"The philosophies of one age have become absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow." - Sir William Osler, Aequanimitas and Other Addresses
Atherosclerosis is characterized by the presence of irregular patches or plaques in the intima and subintima (inner wall) of arteries near their branchings or bends. The name atherosclerosis was copinted to describe the late-stage, “vulnerable” plaque seen in victims of cardiovascular deaths, This plaque was noted to have two components: a gruelly lipid-rich material (athero, wihch means “gruel”) and a hard fibrous tissue (sclerosis). But atherosclerosis is a long, long process, perhaps lifelong, and asymptomatic for the greater part (90 percent or more) of its course. It is said - because who can say what really happens when we rely only on autopsy findings of humans (e.g. P-Day) and cannot rely on so called atherosclerosis findings in animals - that the earliest lesions are intimal thickening and fatty streaks. These are accidental findings during autopsies of children, even infants and their genesis is mysterious. Many theories are proposed - mechanical process, a good study should be a comparison of breast-fed against milk-fed infants.
Atherosclerosis continues silently into adulthood. Whether it may regress in some is not knowable with present investigational techniques. Only much latter (at forty to fifty of age), especially in those who smoke or are obese, hypertensive, diabetic and genetically predisposed, may it become a disease and lead to a fatal heart attack or stroke.
R.W. Wissler’s ten-year research program on pathological determinants of atherosclerosis in youth (P-Day) and other studies identified the atherosclerosis-prone regions of the circulatory system. Also identified were the plaques that are innocuous and benign; and malignant or vulnerable. Antherosclerosis lesions are divided into two stages or forms: the benign and the malignant. The benign form may progress to the malignant form or may remain benign throughout life. Many elderly patients who die of causes other than cardiovascular disease (CVD) are found to have atherosclerosis only at autopsy. They usually show no signs of disease in life. Such cases probably constitute the greater majority in the developing countries of the world as well as in some highly developed ones like Japan, France, Switzerland and the Mediterranean countries.
The Benign Forms or the Quiescent Stage
Three types of plaques are classed as benign: the initial fatty streak which eventually may or may not become fibrofatty and then fibrous. All are flat, non-obstructive and asymptomatic. They are found at bends, bifurcations or branchings of arteries where the bloodstream becomes turbulent and jet streams produce high-and-low-shear stress areas. Plaques form in the low-shear areas where large circulating bodies like lipoproteins and white cells can congregate and adhere to the wall. Lipid accumulation can be induced in animals with low plasma cholesterol simply by hemodynamic stress. Plaques do not form in veins where the blood is steadily flowing and pressure is very low.
The fibrous plaque, being asymptomatic like its predecessor, is discovered only at necropsy or in X-ray films or scans. Like skin wrinkles and white hair, it is often just a sign of aging. Autopsies of young adults who died in accidents, however, have revealed such plaques in the aorta and larger arteries. Fibrotic plaques have been reported to be as frequent among the young Japanese in Japan as in young American casualties of war, indicating that cultural, dietary, or environmental influences are of little importance. In the elderly, fibrotic plaques are expected to be present and one without any would be a rare individual. The interesting 64-million-dollar question is why plaques remain stable and innocuous in many people while in some they become malignant.
On microscopic examination, fibrous plaques have little cholesterol deposit; instead they have much collagen and elastic fibers, T lymphocytes, macrophages and monocytes coming from the muscle layer of the artery. The migration of smooth muscle cells was first described in 1977 by Earl P. Benditt, who proposed this as the first step of atherogenesis. The migration is said to be stimulated by a platelet-derived or endothelium-derived growth factor (PDGF or EDGF). When activated, monocytes are transformed into macrophages. These cells as well as fibroblasts secrete collagen and elastic fibers to make the plaque fibrotic but flat. Other cells attracted to the site are granulocytes, mast cells and B lymphocytes from the bloodstream. To gain entry into the subintimal area, adhesion molecules (VCAM, ICAM) are secreted by the endothelium to facilitate the process wherein circulating cells stick to the intima and enter through gaps in the endothelium.
Inflammation
Inflammation is the body’s defense and repair system. The many kinds of cells that gather in a diseased site, attracted there by chemoattractants, lympokines, and cytokines, are there to kill invading organisms, remove foreign bodies or cancer cells and repair damage. A successful inflammation should end in cure and recovery. Failure to achieve cure, however, leads to a continuing effort, a chronic inflammatory effort, that itself ultimately creates the damage and becomes the disease. Chronic inflammation of the joints (arthritis), of muscles and connective tissues (fibromyalgia), of blood vessels (systemic lupus, microvasculitis, atherosclerosis), of bronchial tubes (chronic asthma), of skin (scleroderma), etc. are damages caused by the body’s defensive mechanism, inflammation, and are thereby called “autoimmune” diseases.
Inflammation also underlies the whole atherogenic process. Whatever role cholesterol plays is minimal or nil in the early stages and may become important only in the late stage of the disease and only in persons with risk factors and genetic tendencies. Those persons at risk are definitely a small minority even in developed countries and comprise and even smaller group in developing and coconut oil-consuming countries. The big majority of people carry their fibrotic plaques to their graves and never develop heart disease or suffer strokes even if they smoke and eat saturated fats and cholesterol and are hypercholesterolemic.
The Malignant Plaque
On dissecting open the clogged artery of a heart-attack victim, the occluded site is found to be filled up with a thrombus (blood clot) of different ages, new and old, attached to a large soft plaque filled with gruelly material and a fibrotic cap with a rupture at its base.
Malignant plaques are called “vulnerable” as they are prone to hemorrhage and to fissure and rupture, discharging their gruelly contents and exposing their internal collagenous material. To tis collagenous material, platelets with their Von Willebrand receptors love to adhere, aggregate, form platelet plugs and start the coagulation cascade. In the presence of gene-promoted hyperfibrinogenemia and dysfunctional endothelium-secreting procoagulant factors, cloths (thrombi) adhere to the plaque and slowly grow. The occlusion of the arterial lumen by the complex athero-thrombotic plaque is just a matter of time. Before occlusion, bits of thrombi may break off to embolize particularly the brain. This process is common in the large vessels like the aorta and carotid arteries, where the blood pressure is highest. The distinguishing of the vulnerable malignant plaque from the fibrous innocuous one has been a most important addition to our knowledge. The formation of the malignant plaque starts the clinical phase of cardiovascular disease. The onset of the clinical phase can be sudden or very slow. Acute coronary events or heart attacks are usually due to large ruptures of plaques with massive occlusive clotting. More common is a slow strangulation of the blood supply by a slowly growing complex plaque, causing episodes of angina or no pain whatever. Such silent heart attacks are now quite frequently seen during routine checkups.
The events leading to the formation of the malignant plaque can be deduced as follows, starting with the flat stable fibrous plaque:
First - LDL laden with cholesterol ester (CE) enters the subendothelium. Cholesterol is an unsaturated steroid molecule and its linoleate or oleate esters are unsaturated fatty acids. The phospholipids of the carrier LDL have polyunsaturated fatty acid tails. LDL-C, therefore, is an unsaturated body ready to be oxidized.
Second - These unsaturated fats (CE and LDL phospholipid tails) are peroxidized by the free radicals (e.g. H2o2) secreted by monocytes and macrophages that have entered and are in temporary residence in the subendothelial space. Peroxidation is a rapid self-sustaining process that continues as long as there is something to be oxidized. The oxidized LDL (oxLDL) now becomes a toxic body.
Third - The macrophages engulf the oxLDL through endocytosis. They also secrete 11-1 (interleukin 1) and other cytokines to attract more macrophages and other inflammatory cells (T and B lymphocytes, mass cells, polymorphonuclear leukocytes) to the site. This cellular invasion is the body’s defensive inflammatory response. Macrophages that had taken up and are laden with oxLDC are the foam cells seen in the now softened plaque. These foam cells die and release their oxidized fats and cholesterol esters to form a gruelly mass - the athero of atherosclerosis. Linoleates and oleates are the fatty acids found in plaques - never lauric acid or any of the medium chain fats of coconut oil. How, therefore, can coconut oil be even suspected of causing heart disease?
Fourth - The thinning of the fibrotic cap of the plaque weakens it and leads to cracking, hemorrhaging, and rupture, usually near the base of the plaque. The reason for the thinning of the cap, a reverse inflammation, is not known.
Fifth - The collagen fibers exposed in the ruptured site(s) and the gruelly mass that oozes out of the plaque are highly thrombotic; they cause platelets to aggregate, and blood to clot over the plaque.
Sixth - Endothelial dysfunction (q.v.) promotes an increase of pro-clotting and antifibrinolytic factors, while decreasing the production of anti-clotting factors, thus enhancing thrombus formation. The large athero-thrombotic plaque often with the help of vasospasm of the artery is what occludes the vessel finally. The role of vasospasm may be most important in sudden-death cases.
Endothelial Dysfunction
Box 2 summarizes the many functions of the vascular endothelium. It shows what a mighty organ this innocent-looking membrane is, which once was likened to an inert cellophane lining.
The endothelium secretes its own basement structure, the subendothelium, where most of the action occurs. In this “arena” enter the combatants: oxyfreen-free radicals exuded by macrophages and polymonphonuclears (PMNs), T and B lymphocytes, cholesterol-bearing LDLs. The other arena is the blood where the endothelium’s clotting and anticlotting factors react with platelets and coagulation factors. Lastly, there are the ecto-enzymes on the endothelial surface that converts inactive angiotensin I to angiotensin II, another vasoconstrictor. In health, these factors are in balance - the pro- and anti-flammatory, the pro- and anticlotting, the vasoconstrictors and vasodilators.
When the endothelium is injured by stress or disease, this delicate balance is lost; the endothelium secretes more of the damaging pro-inflammatory, pro-vasoconstriction, pro-coagulation enzymes and less of the anti-inflammatory, vasodilator and anticlotting enzymes. It even prevents the dissolution of blood clots by producing an inhibitor of a clot-dissolving enyzme. This pathogenic state is called “dysfunction.” Endothelial dysfunction helps to destabilize the fibrous plaque and make it more inflamed and clot-prone.
Cholesterol: The True Story
Low-density lipoproteins, especially the larger ones, are the vehicles with which the body distributes cholesterol to all its cells for their needs. The few small dense LDLs that are trapped in the subendothelial space of arteries are attacked by free radicals, their polyunsaturated fatty acids peroxidized, oxidizing the LDL and making it toxic. Macrophages then engulf the oxLDL, and these macrophages become the foam cells that form the gruel of the atherosclerotic artery. The LDL-cholesterol molecules that participate in this lethal role are a mere pinchful compared to the circulating 200 mg/deciliter (6-8 gm total) serum cholesterol that serve the body’s needs. These few small dense LDLs are the “bad cholesterol” - “bad LDL” would be a more appropriate name. The poor cholesterol up to this time has been just a passenger. In the foam cell, the cholesterol is inside the LDL which is inside the macrophage. Only after the macrophage disintegrates and relieves itself of its contents can the peroxidized fatty acids and cholesterol take part in provoking more inflammation - a late participation but important in creating the “vulnerable” condition of the plaque.
The $64-Million Question
When and why does the benign fibrotic plaque become malignant and vulnerable?
When? Among westernized women only, after menopause, and among Caucasian and westernized men, starting from mid- to late adulthood - the ages that Victor Hugo described as “the old age of youth (40s) and the youth of old age (50s).” But, among peoples untouched by Western ways and processed foods, heart attacks and strokes are rare.
The important risk factors believed to play roles in the making of the malignant plaque are listed in Fig. 4. “Risk factor” is a term that denotes only an association, not a causation. Those possessing these risk factors - e.g. those who smoke or are hypertensive, diabetic or obese - are more likely to develop heart disease and to suffer from attacks although there are many cases in which this does not happen, even though the risk factors are present. Why? One explanation is that the risk factors may be operating not alone but in combinations, to which the body’s defenses may respond differently and in various degrees. Hence, atherogenesis is called multifactorial - not only in number and causative combinations of the risk factors but also in the ability of the body to defend itself and repair (or try to repair) the damage inflicted. Ultimately, the answer may be in our genes, which are responsible for all the enzymes and proteins involved in atherogenesis (Table 3). As regards saturated fats, these are at best only one risk factor. To say that they are the cause of heart disease, as the Lipid-Heart Theory claims, is, to put it bluntly, absurd.
Table 3
Gene Expressions That Impact on Atherogenesis
Cholesterol biosynthesis enzymes
Apo E2/E4 protein regulating cholesterol absorption
Lipoprotein Lipase regulating VLDL-IDL-LDI conversion
APO AI/II HDL proteins
Lipoprotein(a)
All growth factors, lymphokines, cytokines
All receptors of (6)
Macrophage scavenger receptors for
SR-AI/AII, CD-36, CD-68, LOX-1
SR-PSOX, Galectin-3
Chemokine receptors for CXCR-2, CCRS, CS3CRI, MCP-1
Fibrinogen level
Nitric Oxide Synthase (NOS)
Clotting/anticlotting factors
Fibrinolytic/antifibrinolytic factors
What is Wrong with the Lipid-Heart Theory?
The seven-country study of Ancel Keys is the seminal paper that launched the Lipid-Heart Theory. The theory states (a) that dietary saturated fats and cholesterol causes high blood cholesterol; (b) that high cholesterol causes coronary heart disease; and (c) that, therefore, fats and cholesterol cause heart disease. Keys selected sixteen localities in seven countries - the Netherlands, Finland, Italy, Yugoslavia, Greece and U.S. and Japan. He was assisted by local physicians and health workers. After almost a decade of study (in the 1960s), the authors came out with the conclusion that the countries with the highest animal fat consumption had the highest cholesterol levels and incidence coronary deaths. These conclusions were promptly accepted by 99.9 percent of researchers. Dissenters who criticized the design, methodology, execution or analysis were ignored. The Lipid-Heart Theory struck such a responsive chord among heart specialists, funding agencies and especially drug manufacturers that those whose findings did not support or, worse, contradicted the hypothesis tried to soften/modify their conclusions and sought to explain why their studies were at variance with such an established theory. (Note: theory=hypothesis=conjecture=guess.)
M.I. Gurr and Uffe Ravnskov analyzed all the evidence presented for the Lipid-Heart Theory including the largest, most expensive studies like the MRFIT (Multiple Risk Factor Intervention Trials), the Framingham studies, the WHO (World Health Organization) conducted twenty-seven country Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study, and the LRC (Lipid Research Clinic) trials. With irrefutable arguments, they showed how untrue were the theory’s claims that (a) saturated fats cause heart disease; (b) high serum cholesterol causes atherosclerosis and heart disease; (c)saturated fats increase serum cholesterol; and (d) lowering cholesterol improves coronary heart condition. Gurr and particularly Ravnskov enumerated the many defects in these studies ranging from “errors” in technique to obvious bias and “scientific fraud,” viz:
faults in design and/or execution;
selection of supportive data and omission/rejection of what are not supportive;
lowering original prestated statistical goals;
magnifying insignificant results by statistical manipulations like taking percent differences of insignificant percent differences and
making conclusions contrary to the results or misquoting data and conclusions of others to favor their own
Fig. 7 (not from Ravnskov) illustrates one common accepted method of presenting data that hides facts behind generalizations, showing that “One can prove anything by statistics” and “The three lies are the small lie, the big lie and, statistics.”
On the other hand, Ravnskov and Gurr cited studies that directly contradicted and negated the Lipid-Heart claims - of populations who ate saturated fats and were healthy, had low cholesterol and no heart disease; and of persons with low cholesterol levels but with heart disease (see quotations below).
Cholesterol (as fully discussed in Appendix B), is an essential element and its level in the plasma is well regulated presumably by need. French researchers (Forette et al.) found that elderly women with the highest cholesterol lived longer and were healthier than women with the lowest cholesterol. SImilar findings in elderly men were reported by Krumholz et al. These indicate how useful cholesterol is to the health of the body. The Framingham study findings are in accord and support these observations:
In Framingham, Massachusetts, the more saturated fat one ate, the more cholesterol one ate, the more calories one ate, the lower the person’s cholesterol… the opposite of what the equations provided by Hegsted et al. (1965) and Keys et al (1957) would predict… In Framingham, for example, we found that the people who ate the most cholesterol… saturated fat.. calories.. weighed the least and were most physically active.
Eighty percent of individuals who develop coronary artery disease (CAD) have a total plasma cholesterol within the same range as those who do not develop CAD.
Therefore, present attempts to keep loewring the target levels of serum cholesterol, such as the latest advice to reduce cholesterol (LDC-C) down to 70 mg/dl by administering large doses of the statin drugs to high-risk patients, might succeed but for the wrong reason: not because of the low cholesterol level but because of the anti-inflammatory effects of the statins.
Paul Ridker, noting that half of myocardial infarcts and strokes occur in people with normal cholesterol, showed that C-reactive protein (CRP), a known marker for inflammation, was found in high levels in such patients and that high doses (80 mg) of atorvastatin given to heart-attack survivors reduced the risk of a second heart attack from 10 percent in two and a half years to 4 percent when the CRP was brought down to less than 1 mg per L. This strongly supports the inflammatory nature of vascular occlusion and the anti-infammatory action of the statin.
The use of such high doses of atorvastatin should be approached with caution because the cholesterol level is also brought down so low - as low as 70 mg/dl! While acute coronary or cerebral events might be prevented in the short term in those with bad genes and already have heart disease damage to other organs, particularly the brain, may be a long-term complication in the offing. The latter event becomes even more objectionable and reprehensible among healthy persons induced to lower their cholesterol to such levels for no reason other than misguided advice. In healthy persons with good genes, high cholesterol is not bad and may even be desirable.
Dieting is Ineffective
The Lipid-Heart Theory continued to hold despite the fact that all attempts to lower cholesterol and decrease the likelihood of heart disease by diet alone failed. L.A. Corr and M.F. Oliver, in a 1997 review entitled “the low fat/low cholesterol diet is ineffective,” analyzed the six randomized controlled trials for primary prevention (i.e., healthy subjects) and the two trials of low-fat diet for secondary prevention (i.e., patients with coronary heart disease). Their conclusions were (1) that “dietary advice to reduce saturated fat and cholesterol intake, even combined with intervention to reduce other risk factors, appears to be ineffective for the primary prevention of coronary heart disease and has not been shown to reduce mortality” and (2) that “low-fat diet has no place in the treatment of myocardial infarction.”
Lifestyle Change Is Necessary
Shortly after the publication of Corr and Oliver’s paper, Dean Ornish and his colleagues went on to demonstrate that coronary atherosclerosis could be controlled, even reversed, by a more rigid fat and cholesterol restriction plus changes in lifestyle. They confirmed Corr and Oliver’s findings that the recommended 30 percent dietary fat restriction did not go far enough. Ornish’s diet allowed no more than 10 percent of fat calories and 2 mg of cholesterol a day. This diet (starvation to some people) included lifestyle changes such as giving up smoking, limiting alcohol intake, regulating exercises and most importantly, managing stress by daily meditations, yoga exercises, stretching and relaxing, breathing exercises and continuing cohort support. Without stress management, fat restriction and control of other risk factors were found ineffective. Ornish also observed subjects with high serum cholesterol (above 200 mg%) whose atherosclerosis had been reversed, and others with low cholesterol (180 mg or less) whose atherosclerosis progressed. Such findings show the weakness of the fat/cholesterol-heart association and instead, the importance of mental health and equanimity to the overall health of the body.
Wrong Therapeutic Goal
Despite the acceptance of the inflammatory nature of atherosclerosis, it is still being through a cholesterol-lowering diet that restricts the consumption of saturated fats, cholesterol, and coconut oil. In the next chapter we will look at the real relationship between coconut oil consumption and heart disease.