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Nutrition in Clinical Practice
DOI: 10.1177/0884533608324586
2008; 23; 464 Nutr Clin Pract
William C. Roberts The Cause of Atherosclerosis The online version of this article can be found at:
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The Cause of Atherosclerosis
William C. Roberts, MD
Financial disclosure: none declared.
Most physicians, I believe, consider atherosclerosis
to be a multifactorial disease, and the greater the
number of atherosclerotic risks factors present,
the greater the chance of having an atherosclerotic event.
I am in the minority in believing atherosclerosis to be a
unifactorial disease, the result of abnormal serum or
plasma cholesterol levels. If dyslipidemia is present, then
systemic hypertension, diabetes mellitus, cigarette smok-
ing, inactivity, and excessive body weight increase the like-
lihood of an atherosclerotic event, but none of them in
and of themselves is required for severe atherosclerosis to
occur. In contrast, atherosclerosis does not occur if dys-
lipidemia is not present, irrespective of the blood pressure
level, blood glucose level, the degree of obesity, the degree
of activity, or the number of cigarettes smoked daily.
There are 4 factors supporting the proposition that
cholesterol is the cause of atherosclerosis:
1. Atherosclerosis is easily produced in nonhuman
herbivores (eg, rabbits, monkeys) by feeding them
a high cholesterol (eg, egg yolks) or high saturated
fat (eg, animal fat) diet. These studies initially were
done by some Russian physiologists beginning in
1908. And atherosclerosis was not produced in a
minority of rats fed these diets, it was produced in
100% of the animals! Indeed, atherosclerosis is one
of the easiest diseases to produce experimentally,
but the experimental animal must be an herbivore.
It is not possible to produce atherosclerosis in a
carnivore but with one exception, and that is in car-
nivores that have hypothyroidism due to thyroidec-
tomy. The only condition that is easier to produce
experimentally than atherosclerosis is an endocrine
deficiency. If the thyroid gland is removed, the con-
sequence is hypothyroidism, unless the thyroid
hormone is replaced. In contrast to feeding choles-
terol and/or saturated fat, it is not possible to pro-
duce atherosclerotic plaques in herbivores by
raising the blood pressure chronically, by blowing
cigarette smoke in their faces for their entire life-
times, or by somehow raising the blood glucose lev-
els without simultaneously feeding them an
atherogenenic diet. Presently, it is commonly
stated that “atherosclerosis is an inflammatory dis-
ease.” Inflammatory cells, however, are infrequent
in plaques of coronary arteries studied at necropsy or
in endarterectomy specimens. When present, the
few mononuclear cells—even giant cells—appear
to be present due to a reaction to the deposits of
lipid (pultaceous debris) present in the plaque.
“Inflammation” appears to be a surrogate for eleva-
tion of serum C-reactive protein or various
cytokines (interleukins 1 and 6, tumor necrosis fac-
tor, etc), not for inflammatory cells in plaques.
Thus, it is a definition situation, and the morpho-
logic definition of inflammation is not applicable.
2. Cholesterol is present in the plaques. Several
studies in the 1930s nicely demonstrated that
experimentally produced plaques in herbivores
were similar to plaques in humans.
3. Populations with relatively high serum choles-
terol levels compared to populations with rela-
tively low serum cholesterol levels have a much
higher frequency of atherosclerotic events, a
much higher frequency of dying from these
events, and a much greater quantity (burden) of
plaque in their arteries. This factor was nicely
supplied by the 7-country study and the
Framingham study among others.
4. Lowering serum total cholesterol and low-density
lipoprotein (LDL) cholesterol levels decrease
first and repeat atherosclerotic events. Additionally,
plaque size may decrease.
In summary, the connection between cholesterol ele-
vation and atherosclerotic plaques is clear and well estab-
lished. Atherosclerosis is a cholesterol problem! If one has
elevated cholesterol, has an elevated blood pressure,
smokes cigarettes, or has an elevated blood sugar, these
additional factors serve to amplify the cholesterol damage
but they by themselves do not produce atherosclerotic
plaques! Societies with a high frequency of systemic
Nutrition in Clinical Practice
Volume 23 Number 5
October 2008 464-467
© 2008 American Society for
Parenteral and Enteral Nutrition
hosted at
Invited Commentary
From the Baylor Heart and Vascular Institute, Baylor University
Medical Center, Dallas, Texas.
Address correspondence to: William C. Roberts, MD, Baylor
Heart and Vascular Institute, 621 N. Hall Street, Dallas, TX
75226; e-mail:
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Editorial / Roberts 465
hypertension or a high frequency of cigarette smoking but
low cholesterol levels rarely get atherosclerosis.
Differences Between Herbivores
and Carnivores
Because humans get atherosclerosis, and atherosclero-
sis is a disease only of herbivores, humans also must be
herbivores. Most humans, of course, eat flesh, but that
act does not make us carnivores. Carnivores and her-
bivores have different characteristics. (a) The teeth of
carnivores are sharp; those of herbivores, flat (humans
have some sharp teeth but most are flat for grinding
the fruits, vegetables, and grains we are built to eat).
(b) The intestinal tract of carnivores is short (about 3
times body length); that of herbivores, long (about 12
times body length). (Because I am 6-feet tall my intes-
tinal tract should be about 60-feet long. As a conse-
quence if I eat bovine muscle [steak], it could take 5
days to course through those 20 yards.) (c) Body cool-
ing for carnivores is done by panting because they have
no ability to sweat; although herbivores also can pant,
they cool their bodies mainly by sweating. (d) Drinking
fluids is by lapping them for the carnivore; it is by sip-
ping them for the herbivore. (e) Vitamin C is made by
the carnivore’s own body; herbivores obtain their
ascorbic acid only from their diet. (f) the appendages
are different: Carnivores have claws; herbivores have
hands or hooves. Thus, although most human beings
think we are carnivores or at least conduct their lives
as if they were, basically humans are herbivores. If we
could decrease our flesh intake to as few as 5 to 7
meals a week, our health would improve substantially.
Conditions Uncommon in Human
Non–Flesh Eaters
Some extremely common conditions in the Western
world are relatively uncommon in purely or predomi-
nately vegetarian fruit-eating societies. These include (a)
severe atherosclerosis and its devastating consequences
(heart attacks, strokes, etc); (b) systemic hypertension: in
societies that eat not enough salt for it to be measurable,
the systemic arterial blood pressure is usually about
90/60 mm Hg, a level near what it is at birth, but a level
in the Western world often associated with shock;
(c) stroke; (d) obesity; (e) diabetes mellitus; (f) some
common cancers (colon, breast, prostate gland); (g) con-
stipation, cholecystitis, gallstones, appendicitis, divertic-
ulosis, hemorrhoids, inguinal hernia, varicose veins; (h)
renal stones; (i) osteoporosis and osteoarthritis; (j) sal-
monellosis and trichinosis; and (k) cataracts and macu-
lar degeneration.
Cholesterol Numbers Needed to Prevent
and Arrest Atherosclerotic Plaques
The guidelines for cholesterol-modifying therapy pub-
lished in 1988, 1993, and 2001, and modified subse-
quently, brought some rationale into the arena of who
should and who should not be treated with “lifestyle
changes” and/or lipid-lowering drugs or both. These
guidelines, however, were based exclusively on the con-
cept of “decreasing risk” of events, not decreasing the for-
mation of plaques. Because atherosclerosis is rarely
genetic in origin (1 in 500), and because the pharmaceu-
tical industry has provided us with truly miracle drugs
for lowering serum LDL cholesterol levels, it is time to
switch gears from the concept of decreasing risk of ather-
osclerotic events to actual prevention of atherosclerotic
plaques. To make this change, the guideline-recom-
mended numbers must be lowered substantially.
According to the published guidelines, initiation of
lipid-modifying drug therapy should be based on the
serum LDL cholesterol level and the presence or absence
of other atherosclerotic risk factors. Lipid-lowering drug
therapy is recommended in people with only 1 or no non-
LDL-cholesterol risk factors if the LDL cholesterol is
>190 mg/dL with a goal of <160 mg/dL. But the most
common LDL cholesterol number in people with heart
attacks is about 140 mg/dL, so this recommendation is
not “preventive.” If >1 non-LDL-cholesterol risk factor is
present, then the LDL cholesterol drug-treatment num-
ber is >160 mg/dL with a goal of <130 mg/dL. If a patient
has a coronary event, however (or is at high risk of an ath-
erosclerotic event such as having diabetes mellitus or a
previous non–coronary atherosclerotic event), the LDL
cholesterol goal is <100 mg/dL (with an “option” of <70
mg/dL). If it is useful for the LDL cholesterol to be <100
mg/dL after a heart attack, surely it must be useful for the
LDL cholesterol to be <100 mg/dL before a heart attack!
Therefore, in my view, the goal for all populations—not
just those with heart attacks or strokes, diabetes mellitus,
or non–coronary atherosclerotic events—must be LDL
cholesterol <100 mg/dL and ideally <70 mg/dL. If such a
goal was created, the great scourge of the Western world
would be essentially eliminated, “primary” and “second-
ary” prevention would be the same, and >100 million
Americans—rather than the present 13 million—would
need to be on a statin drug with or without ezetimibe or
be pure vegetarian fruit eaters.
Thus, although not clearly established at this time, to
prevent atherosclerotic plaques, the serum LDL choles-
terol must be <70 mg/dL, the serum total cholesterol cer-
tainly <150 mg/dL, and the high-density lipoprotein
(HDL) cholesterol >20 mg/dL. The latter—surely a sur-
prise to most readers—is in patients with a serum total
cholesterol level about 130 mg/dL and a LDL cholesterol
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Table 1. Statins and Their Equivalent Efficacious Doses, Their Effects on Total Cholesterol (TC) and Low-Density
Lipoprotein (LDL) Cholesterol, and Effect on LDL Cholesterol by Ezetimibe Alone and in Combination With a Statin
Reduction of Total LDL
LDL by Reduction by
Rosuvastatin Atorvastatin Simvastatin Lovastatin Pravastatin Fluvastatin Reduction Reduction Ezetimibe Statin + Ezetimibe
(Crestor) (Lipitor) (Zocor) (Mevacor) (Pravacol) (Lescol) of TCaof LDLa10 mg 10 mga
1.25b5 10 20 20 40 22% 27% 18% 45%
2.5c10 20 40 40 80 27% 34% 18% 52%
5 20 40 80 80 32% 41% 14% 55%
10 40 80 37% 48% 12% 60%
20 80 42% 55% 10% 65%
40 47% 60% 10% 70%
aThese reductions are ±3%.
bNot available.
cThe 2.5-mg tablet is available in Japan but not in Western countries.
Crestor: AstraZeneca, Wilmington, DE; Lescol: Novartis, Basel, Switzerland; Lititor: Pfizer, New York, NY; Mevacor: Merck, Whitehouse Station, NJ; Pravacol: Bristol-
Myers Squibb, New York, NY; Zocor: Merck, Whitehouse Station, NJ.
Statin (mg)
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Editorial / Roberts 467
level of about 60 mg/dL. Exactly what HDL cholesterol
level is required to prevent plaques is unclear at this time,
but clearly if the LDL cholesterol is very low (eg, 50
mg/dL), then a low HDL cholesterol—as long as it is >20
mg/dL—appears not to be dangerous. Ideal may be equal
serum HDL and LDL cholesterol levels or an HDL cho-
lesterol >LDL cholesterol. In summary, the recom-
mended guideline numbers—particularly those for
primary prevention—are intended for decreasing the risk
of atherosclerosis events, not for preventing formation of
atherosclerotic plaques.
The Rule of 5 and the Rule of 7 in Lipid-
Lowering Therapy and the Goal for All
The statin drugs, in my view, are the best cardiovascular
drugs ever created in that they have the greatest potential
to prevent atherosclerotic plaques and therefore their
complications; statin drugs also have the greatest poten-
tial to arrest plaque formation and therefore to prevent
additional atherosclerotic events. The statin drugs are to
atherosclerosis what penicillin was to infectious diseases.
Despite being truly miracle drugs, they are terribly under-
used and underdosed.
The average serum LDL cholesterol level in American
adults is about 130 mg/dL. Therefore, if we want to pre-
vent plaque formation in the United States, most of us
will need a 50% LDL cholesterol reduction! As shown in
Table 1, that goal can be achieved by 3 doses of statin
monotherapy (rosuvastatin 20 and 40 mg daily or ator-
vastatin 80 mg daily) or by adding ezetimibe 10 mg to all
statin doses except the lowest level of recommended
statin doses. Because titration is often neglected, starting
the dose from the beginning, which achieves the preven-
tive goal (LDL cholesterol <70 mg/dL), appears reason-
able. Most American adults have life insurance, which, in
actuality, is death insurance. The insured pays for the policy,
dies, and then someone else gets the money. The statin
drugs—with or without ezetimibe—represent true life
insurance. The taker of the drug lives longer and is able
to provide for his/her family longer. These drugs are safe.
(Myopathy occurs in only 1 in 10,000 persons.) The risk
of taking the drug is far less than the atherosclerotic con-
sequences that might occur from not taking the drug! Of
course, a vegetarian fruit diet is the least expensive and
safest means of achieving the plaque-preventing LDL
goal, but few in the Western world are willing to live on
the herbivore diet. If we did so, however, we would pre-
vent the daily killing in the United States of 100,000
cows, of 300,000 pigs, and of 15 to 20 million chickens!
Thanks to the pharmaceutical industry, we now have the
armamentarium to change our cardiovascular health. We
will not do so by waiting to treat our serum LDL choles-
terol levels until an atherosclerotic event occurs, or by
using guidelines such as LDL cholesterol >190 or >160
mg/dL before lipid-lowering drug therapy is initiated. The
blowing up of balloons, the placing of stents in our arter-
ies, or the performing of bypass operations (with all of
their damaging incisions, such as median sternotomy)
can be prevented or their need enormously reduced if the
statin drugs with or without ezetimibe are used in proper
doses to produce serum LDL cholesterol levels low
enough to where atherosclerotic plaques do not form.
Life insurance policies are often purchased by individuals
in their 20s. Statin drugs with or without ezetimibe can
be started at the same time because they—along with
antihypertensive drugs—represent true life insurance.
And to smoke cigarettes, to eat excess calories, not to put
on a seatbelt in an automobile or airplane, or to ride a
motorcycle or not to control our cholesterol numbers is
simply not to use our brain as it was intended to be used!
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... Although some investigators have considered cholesterol the cause of atherosclerosis for several decades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), 26 authors, mainly from Europe, in April 2017 published an article titled "Lowdensity lipoproteins cause atherosclerotic cardiovascular disease," a consensus statement from the European Atherosclerosis Society Consensus Panel (16). I was glad to see the article that soundly supports the view that cholesterol is the cause of atherosclerosis. ...
... Although some investigators have considered cholesterol the cause of atherosclerosis for several decades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), 26 authors, mainly from Europe, in April 2017 published an article titled "Lowdensity lipoproteins cause atherosclerotic cardiovascular disease," a consensus statement from the European Atherosclerosis Society Consensus Panel (16). I was glad to see the article that soundly supports the view that cholesterol is the cause of atherosclerosis. ...
... Studying atherosclerosis at necropsy or after endarterectomy has convinced Roberts that the only real long-term therapy for the Western world's number one disease is prevention. Although the Framingham investigators and others have convinced most physicians and the lay public that atherosclerosis is a multifactorial disease, Roberts is convinced that the disease has a single cause, namely cholesterol, and that the other so-called atherosclerotic risk factors are only contributory at most (9)(10)(11)(12)(13). As shown in Figure 1, most of the risk factors do not in themselves cause atherosclerosis. ...
This review tries to answer the following 15 questions: Is atherosclerosis a systemic or a regional disease? Is atherosclerosis in any particular region focal or diffuse? What is the quantity of atherosclerotic plaques in endarterectomy specimens of the right coronary artery in patients undergoing coronary artery bypass grafting (CABG) compared to that in the right coronary artery in patients with fatal coronary artery disease? How do the units used for measuring arterial narrowing by angiography compare to the units used for measuring arterial narrowing at necropsy? What do atherosclerotic plaques consist of in coronary arteries in patients with fatal coronary disease? What is the quantity of atherosclerotic plaque in bypassed -vs- non-bypassed native coronary arteries in patients dying early (<60 days) or late (>60 days) after coronary artery bypass grafting? What is the frequency of acute coronary lesions and multi-luminal channels at necropsy in patients with unstable angina pectoris, sudden coronary death, and acute myocardial infarction? What is the mechanism of luminal widening by angioplasty in the coronary arteries? What observations suggest that atherosclerotic plaques are the result at least in part of organization of thrombi? Is atherosclerosis a multifactoral or a unifactoral disease? What characteristics distinguish carnivores and herbivores? What are reasonable guidelines for whom to treat with lipid-altering agents? What is the rule of 5 and the rule of 7 in statin therapy? What is the effect of lipid lowering drug therapy on coronary luminal narrowing? What are some requisites for a healthy life?
Cardiovascular disease and type 2 diabetes are uncommon in people consuming vegetarian and vegan diets. Vegetarian and vegan dietary patterns tend to result in lower body weight and better nutritional profiles than conventional healthy eating patterns and have been shown to be an effective tool for management of cardiovascular disease and diabetes risk. The consistency of observed beneficial outcomes with vegetarian and vegan eating styles warrants the expansion of dietary guidelines for prevention and treatment of cardiovascular disease and diabetes to include well-planned vegetarian dietary patterns as a viable alternative to conventional dietary treatments.
Panax quinquefolium saponins (PQS), a water-soluble antioxidant extracted from a natural herb, radix panacis quinquefolii (American Ginseng), has yielded encouraging results in the treatment of atherosclerotic diseases. However, the underlying mechanisms remain unclear. Here, we tested the hypothesis that the anti-atherosclerotic effect of PQS might be mediated by suppressing human monocyte-derived dendritic cells (DCs) maturation. DCs were derived by incubating purified human monocytes with granulocyte macrophage colony stimulating factor (GM-CSF) and IL-4. DCs were pre-incubated with or without PQS and stimulated by oxidized low density lipoprotein (ox-LDL). Expression of DCs membrane molecules (CD40, CD86, CD1a, HLA-DR) and endocytotic ability were analyzed by FACS, cytokines (IL-12 and TNF-α) were measured by ELISA. Nuclear factor (NF)-κB signaling pathway was determined by Western blotting, and RT-PCR. NF-κB activation was quantified by ELISA. PQS reduced ox-LDL induced immunophenotypic expressions (CD40, CD1a, CD86, and HLA-DR) and cytokine secretions (IL-12 and TNF-α), and improved endocytotic ability of DCs. These above phenomena were accompanied by decreased protein expression and binding activity of nuclear localized c-Rel subunit. Our study suggested that PQS inhibited ox-LDL induced immune maturation of DCs in vitro, which might be in part mediated by NF-κB signal transduction pathway.
To investigate the association between hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) and mood disturbance. The confirmation that high serum cholesterol levels increase the risk of coronary heart disease has resulted in statins becoming the most widely prescribed drugs in the treatment of hypercholesterolaemia. However, a positive relationship between low serum cholesterol levels and increased non-illness mortality from accidents and suicide has been reported. Eight papers reporting the effect of statins on one or more of six mood states: depression, anxiety, anger, hostility, fatigue, confusion and vigour in adults older than 18 years were identified from a search of Cinahl, Medline and Cochrane electronic databases. The review focused on studies where the outcome of interest was self-reported mood disturbance as non-illness mortality is problematic. Three papers reported some evidence of a positive association with depression, whilst another reported a decreased incidence of depression and the remainder reported no association. Of the six papers which studied anxiety, only one reported a statistically significant decrease in the incidence of anxiety. Two out of six papers reported increased aggression with statin usage, with one study further indicating a stronger effect with lypophylic statins. In contrast one paper reported an outcome of decreased hostility. This review found conflicting evidence of a relationship between statins and mood. Further research is recommended in particular with older, female and lower socioeconomic samples. However, nurses should be alert to the risk and ready to intervene in cases of mood disturbance.
The preventive and therapeutic effects of eicosapentaenoic acid (EPA) on diet-induced hyperlipidemia in rabbits have been investigated. Eighteen New Zealand rabbits were randomly divided into three groups of 6 subjects each; experimental group-I (EG-I) was administered a cholesterol rich diet, experimental group-II (EG-II) was treated with EPA (300 mg/kg/d) following a cholesterol-rich diet and the control group (CG) had a standard diet. Blood samples were collected at day 0 and at the 4th and 12th weeks of EG-II to obtain serum levels of total cholesterol (TC), high density lipid-cholesterol (HDL-C), low density lipid-cholesterol (LDL-C) and triglyceride (TG). From each group tissue samples were collected from the carotid artery for immunohistochemistry and electron microscopy. Our results showed that EPA could significantly lower (p<0.001) serum TC, LDL-C, HDL-C and TG levels with a reduction of 35%; 55%; 44% and 51%, respectively. Scanning and transmission electron microscopy results revealed that endothelial damage was more prominent in EG-I when compared to EG-II. The ruptured endothelial lining and damaged cellular surface was increased in EG-I when compared to EG-II. Ultrastructural observations showed that after EPA treatment, the degeneration and cellular surface damage on the endothelium were also decreased. These biochemical and ultrastructural results suggest that EPA is a potential drug which significantly lowers the serum lipid profile and partially repairs endothelial dysfunction due to hyperlipidemia.
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