Simopoulos AP, De Meester F (eds): A Balanced Omega-6/ Omega-3 Fatty Acid Ratio, Cholesterol and Coronary
Heart Disease. World Rev Nutr Diet. Basel, Karger, 2009, vol 100, pp 90–109

 

 

 

 

Cholesterol Was Healthy in the End

Uffe Ravnskov
Magle Stora Kyrkogata 9, Lund, Sweden
ravnskov@tele2.se

 

 

 

 

 

The idea that a high intake of saturated fat and a high cholesterol concentration in the
blood lead to atherosclerosis and cardiovascular disease emanates from a variety of
sources. When considered together, it is understandable that a whole world of doctors
and medical scientists have embraced the diet-heart idea and the cholesterol hypothesis,
in particular because two of the main supporters, Joseph Brown and Michael
Goldstein, have been honored with the Nobel Prize.
      According to Karl Popper, a scientific theory is genuinely scientific only if it is possible
to create falsifiable predictions; no number of positive outcomes is able to prove
a scientific theory, whereas contradictory and reproducible observations show that
the theory is false. By this definition, the diet-heart idea and the cholesterol hypothesis
indeed satisfy Popper’s criteria, because there are a large number of observations
that are falsifiable, and indeed have been falsified again and again, as will be shown
in the following:

1 A high intake of saturated fat raises blood cholesterol.
2 Cholesterol is a main constituent of atherosclerotic plaques.
3 Premature atherosclerosis is seen in animals with hereditary, or dietary induced,
hypercholesterolemia.
4 High cholesterol is a risk marker for coronary heart disease (CHD).
5 People with familial hypercholesterolemia (FH) run a greater risk of dying from
CHD.
6 Cholesterol lowering prevents cardiovascular disease.

      But it is also obvious that as soon as we start analyzing them, we find that all of
them have been falsified again and again. Great problems also arise when we try to
explain the pathogenic mechanisms, but let me start by reviewing the most striking
falsifications.
 

The Effect of Saturated Fat on Blood Cholesterol

The idea that saturated fat raises blood cholesterol was originally based on a number
of short-term laboratory studies. In a review from 1973, Reiser pointed at several
types of methodological and interpretational errors [1]. Instead of natural saturated
fat, many authors had used vegetable oils saturated by hydrogenation, and effects on
cholesterol were attributed to increased or decreased intakes of saturated fat when it
could be due to opposite changes of the intake of polyunsaturated fat.
      In spite of these flaws, most authors maintain that saturated fat raises cholesterol,
whereas monounsaturated and in particular polyunsaturated fat lowers it, and some
saturated fatty acids are neutral [2–7]. These conclusions have been based mainly on
mathematical formulas using data from a large number of trials. But as most trial
directors have introduced similar types of bias, for instance by changing the intake of
several fats at the same time without controlling for intake of trans fat, it is obviously
difficult to rule out the effect of each type of fat.
      No association has been found either in cross-sectional studies between total cholesterol
(tC) or low-density lipoprotein cholesterol (LDL-C) and the intake of saturated
fat, determined by questionnaires and interviews [9]. Also contradictory is that
populations who live almost entirely on animal food have the lowest cholesterol ever
measured in healthy people [10–12].
      The strongest falsifications come from the controlled, randomized dietary trials. In
a review of eight such trials, where the intake of saturated fat was reduced by 30–40%,
the net reduction of tC was only 0–4% [13], and in more recent trials, where carbohydrates
were substituted with saturated fat, not even intakes between 20 and 50% of
calories influenced tC or LDL-C [14–23].
      As cardiovascular disease is strongly associated with the concentration of small,
dense LDL than with other lipid fractions, it is also contradictory that the intake of
saturated fat is inversely associated with LDL size [24].
 

The Effect of Saturated Fat on Cardiovascular Disease

In a study considered as the strongest argument for the diet-heart idea, Keys selected
16 cohorts in seven countries and found a weak association between intake of saturated
fat and the prevalence and 5-year incidence of coronary mortality. But within
each country, there were great differences although intake of saturated fat was similar.
Coronary mortality for instance was three times higher in Karelia than in West
Finland and more than sixteen times higher on Corfu than on Crete [25].
      Other epidemiological observations have been just as contradictory. More than
twenty cohort studies found no difference between the intake of saturated fat in
patients with CHD and healthy controls [9, 26]; and in seven of ten such studies
stroke patients had eaten less [27–36].
      A relevant objection against such studies is that dietary information is inaccurate.
More reliable are analyses of fat tissue, because intake of saturated fat during the last
weeks or months is reflected by the concentration of the short chain fatty acids 12:0–
15:0 in fat cells [37–41]. Using this method, no difference was found between patients
with CHD and healthy controls; in two studies, the content of the short-chain fatty
acids was even significantly lower in the patients [42–46], and no association was
found with degree of atherosclerosis, determined either by autopsy [47] or by coronary
angiography [48]. These studies concerned only patients with first myocardial
infarction or patients who were not on a diet, and a diet bias is therefore unlikely.
      The most important argument for causality is improvement or disappearance of the
disease after a decrease or discontinuation of the exposure to the suspected causal factor.
Two meta-analyses of the clinical trials where the only intervention was a change
of dietary fat found no effect, either on cardiovascular or total mortality [9, 49, 50].
      Angiographic trials have given disparate results. In two studies, progress of the vascular
changes was associated with the intake of saturated fat, but both of them were
multifactorial, because in addition to lowering the intake of saturated fat, patients in
the treatment group were also instructed to eat more fish, fruit and vegetables [51,
52]. In contrast, a highly significant inverse association was found between intake of
saturated fat and progress of angiographic lesions in a 3-year follow-up study of 235
postmenopausal women with CHD [53]. No dietary advice was given in that study;
instead, the participants’ diets were recorded meticulously.
      Two randomized, controlled dietary trials have succeeded in lowering both heart
and total mortality by changing dietary fat. However, the effect was most likely due to
an increased intake of omega–3 polyunsaturated fat, and it concerned sudden death
only, not coronary death, and the effect was not due to cholesterol lowering, because
no lowering was achieved [54, 55].
 

The Effect of High Cholesterol on Atherosclerosis 

It is true that hypercholesterolemic rodents develop atherosclerosis, but it is also true
that although these experimental models have been used for about 100 years, no one
has ever been able to produce an occluding thrombus or a myocardial infarction by
this method, and there is little evidence, if any at all, that high cholesterol causes
atherosclerosis in man. If too much cholesterol should cause atherosclerosis, people with
high cholesterol should be more atherosclerotic than people with low cholesterol, and
the progress of atherosclerosis in a cholesterol-lowering trial should depend on the
degree of cholesterol lowering, but this is not so.
      Already in 1936, Landé and Sperry falsified the first prediction. In a study of a
large number of healthy people who had died violently, they found that on average
those with low cholesterol were just as atherosclerotic as those with high cholesterol
[56], and their result has been confirmed by others [57–61]. Weak associations have
been present between blood cholesterol and degree of atherosclerosis in studies of
selected patient groups. As these groups mainly included patients with cardiovascular
diseases, individuals with FH must have been much more frequent than in unselected
cohorts. In accordance, the associations disappeared after exclusion of people with
extremely high cholesterol, or the association was inconsistent and present in small
subgroups only [62–72] (table 1).
     The second prediction is false as well. With a single exception, dose-response
between degree of cholesterol lowering and the angiographic changes has not been
found in any cholesterol-lowering trial [73]. In observational angiographic studies,
no or even an inverse association was found between the spontaneous changes of
cholesterol and the degree of progress [74–77].


The Effect of High Cholesterol on Cardiovascular Disease 

If high cholesterol leads to CHD or ischemic stroke, people with these diseases should
have higher cholesterol than others before the arrival of their disease, and the outcome
of a trial should depend on the degree of cholesterol lowering. Also these predictions
have been falsified in countless studies.
      High cholesterol was found to be a risk factor for CHD for the first time in the
Framingham project. However, at the 30-year follow-up, it appeared that high cholesterol
was not a risk factor after age 47. Even more contradictory was that both coronary
and total mortality was higher in those whose cholesterol had decreased during
these years than in those whose cholesterol had increased. ‘For each 1% mg/dl drop of
cholesterol there was an 11 percent increase in coronary and total mortality’ [78]. It is
not too farfetched to assume that, being taken care of by the Framingham researchers,
most of these people had been on cholesterol lowering treatment, which adds further
strength to this falsification.
      Since then, numerous studies have shown that for most populations high cholesterol
is not a risk factor. They included Canadian men [79], diabetics [80–93], patients with
renal failure [94, 95], patients who already had CHD [96–101], and almost all studies
have found that it is not a risk factor for women [102] or for old people either [103].
Indeed, old people with high cholesterol live longer than old people with low cholesterol
[104–120]. The two last-mentioned falsifications are particularly strong, because
at least in Sweden more than 90% of all cardiovascular deaths occur after age 65.
 

The Effect of High Cholesterol in Familial Hypercholesterolemia 

If high cholesterol is the cause of atherosclerosis and early CHD in FH, those with the
highest values should of course be at greater risk than those whose cholesterol is only
a little higher than normal. This is not so, however.

 

Table 1. Studies of the association between the concentration of cholesterol in the blood and degree of
atherosclerosis at autopsy 

Study Type of investigated individuals Association between blood cholesterol and degree of atherosclerosis
Landé and Sperry [56] Healthy people who have died none
Paterson et al. [57]

unselected group of war veteran s

none
Mathur et al. [58) healthy people who have died
from accidents		 none
Marek et al. [59] healthy people who have died
from accidents		 none if those with very high cholesterol were excluded
Schwartz et al. [60] unselected hospital patients none for women, weak for men
Méndez and Tejada [61 healthy people who have died from accidents none
Rhoads et al. [62] a selection of hospital patients very weak
Feinleib et al (63) a selection of dead people men: very weak; women: none
Sadoshima et al. (64) a selection of dead people
Oalman et al. [65] a selection of dead people Black people: none
White people: none if those with very high
cholesterol were excluded
Sorlie et al. [66] a selection of dead people coronary arteries: weak
aorta: very weak
Solberg et al. [67, 68] a selection of dead people weak
Okumiya et al. [69] a selection of dead people weak
Reed et al. [70] a selection of dead people large arteries: weak
small arteries: none
Reed et al. [71] a selection of dead people coronary arteries: weak (tC)
cerebral arteries: none (tC)
none anywhere for LDL-C

   At least eight studies have shown that neither the incidence nor the prevalence of
cardiovascular disease is associated with the lipid levels [121–128]; in one of these
studies, mean cholesterol was even lower in those who died from CHD [125]. A striking
fact is also that in people with FH and severe atherosclerotic changes in their
coronary arteries, no changes were seen in the cerebral arteries [129, 130].
     That the vascular changes in FH are independent of blood cholesterol was noted even
by Brown and Goldstein. In a 1983 paper, they wrote the following: ‘Among patients
with FH (both heterozygous and homozygous), there is considerable variation in the
rate of progression of atherosclerosis, despite uniformly elevated LDL levels’ [132].
     The number of those who die at a young age from CHD is not very large either.
In the Simon Bromee study, the authors followed almost 3,000 individuals with FH
for many years and found that their mean life span was similar as for normal British
citizens of the same age and sex; more died from heart disease, but fewer died from
cancer and other diseases [133].
    A possible cause of cardiovascular disease in FH may be inborn errors of the coagulation
system. In cohort studies of people with FH, plasma fibrinogen and factor VIII
were significantly higher in those with CHD than in those without [134], whereas tC
and LDL-C did not differ significantly. Recently, Kastelein’s group found that polymorphism
in the prothrombin gene is strongly associated with cardiovascular risk in
people with this disorder [128]. The reason why statin treatment is of benefit in FH
may therefore be their antithrombotic effects, not their effect on cholesterol.


The Effect of Cholesterol Lowering 

If high cholesterol causes cardiovascular disease, the most important prediction is
that its lowering alone should reduce that risk. Most studies used as support before
the statins were introduced were multifactorial. But a meta-analysis of all controlled
and randomized cholesterol lowering trials performed before the advent of the statins
found no effect on coronary mortality, and total mortality was increased [135].
     That cholesterol lowering by the HMG coenzyme A inhibitors is able to lower the
risk of cardiovascular disease in high-risk patients is seen as evidence of the cholesterol
hypothesis. However, and as mentioned above, no trial has found any association
between the degree of cholesterol lowering and the clinical or angiographic outcome;
those whose cholesterol was lowered a little only had the same small benefit as those
whose cholesterol was lowered by more than 50%. Lack of exposure response means
that the statins must have other effects that are more beneficial than cholesterol lowering,
as suggested already after the publication of one of the first clinical statin trials
[136], and several such effects have indeed been documented.
     But even if the lowering of cholesterol by these drugs were unimportant, there
should have been exposure response between cholesterol and outcome, because both
the pleiotropic effects and cholesterol lowering are caused by the same drug. A more
complete blockage of the mevalonate pathway should result in stronger pleiotropic
effects and a more pronounced lowering of cholesterol, and vice versa. As this was
not the case, the findings imply that high cholesterol is protective and that its lowering
therefore counteracts exposure response. There is indeed much support to that
interpretation.   

Table 2. Studies of the lipoprotein immune system 

Study Microbial product Source of lipoprotein Methods used to demonstrate inactivation and/or binding of the microbial products by the lipoproteins
Stollerman et al. [140] Streptolysin S man inhibition of streptolysin S
Stollerman et al. [140] Streptolysin S man

same                          

Skarnes (141) (S- enteritides) rodents immunodiffusion
Shortridge et al. [142] Togaviruses man inhibition of hemagglutination
Whitelaw et al. [143] S. aureus δ-hemolysin man  inhibition of δ-hemol ysin
Freudenberg et al. [144] S. abortus equi;
S. minnesota 		rat crossed immunoelectrophoresis
Ulevitch et al. [145] LPS (S. minnesota) rabbit binding of LPS to apoA1
Bhakdi et al. [146 S. aureus α-toxin man hemolytic titration; EM
Seganti et al. [147] Rhabdovirus man inhibition of hemagglutination
van Lenten et al. [148] LPS (Escherichia coli) man, rabbit inhibition of scavenger receptor
Huemer et al. [149] herpes simplex man E M
Flegel et al. [150] LPS (E. coli) man inhibition of endotoxin activation
Cavaillon et al. [151] LPS (E. coli) rabbit inhibition of cytokine respon se
Northoff et al. [152] LPS (?) man inhibition of cytokine response
Superti et al. [153] SA rotavirus man inhibition of viral hemagglutina- tion and replication; EM
Weinstock et al. [154] LPS (S. typhi) man inhibition of endotoxin production
Flegel et al. [155] LPS (S. typhi) man inhibition of endotoxin production
Feingold et al. [156] LPS (E. coli) man endotoxin sensitivity
Netea et al. [157] (LPS) E. coli) mouse LD50 after experimental infection

          

The Lipoprotein Immune System 

It is little known that the lipoproteins partake in the immune system. For many years,
a normal serum factor, named antistreptolysin S because it was able to neutralize the
hemolytic effects of streptolysin S, was considered to be an antibody. In 1937, Todd et
al. [137] found that it did not behave as a normal antibody because its titer fell below
normal values in patients with rheumatic fever at the peak of the clinical symptoms,
and a few years later, Stollerman and Bernheimer noted that, in contrast to the anti-
streptococcal antibodies, the antistreptolysin S titer did not rise above its normal level
during convalescence [138]. Humphrey discovered that antistreptolysin S was located
within the lipid fraction of the blood [139], and Stollerman et al. [140] identified it
as a phospholipoprotein complex. Since then, at least a dozen research groups have
established that antistreptolysin S is identical with the lipoproteins and constitutes a
nonspecific host defense system able to bind and inactivate not only streptolysin S but
also other endotoxins and several virus species as well (table 2) [139–157]. In rodents,
the main bulk of cholesterol is transported by high-density lipoprotein (HDL), and
in these species HDL has the main protective effect [144, 145], whereas most human
studies have found that all lipoproteins participate in the nonspecific defense system.
     The immunoprotective role of the lipoproteins has been shown by their inhibition
of the biological effects of various microorganisms and endotoxins, such as hemagglutination,
hemolysis, the cytokine response of human monocytes, and virus replication
(table 2).
     That lipoproteins also form complexes with microbial products was shown first
by Skarnes [141]. By using immunodiffusion with anti-endotoxin and serum from
various rodents that had been injected with Salmonella enteridis endotoxin, he demonstrated
lipoprotein-positive staining and esterase activity on the precipitation lines.
Using crossed immunoelectrophoresis, Freudenberg and Galanos [144] found that
the HDL peak of rat plasma changed position after injection with various lipopolysaccharides
(LPS), and Ulevitch et al. [145] found evidence of complex formation
between LPS from Salmonella minnesota and apoprotein A1, the major protein of
rabbit HDL.
     Bhakdi et al. [146] have documented that human lipoproteins complex with microbial
components as well. By electron microscopy (EM), they found that the inactivation
of Staphylococcus aureus α-toxin by purified human LDL led to oligomerization
of 3S native toxin molecules into ring structures of 11S hexamers that adhered to the
LDL molecules.
     Lipoproteins also form complexes with viruses. Thus, using various techniques
Huemer et al. [149] found that all lipoprotein subclasses were able to bind purified
herpes simplex virus, as demonstrated by EM, enzyme-linked immunoabsorbance
assay technique, and column chromatography. Superti et al. [153] confirmed that all
human subclasses of lipoproteins were able to inhibit the infectivity and hemagglutination
by SA-11 rotavirus, and complex formation was visualized by EM.
     The lipoprotein immune system may be particularly important in early childhood
as, in contrast to antibody-producing cells, this system works immediately and with
high efficiency. For instance, human LDL inactivated up to 90% of S. aureus α-toxin
[146], and it inactivated an even larger fraction of bacterial LPS [150]. In agreement
with these findings, hypocholesterolemic rats injected with LPS had a markedly
increased mortality compared with normal rats, which could be ameliorated by
injecting purified human LDL [156]. On the other hand, hypercholesterolemic mice
challenged with LPS or live bacteria had an 8-fold increased LD50, compared with
normal mice [157]. That high levels of lipoproteins protect against infectious diseases
is also evident from clinical and epidemiological studies.
 

The Benefits of High Cholesterol 

If the lipoproteins have an immunoprotective role, high cholesterol should be an
advantage, not a risk factor, and there is indeed many observations in support. Thus,
a meta-analysis of 19 cohort studies including almost 70,000 deaths found an inverse
association between tC and mortality from respiratory and gastrointestinal diseases,
most of which are of an infectious origin [102]. It has been argued that low cholesterol
was secondary, but this explanation was disproved by Iribarren et al. [158, 159]. They
followed more than 20,000 healthy individuals for 15 years and found a strong inverse
association between tC and the risk of being admitted to hospital because of an infectious
disease. The association included all types of infection, and it was statistically
significant for most of them. As regards respiratory diseases, the association was significant
for pneumonia and influenza, but not for asthma. As all of the participants
were healthy at the start, it is obvious that their low cholesterol could not be secondary
to a disease they had not yet manifested.
     There is evidence that subclinical infections participate in chronic heart failure. In
accordance, patients with heart failure and low cholesterol run a greater risk of premature
death than patients with high cholesterol [160]. Low cholesterol is also a risk
factor for HIV and AIDS [161, 162], hepatitis B [163], and for death due to an infectious
disease in patients with chemotherapy-induced neutropenia [164].
     The protective role of high cholesterol is also evident from observations in people
with inborn errors of cholesterol metabolism. For instance, the frequent and severe
infections in children with extremely low cholesterol that are found in the Smith-
Lemli-Opitz syndrome are alleviated by the addition of cholesterol to their diet
[165].
     Even in FH, a high cholesterol seems to protect against infections. Thus, before the
year 1900, when infectious diseases were the commonest cause of death, the life span
of people with a 50% risk of having FH was longer than for other people [166].
Cholesterol and Cancer
     Many cohort studies have found that low cholesterol is a risk factor for cancer. The
usual explanation is that cancer causes low cholesterol because cholesterol is consumed
by the cancer cells. However, in the Framingham project low cholesterol was
a risk factor for cancer even after 18 years of follow-up [167], and as mentioned,
cancer mortality in people with FH is lower than in the general population. Many
observations are also in better accord with the opposite interpretation that low cholesterol
predisposes to cancer.
     First, in a review of cholesterol-lowering experiments in laboratory animals, the
authors concluded that most studies produced cancer [168]. As this effect was seen
also after nonstatin drugs, and as no chromosomal aberrations were noted in the animals,
there is reason to suspect that the culprit was not the drugs, but rather their
effect, the lower concentration of cholesterol; an interpretation that is supported by
epidemiological observations and human experiments.
     In 4S, the Scandinavian Simvastatin Survival Study [169], and in HPS, the Heart
Protection Study [170], the two first simvastatin trials, nonmelanoma skin cancer was
observed more often in the treatment groups. The difference was statistically significant
when the results from both studies were combined (in the simvastatin groups,
256 of the 12,490 participants, and in the control groups, 208 of the 12,490 participants;
p = 0.028). For unknown reasons, the number of nonmelanoma skin cancers
has not been reported in any of the trial reports that followed.
     The clinical appearance of a cancer depends on its location. Lung cancer, for
instance, is not diagnosed until after decades of smoking, whereas superficial nonmelanoma
cancers may be observed much earlier. An increased number of patients
with skin cancer in a trial is therefore alarming because this is the first cancer type
that we should expect to find under conditions of general carcinogenicity.
     In CARE, the Cholesterol and Recurrent Events Trial [171], 12 of the 286 women
in the pravastatin group but only 1 of the 290 in the placebo group had breast cancer
at follow-up (p = 0.002). Again, breast cancer is a superficial malignancy that is easier
to observe and should therefore occur much earlier than for instance a cancer located
in the pancreas. Furthermore, several of these breast cancers were recurrences, and
recurrences may appear earlier than primary cancers. However, it is not possible to
test the hypothesis that cholesterol lowering by statin treatment may provoke recurrences
because after the publication of the CARE report, previous cancer has become
an exclusion criterion in all trials.
     Dormant cancer is a common finding in elderly people, and a carcinogenic effect
should therefore appear earlier in that patient group. Indeed, in the PROSPER trial [172],
which included elderly people only, 245 of the 2,891 participants in the pravastatin group
but only 199 of the 2,913 in the placebo group had new cancer. The difference was already
obvious after 1 year, and it increased steadily during the trial period to become statistically
significant (p = 0.02) after 4 years. The authors claimed that a meta-analysis of all
pravastatin trials did not confirm a carcinogenic effect. This is not reassuring because
the mean age in these trials was about 25 years lower than in the PROSPER trial.
     In a cohort study of 47,294 Japanese patients treated with low-dose simvastatin
and followed for 6 years, the authors found that the number of cancer deaths was
significantly higher in patients whose tC at follow-up was less than 160 mg/dl than
in those whose cholesterol was 200–219 mg/dl (relative risk = 3.16; 95% CI = 1.72 to
5.81; p = 0.001) [173].
     Another argument in support of carcinogenicity is a report by Iwata et al. [174],
who found that recent or previous statin treatment was seen twice as often in patients
with lymphoid cancer compared with patients admitted to the hospital for noncancer
diseases. Again, lymphoid cancer belongs to the types of malignancies that are easy to
diagnose at an early stage.
     Several authors have claimed that statin treatment prevents cancer. However, a bias
is introduced by the method used in these studies because in all of them patients on
statin treatment were compared with untreated individuals. The first group is a selection
of people who initially had high cholesterol, which has been lowered for a few
years only; the second is dominated by people who might have had low cholesterol for
most of their life and are therefore at an increased risk of cancer.


The Pathogenic Mechanism 

Today, most researchers agree that atherosclerosis starts as an inflammation in the
arterial wall. What is also common knowledge is that the starting point of the occluding
thrombosis is the vulnerable plaque. Therefore, any credible hypothesis must be
able to explain how and why the inflammation starts and how a vulnerable plaque is
created.
     According to the current view, the first step is endothelial dysfunction or damage
caused by hypercholesterolemia or other toxic factors in the circulation allowing the
migration of LDL-C and monocytes into the arterial wall. Here, LDL is said to be
modified by oxidation leading to an accumulation of T cells and the production of
LDL autoantibodies. Modified LDL is taken up by macrophages that are converted to
lipid-laden foam cells, considered as the early lesion of atherosclerosis. The inflammatory
processes, probably aggravated by antigens from microbes such as chlamydia,
herpes simplex and cytomegalovirus, are followed by smooth muscle cell proliferation
and the synthesis of extracellular matrix. The macrophages may become overloaded
and die resulting in the creation of a vulnerable plaque that by bursting initiates the
formation of an occluding thrombus [175]. There are a number of contradictions to
this hypothesis, however.
     There is no association between the concentration of LDL-C in the blood and the
degree of endothelial dysfunction [176]; the atherosclerotic plaques seen in extreme
hyperhomocysteinemia due to inborn errors of methionine metabolism do not contain
any lipids in spite of pronounced endothelial damage [177].
     A more likely mechanism is that aggregated complexes formed by lipoproteins
and microorganisms or their toxins may occlude vasa vasorum of the major arteries
because of the high extracapillary pressure, resulting in local ischemia, liberation of
microorganisms that are attached to the complexes and the formation of a microabscess,
the vulnerable plaque. Rupture of the latter may result not only in local clot
formation around the rupture, but also in an emptying of the microbial content of the
vulnerable plaque into the circulation [178].
     Extensive aggregation may occur in severe infections, and it may be furthered by
hyperhomocysteinemia, because homocysteine thiolactone, the reactive cyclic anhydride
of homocysteine, reacts with free amino groups of protein to form peptidebound
homocysteine [179]. In accordance, in vitro experiments have shown that
thiolated LDL becomes aggregated and subject to spontaneous precipitation in vitro
[180]. Thiolated and oxidized LDL may also stimulate the formation of anti-LDL
autoantibodies [181], furthering complex formation and aggregation.
     As macrophages take up aggregated LDL by phagocytosis after modification by
vortexing or by digestion with phospholipase C [182], they may do it with LDL molecules
modified by complex formation, oxidation or thiolation as well and in this way
be converted to foam cells. In support of that, in vitro experiments have shown that
LPS from Chlamydia pneumoniae [181] and also from several periodontal pathogens
[182] is able to convert macrophages to foam cells in the presence of human LDL.
     The suggested mechanism explains how cholesterol enters the arterial wall, the
many associations between cardiovascular and infectious diseases and the similarities
between their clinical and laboratory symptoms and signs, why many bacterial and
viral remnants are present in atherosclerotic lesions [183, 184], why neutrophils are
found in the vulnerable plaques but not in the stable, fibrous plaques [185], why the
temperature of vulnerable plaques is higher than that of its surroundings [186], why
leucocytes are found preferably around vasa vasorum [187], and why bacteremia and
sepsis are often seen in myocardial infarction complicated with cardiogenic shock
[188].
     The hypothesis is open for falsification as well. Viable microorganisms and endotoxins
in the arterial wall should be located within developing vulnerable plaques.
Arteries of germ-free animals should have fewer foam cells and fatty streaks than
their conventionally reared littermates.
     A blood culture should be taken in all patients with unstable angina or myocardial
infarction, and we anticipate that if it is positive, the course of the disease should be
improved with an appropriate antibiotic.
 

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