One of the rationales for adding folic acid is the demonstration that deficiency of dietary folic acid is implicated in susceptibility to birth defects of the neural tube type.  An additional rationale, not officially cited by the FDA, was the hope that vascular disease incidence and complications might also be prevented in the US.  Studies have indeed shown that birth defects have decreased about 19% in the US and up to 78% in Canada in Newfoundland since fortification by folic acid.  In a recent study by the Centers for Disease Control and Prevention in Atlanta, the declining incidence of mortality from stroke accelerated in 1998 in the US, but no change was found in the United Kingdom, where folic acid fortification is not mandated.  Last year in 2007 a meta-analysis, as reported in Lancet, concluded that trials yielding significant reduction in blood homocysteine levels from folic acid, pyridoxine, and cobalamin over a 3 to 5 year period produced significant reductions in mortality from stroke.  Trials with participants with a history of advanced vascular disease, heart attack and stroke, have been less successful.  The Swiss Heart Study showed that restenosis following coronary angioplasty was benefited by B vitamins, but a later trial with stented patients showed no benefit.

In the 1970s, before my removal from Harvard medicine, and in the 1980s and 1990s my research groups at Massachusetts General Hospital and at the VA Medical Center in Providence made some additional discoveries in the homocysteine field.  By using cultured cells from children with homocystinuria, we were able to demonstrate a new pathway for sulfur metabolism by showing that homocysteine thiolactone, the reactive anhydride of homocysteine, is a precursor of sulfate.  We discovered that this pathway is depressed in aging animals and completely blocked in cultured cancer cells.  Using methods of organic synthesis, we developed and discovered new derivatives of homocysteine thiolactone, retinoic acid, and cobalamin named thioretinamide and thioretinaco.  These compounds are effective in preventing arterial plaques in animals treated with homocysteine.  Theorizing that these compounds are deficient in cancer cells, we were able to decrease cancer formation from chemical carcinogens and to decrease growth of transplanted cancers in mice.  These compounds have not as yet been tested in human trials.  My second monograph describes a theoretical biochemical process by which these compounds support the normal oxidative metabolism in normal cells that is deficient in cancer cells.


Infections and vulnerable plaques

We have learned that cholesterol plays a minor role in creation of plaques, at least in younger men, and that homocysteine elevation increases the formation of plaques and risk of disease in animals and in human populations, through dietary deficiency of B vitamins, genetic factors, and altered metabolism of methionine.  However, there are many other factors that are known to increase risk of vascular disease.  In particular, mental and emotional stress, smoking, aging, male gender, postmenopausal status in women, diabetes, kidney failure, hypothyroidism, and high blood pressure are all important determinants of disease risk.  Surveys, case control studies, and experimental studies have shown that each of these factors increases homocysteine levels in animals and man.   How do these diverse factors conspire to produce vulnerable plaques in the arteries that by rupturing cause hemorrhage, thrombosis with occlusion, and death of heart, brain and other tissues in patients with vascular disease?

A century ago the cause of arteriosclerosis was generally considered to originate from “direct irritation of [arterial] tissue by infection or toxins.”  Bacteria and viruses were considered as the main cause of atherosclerosis, because of increased plaques in patients dying of typhoid fever and other infections.  Sir William Osler, the Canadian pathologist and physician who became the Regius Professor of Medicine at Oxford and a leading physician of his time, described the vulnerable plaque as a pustule.  More recently, much evidence has been reported to support the role of infections in vascular disease.  In particular, cardiovascular mortality increases during influenza epidemics.  A third of patients with acute myocardial infarction or stroke have had an infectious disease immediately before onset.  Bacteriemia and periodontal infections are associated with an increased risk of cardiovascular disease.  Serological markers of infection are elevated in patients with cardiovascular disease.  And coronary arteries of children are found to be narrowed in children who died of infectious diseases.

Beginning in 1939 and in the next decade, investigators discovered that lipoproteins function as a nonspecific immune system that is capable of inactivating a wide variety of bacteria, viruses, protozoans and their toxins.  Lipoproteins form complexes with these organisms that render them inactive, and macrophages in the tissues are capable of phagocytosis of these complexes, leading to formation of foam cells that destroy these organisms.  The lipopolysaccharides and lipoteichoic acids of these organisms bind with lipoproteins, probably because of their lipophilic properties, rendering them inactive.  Some examples of organisms that are inactivated this way are Salmonella, the cause of typhoid fever and other gastrointestinal infections, Herpes simplex, Rotavirus and Cytomegalovirus, the cause of ubiquitous viral infections, Chlamydia pneumoniae, a respiratory pathogen, and Staphylococcus aureus, an important cause of boils, carbuncles, and pneumonia.

Beginning in the 1970s investigators found evidence of a wide variety of micro-organisms in human atherosclerotic plaques, as demonstrated by immunohistochemistry, polymerase chain reaction for DNA fragments, and electron microscopy.  Only in the case of Chlamydia pneumoniae were investigators able to culture viable organisms directly from plaques.  In most cases, only remnants of micro-organisms are found, and viable organisms cannot be cultured from plaques.  Using sophisticated DNA technology, a recent report from Germany demonstrated the presence of 50 different micro-organisms in human plaques, and the average number was 12 per plaque.  Arteries without plaques contained no microbial remnants.  As shown in the figure, many common organisms form complexes with lipoproteins, such as Escherichia coli, Staphylococcus, Streptococcus, Salmonella, and rotavirus.  The same organisms are demonstrated in plaques, suggesting an infectious origin of plaques.

Homocysteine participates in the aggregation of lipoproteins by reacting with the protein to form cross-linkages, leading to aggregation, spontaneous precipitation and phagocytosis by macrophages to form foam cells.  Thus in persons with elevated homocysteine levels, there is an increased ability of lipoproteins to form aggregates, leading to foam cell formation from macrophages by phagocytosis.  In addition, lipoproteins containing homocysteine have altered antigenic structure, leading to the formation of antibodies that complex with lipoproteins.  A similar process has been identified with lipoproteins within foam cells, since oxidation reactions create modified or oxidized lipoproteins that incite autoantibody formation.   In the presence of invading micro-organisms, the complexes with lipoproteins theoretically become enlarged and subject to precipitation and phagocytosis by macrophages.

The figure illustrates our concept of the creation of vulnerable plaques within arteries.  In the case of a massive invasion of micro-organisms, or when the immune system is impaired, the complexes of micro-organisms with lipoproteins, enhanced by the effect of excess homocysteine, obstruct the vasa vasorum, the small arterioles, venules and capillaries that normally nourish the wall of the artery.  Obstruction of the blood flow causes ischemia of the artery wall (lack of blood supply), increasing the tendency to cell death and rupture of the capillaries.  These large complexes are phagocytosed by macrophages to form foam cells that accumulate, initially in the adventitia, but then migrating into the intima, where lipoproteins, inflammatory cells, and lipid deposits, including cholesterol, accumulate.  This process is probably increased and enhanced in cases where autoantibodies are formed to homocysteinylated lipoproteins and oxidized lipoproteins.  This process is further exacerbated by swelling of endothelial cells and narrowing of the lumens of vasa vasorum by endothelial dysfunction, caused by elevated homocysteine and other factors.  The result is a vulnerable plaque that by rupturing causes thrombosis, obstruction of the arterial lumen, and death of the heart, brain, kidney or other tissue supplied by the artery.  The vasa vasorum are functionally end arteries, since blood flow ceases at the point where the pressure within these blood vessels is opposed by the pressure within the arterial lumen.  Thus, the process of plaque formation is potentially enhanced in areas of increased blood pressure, such as disrupted laminar flow, turbulence, angulation of arterial lumen, and increased systemic pressure.  In fact, these are the areas in the arteries where vulnerable plaques are most commonly observed.

Fig. 1. Development of the vulnerable plaque. The small globules inside the vasa vasorum and in the vulnerable plaque represent lipoproteins; the black dots represent microorganisms, ndotoxins, anti-OxLDL autoantibodies, and anti-thiolated-LDL autoantibodies; the large globules at the basal part of the vulnerable plaque and inside the macrophages represent lipid droplets. The right capillary represents the situation in a normal healthy artery; there are only a few microbes and the lipoproteins are able to traverse the capillary lumen without adherence or obstruction. The left capillary represents the situation in an artery with a severe microbial invasion; microbial products and autoantibodies stick to the lipoproteins, which aggregate and obstruct the capillary lumen, leading to local ischemia, microbial growth, and inflammation. A monocyte enters the plaque from the arterial lumen by diapedesis between endothelial cells; another monocyte enters the plaque via vasa vasorum, leading to formation of foam cell macrophages within the plaque. In the case of an intact immune system, the inflammatory area heals and becomes converted to a fibrous plaque. In the case of an insufficient immune system, microorganisms escape into the tissue and create a microabscess, the vulnerable plaque. (From Ravnskov U,McCully KS. Ann Clin Lab Sci 2009;39:3-16.

 One can readily understand that our interpretation explains many of the observations about vulnerable plaques and the pathophysiological processes found in vascular disease.  It explains how risk factors, such as stress, B vitamin deficiency, elevated blood pressure, smoking, and kidney failure lead to increased disease risk through formation of homocysteinylated lipoprotein aggregates.  It explains the resistance of persons with elevated lipoprotein levels to infectious diseases.  It explains how cholesterol becomes deposited in plaques.  It explains the inflammatory process and the release of inflammatory cytokines, C-reactive protein, fever, leukocytosis, and the frequent occurrence of bacteriemia and sepsis in myocardial infarction complicated by shock.  It explains the observation of microbial remnants in plaques.  And it explains the inflammatory nature of cardiovascular disease.

Suggestions for prevention and therapy of vascular disease readily follow from our interpretation of the origin of vulnerable plaques.  Risk factors that lead to elevated homocysteine levels need to be addressed by smoking cessation, dietary B vitamins, stress reduction, and control of diabetes and hypertension.  The immune system needs to be enhanced by intake of vitamin A, vitamin D, pyridoxine, and other factors that are needed for proper immune function.  Appropriate antibiotic therapy is needed in heart attack and stroke patients that have evidence of active infection.  Dietary improvement is needed to supply the nutrients that are needed to minimize homocysteine elevation and to support anti-oxidant function.  Attempts to prevent cardiovascular disease and prolong life may be more successful by understanding the fallacies of the “diet-heart” hypothesis and determining what is harmful to the immune system and what may strengthen it.



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McCully KS.  Hyperhomocysteinemia and arteriosclerosis:  historical perspectives.  Clin Chem Lab Med 2005;43:980-986.

Ravnskov U, McCully KS.  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 2009;39:3-16.

Ravnskov U.  The Cholesterol Myths.  Exposing the fallacy that saturated fat and cholesterol cause heart disease.  New Trends Publishing, Washington DC, 2000.

Levy D, Brink S.  A Change of Heart.  How the people of Framingham, Massachusetts helped to unravel the mysteries of cardiovascular disease.  Knopf, New York, 2005.

McCully KS.  The Homocysteine Revolution:  Medicine for the New Millennium.  Keats Publishing, New Canaan CT, 1997.

McCully KS, McCully ME.  The Heart Revolution.  HarperCollins, New York, 1999.

McCully KS.  Homocysteine, vitamins and vascular disease prevention.  Am J Clin Nutr 2007;86:1563S-8S.

Ravnskov U.  Fats and cholesterol are good for you!  GB Publishing, Sweden, 2009.

Peskin BS, Sim D, Carter MJ.  The failure of Vytorin and statins to improve cardiovascular health:  bad cholesterol or bad theory?  J Am Phys Surg 2008;13:82-87.

Kastelein JJP, Akdim F, Stroess ESG.  Simvistatin with or without ezetimibe in familial hypercholesterolemia.  New Eng J Med 2008;358:1431-1443.

McCully KS.  The Chemical Pathology of Homocysteine.  IV.  Excitotoxicity, Oxidative Stress, Endothelial Dysfunction, and Inflammation.  Ann Clin Lab Sci 2009;39:307-320.