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Vulnerable Plaque Formation from Obstruction of Vasa Vasorum by Homocysteinylated and Oxidized Lipoprotein Aggregates Complexed with Microbial Remnants and LDL Autoantibodies

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Vulnerable Plaque Formation from Obstruction of Vasa Vasorum by Homocysteinylated and Oxidized Lipoprotein Aggregates Complexed with Microbial Remnants and LDL Autoantibodies

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Little attention has been paid to the function of lipoproteins as part of a nonspecific immune defense system that binds and inactivates microbes and their toxins effectively by complex formation. Because of high extra-capillary tissue pressure, aggregates of such complexes may be trapped in vasa vasorum of the major arteries. This complex formation and aggregation may be enhanced by hyperhomocysteinemia, because homocysteine thiolactone reacts with the free amino groups of apo-B to form homocysteinylated low-density lipoprotein (LDL), which is subject to spontaneous precipitation in vitro. Obstruction of the circulation in vasa vasorum, caused by the aggregated complexes, may result in local ischemia in the arterial wall, intramural cell death, bursting of the capillary, and escape of microorganisms into the intima, all of which lead to inflammation and creation of vulnerable plaques. The presence of homocysteinylated LDL and oxidized LDL stimulates production of LDL autoantibodies, which may start a vicious circle by increasing the complex formation and aggregation of lipoproteins. The content of necrotic debris and leukocytes and the higher temperature than its surroundings give the vulnerable plaque some characteristics of a micro-abscess that by rupturing may initiate an occluding thrombosis. This suggested chain of events explains why many of the clinical symptoms and laboratory findings in acute myocardial infarction are similar to those seen in infectious diseases. It explains the presence of microorganisms in atherosclerotic plaques and why bacteriemia and sepsis are often seen in myocardial infarction complicated with cardiogenic shock. It explains the many associations between infections and cardiovascular disease. And it explains why cholesterol accumulates in the arterial wall. Some risk factors may not cause vascular disease directly, but they may impair the immune system, promote microbial growth, or cause hyperhomocysteinemia, leading to vulnerable plaques.
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Review and Hypothesis:
Vulnerable Plaque Formation from Obstruction of Vasa Vasorum
by Homocysteinylated and Oxidized Lipoprotein Aggregates
Complexed with Microbial Remnants and LDL Autoantibodies
Uffe Ravnskov
1
and Kilmer S. McCully
2,3
1
Independent Investigator, Magle Stora Kyrkogata 9, 22350 Lund, Sweden;
2
Pathology and Laboratory
Medicine Service, Boston Veterans Affairs Healthcare System, West Roxbury, MA;
3
Department of
Pathology, Harvard Medical School, Boston MA, USA.
Abstract. Little attention has been paid to the function of lipoproteins as part of a nonspecific immune
defense system that binds and inactivates microbes and their toxins effectively by complex formation.
Because of high extra-capillary tissue pressure, aggregates of such complexes may be trapped in vasa vasorum
of the major arteries. is complex formation and aggregation may be enhanced by hyperhomocysteinemia,
because homocysteine thiolactone reacts with the free amino groups of apo-B to form homocysteinylated
low-density lipoprotein (LDL), which is subject to spontaneous precipitation in vitro. Obstruction of the
circulation in vasa vasorum, caused by the aggregated complexes, may result in local ischemia in the arterial
wall, intramural cell death, bursting of the capillary, and escape of microorganisms into the intima, all of
which lead to inflammation and creation of vulnerable plaques. e presence of homocysteinylated LDL
and oxidized LDL stimulates production of LDL autoantibodies, which may start a vicious circle by
increasing the complex formation and aggregation of lipoproteins. e content of necrotic debris and
leukocytes and the higher temperature than its surroundings give the vulnerable plaque some characteristics
of a micro-abscess that by rupturing may initiate an occluding thrombosis. is suggested chain of events
explains why many of the clinical symptoms and laboratory ndings in acute myocardial infarction are
similar to those seen in infectious diseases. It explains the presence of microorganisms in atherosclerotic
plaques and why bacteriemia and sepsis are often seen in myocardial infarction complicated with cardiogenic
shock. It explains the many associations between infections and cardiovascular disease. And it explains
why cholesterol accumulates in the arterial wall. Some risk factors may not cause vascular disease directly,
but they may impair the immune system, promote microbial growth, or cause hyperhomocysteinemia,
leading to vulnerable plaques.
Keywords: vulnerable plaque, lipoprotein aggregates, vasa vasorum, hyperhomocysteinemia, microbial
remnants, autoimmunity, oxidized LDL
Introduction. ere is general agreement that
atherosclerosis begins as an inflammatory process
in the arterial wall, and also that rupture of a
vulnerable plaque is the starting point for the
creation of the occluding thrombus in myocardial
infarction and ischemic stroke [1,2]. erefore, any
hypothesis about the cause of atherosclerosis and its
consequences must necessarily be able to point to
the origin of the inflammation and to explain how
a vulnerable plaque is created [3].
According to the current view, the rst step is
endothelial dysfunction or damage caused by
hypercholesterolemia, hyperhomocysteinemia, or
other toxic factors in the circulation, allowing the
migration of LDL, cholesterol, and monocytes into
the arterial wall. LDL is modified by oxidation,
Address correspondence to Kilmer S. McCully, M.D.,
Veterans Aairs Medical Center, West Roxbury, MA 02132,
USA; tel 857 203 5990; fax 857 203 5623; email kilmer.
mccully@med.va.gov.
0091-7370/09/0100-0003. $4.80. © 2009 by the Association of Clinical Scientists, Inc.
Available online at www.annclinlabsci.org
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
3
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. e inflammatory process,
probably aggravated by antigens from microbes
such as Chlamydia, Herpes simplex and Cytomegalo-
virus, is followed by smooth muscle cell proliferation
and the synthesis of extracellular matrix. e
macrophages may become overloaded with lipids
and die, resulting in the creation of a vulnerable
plaque that by rupturing initiates the formation of
an occluding thrombus [4].
is suggested chain of events is based mainly
on epidemiological observations and experimental
models, where vascular changes similar to human
atherosclerosis have been produced in rodents with
inherited or dietary hypercholesterolemia. How-
ever, it conflicts with many clinical, epidemio-
logical, pathological, and experimental observations.
ere are in particular six disturbing facts:
1. e concept that high LDL cholesterol causes
endothelial dysfunction is unlikely because there is
no association between the concentration of LDL
cholesterol in the blood and the degree of endothelial
dysfunction [5].
2. e concept that endothelial damage leads to
influx of LDL cholesterol is unlikely as well, because
the atherosclerotic plaques seen in extreme hyper-
homocysteinemia caused by inborn errors of
methionine metabolism do not contain any lipids
in spite of pronounced endothelial damage [6,7].
3. No study of unselected individuals has found
an association between the concentration of LDL
or total cholesterol in the blood and the degree of
atherosclerosis at autopsy [8].
4. In studies of women and the elderly, hyperchol-
esterolemia is a weak risk factor for cardiovascular
disease, or, in most cases, not a risk factor at all [9],
although the large majority of cardiovascular deaths
occur in people above 65 years of age.
5. Among individuals with familial hyperchol-
esterolemia (FH) there is no association between
LDL-cholesterol and the prevalence or the progress
of cardiovascular disease [10-15]. e higher
coronary mortality in young people with FH may
instead be due to inherited abnormalities of the
coagulation system, often seen in FH and a strong
risk factor for coronary heart disease in this
population [15,16].
6. With one exception [17], an occluding coronary
thrombus has never been produced experimentally
in rodents by hypercholesterolemia alone [3],
indicating that the pathological process in these
models may differ from that in human beings.
Origin of vulnerable plaques. In the following
discussion we present a new interpretation of the
origin of vulnerable plaques that we think is in
better agreement with presently available evidence.
is interpretation is based on the fact that the
lipoproteins function as a nonspecific immune
system that binds and inactivates microorganisms
and their toxins by complex formation. In the case
of a massive microbial invasion, these complexes
may aggregate, in particular in the presence of
hyperhomocysteinemia, because homocysteine
thiolactone causes aggregation and precipitation of
thiolated LDL [18]. Complex formation and
aggregation may also be enhanced by autoantibodies
against thiolated LDL and oxidized LDL. Because
of high extra-capillary tissue pressure, the aggregates
may be trapped in arterial vasa vasorum, resulting
in local vascular ischemia, intramural cell death,
and the creation of vulnerable plaques.
Such plaques have many characteristics of a
micro-abscess, which, by rupturing, initiates the
occluding thrombosis and releases its content of
infectious material into the circulation and the
myocardium. is suggested chain of events
explains why many of the clinical symptoms and
laboratory findings in acute myocardial infarction
are similar to those seen in infectious diseases. It
also explains the frequent presence of microbial
remnants in atherosclerotic plaques, the many
associations between infections and cardiovascular
disease, the similarities between myocarditis and
myocardial infarction, and why cholesterol
accumulates in the arterial wall.
e microbial hypothesis. A century ago, bacteria
and viruses were considered as the main cause of
atherosclerosis, a view that was based mainly on
post-mortem observations. us, ayer reported
a high frequency of arterial lesions in patients who
died from typhoid fever and a high prevalence of
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
4
hardened radial arteries in those who survived [19].
Wiesel found an association between the degree of
atherosclerosis in people who had died from an
infectious disease and the length of the preceding
infection [20], and Osler described the vulnerable
plaque as an atherosclerotic pustule [21]. e
following statement by Klotz and Manning is
typical for the general view at that time: “ere is
every indication that the production of tissue in the
intima is the result of a direct irritation of that
tissue by the presence of infection or toxins[22].
e molecular mechanisms were unknown and
because of the chemical composition of advanced
atherosclerotic plaques, more recent research has
instead focused on cholesterol.
However, in addition to and in accordance
with the older findings, much epidemiological,
clinical, laboratory, and experimental evidence has
more recently been reported, suggesting that
infectious processes may play a role in cardiovascular
disease [23-27]. Cardiovascular mortality increases
during influenza epidemics [28]. A third of patients
with acute myocardial infarction or stroke have
had an infectious disease immediately before onset
[29]. Bacteriemia and periodontal infections are
associated with an increased risk of cardiovascular
disease [30,31]. Serological markers of infection
are often elevated in patients with cardiovascular
disease and are also risk factors for such diseases
[32]. A role of infectious agents is suggested by the
narrowing of the coronary arteries seen in children
who died from an infectious disease [33] and from
thickening of carotid intima-media on high-
resolution ultrasound in those who survived [34].
e lipoprotein immune system. A normal serum
factor is able to neutralize the hemolytic effects of
streptolysin-S, and, for this reason, the factor was
named antistreptolysin-S and was previously
considered to be an antibody. However, this
concept was questioned in 1939 by Todd et al, who
found that this serum factor 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 [35]. A few years later,
Stollerman and Bernheimer also found that, in
contrast to the antistreptococcal antibodies, the
antistreptolysin-S titer did not rise above its normal
level during convalescence [36]. At the same time,
Humphrey discovered that antistreptolysin-S was
located within the lipid fraction of the blood [37].
Stollerman et al identified antistreptolysin-S as a
phospholipoprotein complex [38]. 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
[39-55] (Table 1). In rodents, cholesterol is mostly
transported by high-density lipoprotein (HDL),
and in these species HDL has the main protective
effect [42,43], whereas human studies have
generally found that all lipoproteins participate in
the nonspecific defense system.
Most investigators have identified the
immunoprotective role of the lipoproteins by
demonstrating inhibition of the biological effects
of various microorganisms and endotoxins, such as
hemagglutination, hemolysis, the cytokine response
of human monocytes, and virus replication.
Skarnes first suggested that the lipoproteins also
form complexes with microbial products [39]. By
using immunodiusion with anti-endotoxin and
serum from various rodents that had been injected
with Salmonella enteridis endotoxin, he demon-
strated lipoprotein-positive staining and esterase
activity on the precipitation lines.
Using crossed immunoelectrophoresis, Freud-
enberg et al found that the HDL peak of rat plasma
changed position after injection with various
lipopolysaccharides (LPS); they concluded that the
effect was due to the formation of a complex
between LPS and HDL [42]. By separating a
mixture of rabbit plasma and LPS from Salmonella
minnesota by column chromatography with
sepharose linked with LPS antibody, Ulevitch et al
found that the eluate from the bound material
contained both LPS and apoprotein A1, the major
protein of rabbit HDL [43]. ere is strong evidence
that human lipoproteins complex with microbial
components as well. By electron microscopy (EM)
Bhakdi et al found that the inactivation of
Staphylococcus aureus alpha-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 [44].
Vulnerable plaques from lipoprotein aggregates
5
Lipoproteins also form complexes with viruses.
Huemer et al found that all lipoprotein subclasses
were able to bind purified Herpes simplex virus, as
demonstrated by EM, enzyme-linked immuno-
absorbence assay, and column chromatography
[47]. Superti et al confirmed that all human
subclasses of lipoproteins were able to inhibit the
infectivity and hemagglutination by SA-11 rota-
virus, and complex formation was visualized by
EM [51].
e 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
Staphylococcus aureus alpha-toxin [44], and it
inactivated an even larger fraction of bacterial
lipopolysaccharide (LPS) [48]. In agreement with
these ndings, hypocholesterolemic rats injected
with LPS had a markedly increased mortality
compared with normal rats, which could be
ameliorated by injecting purified human LDL [54].
On the other hand, hypercholesterolemic mice
challenged with LPS or live bacteria had an
eightfold increase of LD
50
, compared with normal
mice [55].
Hudgins et al demonstrated that high-
molecular weight lipoproteins not only bind LPS,
but lipoproteins disappear from the general
circulation in infected human beings [56]. ey
injected a small dose of LPS in normal volunteers
and demonstrated the expected rise of the usual
inflammatory markers and a fall of total cholesterol,
LDL-cholesterol and apo-B, whereas concentrations
of HDL-cholesterol and apo-A1 were unchanged.
e formation of complexes between
lipoproteins and microbial products may lead to
aggregation of lipoprotein particles. In case of a
Table 1. Binding of microbial products by lipoproteins.
Ref. Microbial product LDL HDL VLDL All Source Methods used to demonstrate inactivation
lipoproteins of lipo- and/or binding of the microbial products
proteins by the lipoproteins
37 Streptolysin S ++ human Inhibition of streptolysin S
38 Streptolysin S ++ ++ human Inhibition of streptolysin S
39 LPS; S. enteritides ++ rodents Immunodiffusion
40 Togavirus ++ + +++ human Inhibition of hemagglutination
41 S. aureus δ-hemolysin ++ ++ human Inhibition of δ-hemolysin
42 S. abortus equi; ++ rat Crossed
S. minnesota 0 ++ 0 rat immunoelectrophoresis
43 LPS; S. minnesota 0 ++ 0 rabbit Binding of LPS to apoA1
44 S. aureus a-toxin ++ 0 human Hemolytic titration; EM
45 Rhabdovirus ++ (+) ++ human Inhibition of hemagglutination
46 LPS; E. coli ++ ++ ++ human, rabbit Inhibition of scavenger receptor
47 Herpes simplex ++ ++ ++ human EM
48 LPS; E. coli ++ human Inhibition of endotoxin activation of
human monocytes
49 LPS; E. coli ++ + ++ rabbit Inhibition of cytokine-response of
human monocytes
50 LPS (?) ++ ++ 0 human Inhibition of cytokine-response of
human monocytes
51 SA Rotavirus ++ ++ ++ human Inhibition of viral hemagglutination
and replication; EM
52 LPS; S. typhi ++ human Inhibition of endotoxin production
53 LPS; S. typhi ++ (+) 0 human Inhibition of endotoxin production
54 LPS; E. coli ++ human Endotoxin sensitivity
55 LPS; E. coli ++ mouse LD
50
after experimental infection
A semiquantitative review presents the binding and inhibitory effects of low-density (LDL), high-density (HDL), and very low-
density (VLDL) lipoprotein on various microbes and bacterial toxins. In 5 studies the total effects of all lipoproteins together
were examined. Abbreviations: electron microscopy (EM); lethal dose 50% (LD
50
); lipopolysaccharide (LPS); apolipoprotein
A1 of high-density lipoprotein (ApoA1).
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
6
massive invasion of microorganisms, the size of
such aggregates, especially those composed of the
high-molecular weight VLDL and LDL, may
impede their passage through capillary networks,
in particular the vasa vasorum of the artery walls,
because of high extra-capillary tissue pressure.
Indeed, aggregated lipid structures similar to the
size of LDL have been demonstrated by electron
microscopy in the extracellular space beneath fatty
streaks [57].
Recent reviews [58,59] summarized the evidence
that both LPS and lipoteichoic acid (the Gram-
positive counterpart of LPS) form aggregates in
solution. In addition, sphingolipids interact with
bacterial toxins, and all lipoproteins isolated from
animals treated with LPS contain high levels of
sphingolipids (ceramide), which promote lipo-
protein aggregation.
An unsettled question concerns the nature of
the process that converts macrophages into lipid-
laden foam cells, one of the main factors in
production of atherosclerotic lesions. Normally
excess cellular uptake of cholesterol is counteracted
by down-regulation of the LDL receptor, indicating
that another pathway must be responsible for foam
cell formation. According to the current view,
oxidized LDL cholesterol in the arterial wall is
taken up by the scavenger receptor of macrophages,
allowing an unlimited uptake of cholesterol,
independent of the LDL receptor. However, macro-
phages also take up aggregated LDL by phagocytosis
after modification by vortexing or by digestion
with phospholipase C [60]. LDL that is modified
by complex binding with microbial products is also
taken up by the same process, because in vitro
experiments have shown that LPS from Chlamydia
pneumoniae [61] and also from several periodontal
pathogens [62] is able to convert macrophages to
foam cells in the presence of human LDL.
A direct attack of microorganisms or their
products on the endothelium, as often suggested,
seems unlikely, as demonstrated by Madjid et al
[63]. In a post-mortem study of 27 patients with
coronary atherosclerosis, 14 of whom had had a
systemic infection within two weeks before death,
luminal coronary thromboses and myocardial
infarction were found in 5 of the infected patients.
ey found that the number of macrophages in the
infected group was much greater in the adventitia
than around the plaques, whereas no difference was
noted in the uninfected control group, which
suggests that the microbes arrive via vasa vasorum.
In agreement with this view, Guyton et al found
that extracellular lipid deposits are almost entirely
located deep within the intima, close to the vasa
vasorum and well below most of the foam cell lipid
[57]. is finding opposes the view that the lipid-
rich core region of plaques originates primarily
from the debris of dead intimal foam cells, but the
finding agrees with the spontaneous athero-
thrombosis observed in genetic double knockout
mice [64]. ese thrombi were demonstrated on
the surface of atherosclerotic lesions similar to
human vulnerable plaques, accompanied by marked
medial degeneration and invasion of inflammatory
cells into the adventitia.
During the oxidative breakdown of microbial
material inside macrophages, cholesterol is partially
oxidized and returned to the liver by HDL, and the
cholesterol content of fibrous plaques is not higher
than in normal arterial tissue [65]. Indeed, several
HDL processes that are able to convert oxidized
LDL cholesterol to free cholesterol have been
identified [66]. Also, esterified cholesterol may be
converted to free cholesterol by microbial processes
[67] and deposited as extracellular cholesterol
crystals found deep within the intima [57].
Hyperhomocysteinemia and autoimmunity.
Homocysteine thiolactone, the reactive cyclic
anhydride of homocysteine, reacts with free amino
groups of protein to form peptide-bound
homocysteine [68]. e process of homocysteinyl-
ation of proteins is termed thiolation, because this
reaction produces a free sulfhydryl group within
the peptide-bound homocysteine molecule. Homo-
cysteine thiolactone reacts with the free amino
groups of apoB protein of LDL [69]. When an
increased concentration of homocysteine
thiolactone reacts with human LDL, the thiolated
LDL becomes aggregated and subject to spontaneous
precipitation [18]. LDL aggregates are phagocytosed
by cultured human macrophages, forming foam
cells with greatly increased cholesterol and
cholesterol ester content.
Vulnerable plaques from lipoprotein aggregates
7
It was suggested [18] that thiolation of LDL
would also alter its antigenic properties and lead to
autoantibody formation. Ferguson et al showed
that thiolated LDL is immunogenic in rabbits,
producing a polyclonal antibody recognizing
thiolated LDL [70]. Antibodies to N-thiolated
serum albumin were demonstrated in patients with
coronary heart disease [71,72]. iolated LDL is
present in human serum at low concentration
(0.04-0.1%), but autoantibodies to human thiolated
LDL have not been reported [73].
e possibility that autoantibodies against
thiolated LDL may play a role in the creation of
atherosclerosis is suggested by other observations.
Hyperhomocysteinemia, a potent risk factor for
atherosclerosis, is found in autoimmune diseases,
such as lupus erythematosus, rheumatoid arthritis,
Behcet’s disease, inflammatory bowel disease, and
myelodysplastic syndrome [74]. ese diseases all
are characterized by increased susceptibility to
vascular disease and activation of immunity and
inflammation. Homocysteine activates cytokines
and pro-inflammatory molecules, such as IL-1beta,
IL-6, IL-12, IL-18, IL-1 receptor antagonist, C-
reactive protein (CRP), adhesion molecules (P-
selectin, E-selectin, ICAM-1), and metallo-
proteinases (MMP-9). Homocysteine up-regulates
reactive oxygen species, leading to NF-kappaB
activation [74]. CRP binds oxidized LDL and
oxidized phospholipids, enhancing phagocytosis to
form foam cells [75].
Oxidized LDL and autoimmunity. Oxidized LDL
(OxLDL) has long been considered as the main
culprit in atherosclerosis. OxLDL stimulates the
production of autoantibodies, but the role of anti-
OxLDL has been controversial because its titer
does not reflect or predict cardiovascular disease
[76-80]. We envision that anti-OxLDL antibodies
may aggregate and participate in the obstruction of
vasa vasorum. erefore, the reason the titer of
anti-OxLDL does not reflect cardiovascular disease
may be that the expected increased level of anti-
OxLDL in patients with cardiovascular disease is
counteracted by a decrease in anti-OxLDL level
because of the accumulation and aggregation of
circulating anti-OxLDL within vasa vasorum of
arteries. In support of this concept, Schumacher et
al found that patients with acute myocardial
infarction and a marked elevation of plasma
creatine kinase had a significant decrease of anti-
OxLDL during the acute phase, whereas this
phenomenon was not seen in patients with only a
minor elevation of creatine kinase [81]. Su et al
found an inverse association between the
concentration of anti-OxLDL and progress of
atherosclerosis in hypertensive patients, measured
as change of the maximum carotid intima-media
thickness, suggesting that anti-OxLDL is protective
against atherogenesis [82]. is interpretation may
be correct in healthy, non-infected people without
hyperhomocysteinemia. However, the association
may also be explained by the disappearance from
the circulation of anti-OxLDL immune complexes
by their aggregation with LDL within vasa vasorum,
because the association was significant for IgM
subclasses only, and the much larger size of such
complexes may render them more susceptible to
aggregation. is interpretation may also explain
the recent finding that low levels of IgM antibodies
against phosphorylcholine, a component of inflam-
matory phospholipids known to cause OxLDL-
related immune reactions, are associated with a
greater risk of ischemic stroke [83].
Creation of the vulnerable plaque. Obstruction of
the vasa vasorum by aggregated lipoprotein
complexes may increase the vulnerability of the
cells that they nourish and lead to cell death because
of localized ischemia of the vascular wall. Vasa
vasorum may rupture, and the aggregated LDL
particles with their load of microbial products will
enter the arterial wall. ese products may include
living microorganisms, because viable Chlamydia
pneumoniae have been cultured from atherosclerotic
plaques by Ramirez [84] and Jackson et al [85].
Probably this is a common phenomenon, because
Maass et al identified viable Chlamydia pneumoniae
in 11 of 70 atheromas, whereas none was present in
17 non-atherosclerotic control samples [86]. e
presence of Chlamydia pneumoniae in human
coronary plaques was confirmed by electron
microscopy [87,88]. ese organisms were also
demonstrated within adventitia by immunohisto-
chemical staining and polymerase chain reaction
(PCR) for microbial DNA, presumably arriving via
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
8
monocytes migrating from vasa vasorum [89].
Other living microorganisms may be present as
well, but to our knowledge no successful isolations
from human plaques have been reported.
Indirect evidence of a role of living micro-
organisms in the creation of vulnerable plaques was
presented by Grattan et al [90]. ey found graft
failure because of accelerated atherosclerosis in
two-thirds of 91 cardiac transplant patients infected
with Cytomegalovirus, but only in one-third of 209
non-infected patients.
With a healthy immune system, the micro-
organisms may be eliminated, new capillaries will
enter the lesion, and reparative processes will
convert the dead tissue into a stable, fibrous plaque.
But in case of an insufficient clearing of the
Fig. 1. Development of the vulnerable plaque. e small globules inside the vasa vasorum and in the vulnerable plaque represent
lipoproteins; the black dots represent microorganisms, endotoxins, 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.
e 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. e 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.
9
Flow chart for development of the vulnerable plaque
Microorganisms and spores continually invade the body through the airways, skin and gastro-
intestinal system, and some of them or their toxic products are bound and inactivated by complex
formation with lipoproteins. In the case of a major microbial invasion, the complexes may aggregate.
Hyperhomocysteinemia may increase the complex formation and aggregation through thiolation
of LDL. Autoantibodies against oxidized and thiolated LDL, aggregated LPS, and lipoteichoic
acid, and complexes between sphingolipids and bacterial toxins may further increase the size of the
accumulated lipoprotein complexes. Because of their size and because of high extra-capillary tissue
pressure, the aggregated complexes are trapped within vasa vasorum of the major arteries.
Monocytes entering either via the endothelium or via vasa vasorum are converted to macrophages,
which take up the aggregates by phagocytosis, forming foam cells.
Foam cells
Normal immune system
e foam cells probably move back to the
circulation. Before re-entering the arterial
lumen, they are seen as fatty streaks just
beneath the endothelium. e micro-
organisms and their products are destroyed
inside the macrophages by oxidation. By
this process both cholesterol and LDL are
oxidized as well. In case of a massive
microbial invasion, some of the foam cells
may die, but more macrophages arrive, new
capillaries are formed, and the surrounding
tissue is strengthened by proliferation of
smooth muscle cells and fibrous tissue.
Stable, fibrous plaque
Disturbed immune system
Vasa vasorum become obstructed, leading
to ischemia of the arterial wall, foam cell
death, and release of their content into
artery wall. Microorganisms and endo-
toxins enter the dead tissue, the capillaries
are damaged, erythrocyte extravasation
may occur, and a micro abscess is created.
Vulnerable plaque
e vulnerable plaque ruptures. Choles-
terol and microbial products are emptied
into the coronary artery and transported
to the heart and the general circulation.
A thrombus is built at the margins of the
burst plaque.
Partial occlusion Total occlusion
Unstable angina Myocardial infarction
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
10
[97], an observation needing corroboration from
future studies.
Fatty streaks are not necessarily the precursors
of atherosclerotic plaques. Fatty streaks are present
in the fetus and are more frequent in early than
late childhood [98,99], presumably reflecting a
normal and reversible response to infections.
Hydrodynamic pressure is usually cited as the
reason that atherosclerosis is localized only within
systemic arteries. is explanation is probably
correct, not because the arterial pressure damages
the endothelium, but because the lipoprotein
complexes are trapped more easily in vasa vasorum
of the systemic arteries where the tissue pressure is
much higher than within vasa vasorum around the
veins and the pulmonary arteries. By the same
reasoning, atherosclerotic plaques are localized to
areas of the intimal surface where the hydrodynamic
forces, turbulence of blood flow, and tissue pressure
are especially high, namely at the branching points
of arteries, within tortuous arteries, and within
coronary arteries that are compressed by myocardial
contractions. Whereas normal pulmonary arteries
are generally free of atherosclerosis, they develop
atherosclerotic intimal plaques in various conditions
that lead to pulmonary hypertension. Current
concepts of the anatomy and physiology of vasa
vasorum [100] emphasize that these vessels are
functionally end arteries, supplying the media to a
depth where blood flow and patency are compressed
by pressure transmitted from the arterial lumen.
e predilection for plaques within systemic
arteries also contradicts the idea that microbes
attack the endothelium directly, because if this
were so, atherosclerosis would be just as common
in veins. Also the focal occurrence of atherosclerotic
lesions is in better accordance with a microbial
genesis, because if elevated LDL cholesterol were
the most important cause, atherosclerosis should be
a more generalized disease.
e increased incidence of cardiovascular events
found after treatment with rofecoxib and other
non-steroidal anti-inflammatory drugs [101]
contradicts the idea that atherosclerosis is caused
by the inflammation itself, but it is in accord with
an infectious origin of atherosclerosis, where
inflammation is a necessary step for healing. e
ability of HMG-coenzyme A reductase inhibitors
microorganisms and the ensuing inflammatory
response, cell death may accelerate and impede
repair processes, creating a vulnerable plaque, the
preferential site for occluding thrombi [91]. e
suggested chain of events is illustrated in Fig. 1 and
in a flow chart (page 10).
Clinical and pathological observations. According
to our hypothesis, LDL-cholesterol does not enter
the artery through the endothelium as suggested
previously, but via the capillary web of vasa vasorum
in and around the arterial walls. Oxidation of LDL
does not take place before LDL has entered the
macrophage but occurs after phagocytosis, as part
of a normal physiological process explaining why
attempts to prevent cardiovascular disease by
antioxidants have been largely unsuccessful.
Some reasons for considering the vulnerable
plaque to be a type of micro-abscess are that more
than one plaque may occur simultaneously [91,92],
and their temperature is higher than that of the
surrounding tissue [93]. Whereas neutrophilic
polymorphonuclear leukocytes, the hallmark of
pyogenic infections, are rare in stable plaques, they
are always found in and around the core of
vulnerable plaques, and there are just as many
neutrophils in the intact as in the ruptured plaques
[94], contradicting the assumption that their
presence is secondary to rupture.
Our interpretation explains the clinical and
laboratory similarities between myocardial infarc-
tion and myocarditis [95], and it explains the
frequent occurrence of bacteriemia and sepsis in
myocardial infarction complicated with cardiogenic
shock [96]. It explains why fever, diaphoresis,
leukocytosis and elevation of inflammatory markers
in the blood, including CRP, the classical symptoms
of an infectious disease, are common findings in
myocardial infarction. Chronic elevation of CRP
in patients with atherosclerosis is a risk factor for
myocardial infarction. Our interpretation agrees
with the almost constant nding of polymorpho-
nuclear leukocytes in the myocardium in acute
myocardial infarction, as well as in infarctions of
other organs. It also explains a recent report of
Chlamydia pneumoniae antigens within cardiomyo-
cytes of patients with fatal myocardial infarction
Vulnerable plaques from lipoprotein aggregates
11
(statins) to prevent cardiovascular disease, in spite
of their non-steroidal anti-inflammatory properties,
is probably attributable to their other pleiotropic
effects, including the enhancement of fibrinolysis
and nitric oxide production, and the inhibition of
platelet activation.
An apparent contradiction to our interpretation
is that prevention of cardiovascular disease by
antibiotics has been largely unsuccessful. However,
in these trials patients have usually received a single
antibiotic, chosen because it was effective against
Chlamydia pneumoniae, the organism that has been
studied most intensively, and the trials have been of
relatively short duration.
Chlamydia pneumoniae is not the only microbe
that is found in atherosclerotic plaques. Ott et al
identified fragments from >50 different microbial
species within atherosclerotic plaques, but not a
single one in normal arterial tissue [102]. On
average, each patient had microbial remnants from
12 different species; some patients had more, some
had fewer [102], and other investigators have found
various virus species as well [103-105]. It is highly
unlikely that a single antibiotic could eliminate
>50 different microbial species. It is not even likely
that antibiotics could eliminate Chlamydia pneu-
moniae, because this species is able to survive inside
living cells, where they are resistant to the effects of
antibiotics [106]. Furthermore, antibiotics are
generally ineffective against viral infections.
Whether the total burden of multiple microbial
invasions or the effect of a single pathogen is the
key to progression remains to be determined [107].
Evidence that high cholesterol is protective. Since
LDL participates in the immune system, high
plasma cholesterol concentrations should be an
advantage to survival, not a risk. ere is much
evidence that high cholesterol is protective against
infectious diseases. Plasma cholesterol levels have
been found to be inversely associated with total
mortality in the elderly and with mortality from
respiratory and gastrointestinal diseases [9], most
of which have an infectious origin. Cholesterol
levels are also inversely associated with mortality
after post-operative abdominal infections, inversely
associated with the risk of being admitted to
hospital because of an infectious disease, and
inversely associated with the risk of contracting
HIV and AIDS [9].
e protective effect of plasma cholesterol levels
is also supported by observations in patients with
inherited disorders of cholesterol metabolism.
Before the year 1900, when infectious disease was
the commonest cause of death, the life span of
people with 50% risk of having familial hyperchol-
esterolemia (FH) was longer than in the general
population [108]. e frequent and severe infections
in children with the extremely low cholesterol levels
that are found in Smith-Lemli-Opitz syndrome are
alleviated by addition of cholesterol to the diet
[109].
e lack of an association between the degree
of cholesterol lowering and outcome that were
found in clinical and angiographic trials [8] could
be explained if the benefits from HMG-coenzyme
A reductase inhibitors (statins) were due to their
pleiotropic effects and not to their inhibition of the
cholesterol synthesis. Even if the lowering of LDL
cholesterol by these drugs were unimportant, there
should have been an exposure-response relationship
between LDL-cholesterol and outcome, because
both the pleiotropic effects and cholesterol lowering
are caused by inhibition of the mevalonate pathway.
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 ndings
imply that high cholesterol is protective and that its
lowering therefore counteracts exposure-response.
is view is in accordance with the trial ndings
and our present interpretation of these findings.
Similar events in other arteries. If an imbalance
between the microbial burden and the immune
system contributes to coronary heart disease, other
parts of the artery system should be affected as well,
and this seems to be true. Stroke and myocardial
infarction commonly occur in the same patient,
and vulnerable plaques in the carotid arteries are
the starting point of thrombosis in cerebral infarcts
[110]. In a consecutive study of the common iliac,
common carotid, and renal arteries of 49 patients
who died in a hospital, those with a history of
cardiovascular events had 2-4 times more intimal
macrophages and a denser network of vasa vasorum
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
12
in all of the arteries than atherosclerotic patients
without cardiovascular events [111]. Foam cells
have been identified adjacent to Bruch´s membrane
of the retina, where their number increases with
the age of patients [112]. Foam cells are also found
in sclerotic glomeruli [113,114]. In addition, adipose
tissue, skin, and muscle specimens from people
over age 70 have about 25% more cholesterol than
those from people age 30, and tendon specimens
have several hundred percent more [115].
Conclusions. Our interpretation of the origin of
vulnerable plaques explains the molecular, cellular,
and tissue processes resulting in atherosclerosis and
cardiovascular disease. Promoting factors may not
necessarily act by damaging the arterial wall
directly, but rather by inhibiting the immune
system, by facilitating microbial growth, by causing
hyperhomocysteinemia, and by promoting complex
formation and aggregation of homocysteinylated
lipoproteins. Our interpretation is in accord with
several of the classical risk factors. Hyperhomo-
cysteinemia is found in B vitamin deficiency,
smoking, hypertension, hypothyroidism, renal
failure, and aging, all classical risk factors for
cardiovascular disease [116]. Mental stress, a well-
known risk factor for cardiovascular disease,
stimulates production of cortisol, and an excess of
cortisol, either from Cushing’s disease of the
adrenal glands or from medical therapy, promotes
infections. Furthermore, mental stress, hostility,
and anger increase the concentration of homo-
cysteine in blood [117,118], potentially promoting
aggregation of LDL particles [18]. Many infectious
diseases are more prevalent in smokers and
diabetics. e suggestion that excess iron is a risk
factor for vascular disease [119] is also in accordance
with our interpretation, because bacterial growth is
stimulated by the presence of free iron [120].
erefore, attempts to prevent cardiovascular
disease and prolong life may be more successful if
we understand the fallacies of the lipid hypothesis
[121] and determine what is harmful to the immune
system and what may strengthen it.
Our interpretation satisfies Karl Popper’s
definition of a scientific hypothesis, because it is
susceptible to falsification:
1. We anticipate that viable microorganisms and
endotoxins in the arterial wall are located within
developing vulnerable plaques.
3. We anticipate that arteries of germ-free, normo-
cholesterolemic animals should have fewer foam
cells and fatty streaks than their conventionally
reared litter mates.
3. 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.
Acknowledgement
We thank Charles F. Foltz, Medical Media Service,
VA Medical Center, West Roxbury MA, for
assistance in preparing the figure.
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Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009
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... At that time, infectious diseases were the commonest causes of death. The reason why the lives of people with FH on average are just as long or longer than those of other people may be that LDL participates in the immune system by adhering to and inactivating almost all types of microorganisms and their toxic products, a little-known fact although it has been documented in various ways by more than a dozen research groups [20]. ...
... It has therefore been suggested that treatment with PCSK9 inhibitors would be able to lower the risk of CVD among people with FH, but hitherto no experiments with clinical outcome have been published. The chance that such treatment may be beneficial is also questionable, because the PCSK9 inhibitors lower LDL-C even more than the statins, and there is much evidence supporting the idea that high LDL-C is beneficial [2][3][4][5]10,20]. ...
Article
Full-text available
For almost a century, familial hypercholesterolemia (FH) has been considered a serious disease, causing atherosclerosis, cardiovascular disease, and ischemic stroke. Closely related to this is the widespread acceptance that its cause is greatly increased low-density-lipoprotein cholesterol (LDL-C). However, numerous observations and experiments in this field are in conflict with Bradford Hill’s criteria for causality. For instance, those with FH demonstrate no association between LDL-C and the degree of atherosclerosis; coronary artery calcium (CAC) shows no or an inverse association with LDL-C, and on average, the life span of those with FH is about the same as the surrounding population. Furthermore, no controlled, randomized cholesterol-lowering trial restricted to those with FH has demonstrated a positive outcome. On the other hand, a number of studies suggest that increased thrombogenic factors—either procoagulant or those that lead to high platelet reactivity—may be the primary risk factors in FH. Those individuals who die prematurely have either higher lipoprotein (a) (Lp(a)), higher factor VIII and/or higher fibrinogen compared with those with a normal lifespan, whereas their LDL-C does not differ. Conclusions: Many observational and experimental studies have demonstrated that high LDL-C cannot be the cause of premature cardiovascular mortality among people with FH. The number who die early is also much smaller than expected. Apparently, some individuals with FH may have inherited other, more important risk factors than a high LDL-C. In accordance with this, our review has shown that increased coagulation factors are the commonest cause, but there may be other ones as well.
... Many studies have shown that high LDL-C is associated with cancer, whereas other studies have found the opposite. In a previous review (2) we have shown that one of the causes of the conflicting findings is that few have realized that the lipoproteins participate in the immune system by adhering to and inactivating almost all types of microorganisms and their toxic products (3) and that 15-20% of human cancers may have a viral or bacterial etiology (4). However, as metastasing cancer cells need much cholesterol, its lowering may perhaps be beneficial in patients with advanced cancer. ...
... This process, called N-homocysteination, is considered as a post-translational modification that severely affects the thiol-dependent redox status of proteins [3,17]. In vivo, N-homocysteination occurs on blood albumin, hemoglobin, transferrin, immunoglobulins, LDL, HDL, antitrypsin and fibrinogen [61][62][63]. The degree of protein N-homocysteination is proportionally associated with an increase in the plasma level of Hcy [3]. ...
Article
Homocysteine (Hcy) is a sulfhydryl-containing amino acid, which is not acquired through the diet, but rather synthesized as an intermediate metabolite in the methionine cycle. Hcy is present in plasma, with normal levels between 5 and 15 μmol/L, a slightly elevated level between 15 to 30 μmol/L, moderate from 30 to 100 μmol/L and a value > 100 μmol/L classified as severe hyperhomocysteinemia (HHcy). HHcy has been associated with inflammation and atherosclerosis and is considered an independent risk factor for cardiovascular diseases (CVD). Here, we review the main evidence showing the association and the possible involvement of HHcy in the most common CVD.
... LDL-C has been suggested to play an important role in host defence against both bacterial and viral pathogens 25 . Many animal and laboratory experiments have shown that LDL could bind to and inactivate a broad range of microorganisms and their toxic products [26][27][28] . It has been proposed that LDL-C may have the potential to protect against cancer as many cancer types are caused by viruses 29 . ...
Article
Full-text available
The association between low density lipoprotein cholesterol (LDL-C) and all-cause mortality has been examined in many studies. However, inconsistent results and limitations still exist. We used the 1999–2014 National Health and Nutrition Examination Survey (NHANES) data with 19,034 people to assess the association between LDL-C level and all-cause mortality. All participants were followed up until 2015 except those younger than 18 years old, after excluding those who died within three years of follow-up, a total of 1619 deaths among 19,034 people were included in the analysis. In the age-adjusted model (model 1), it was found that the lowest LDL-C group had a higher risk of all-cause mortality (HR 1.708 [1.432–2.037]) than LDL-C 100–129 mg/dL as a reference group. The crude-adjusted model (model 2) suggests that people with the lowest level of LDL-C had 1.600 (95% CI [1.325–1.932]) times the odds compared with the reference group, after adjusting for age, sex, race, marital status, education level, smoking status, body mass index (BMI). In the fully-adjusted model (model 3), people with the lowest level of LDL-C had 1.373 (95% CI [1.130–1.668]) times the odds compared with the reference group, after additionally adjusting for hypertension, diabetes, cardiovascular disease, cancer based on model 2. The results from restricted cubic spine (RCS) curve showed that when the LDL-C concentration (130 mg/dL) was used as the reference, there is a U-shaped relationship between LDL-C level and all-cause mortality. In conclusion, we found that low level of LDL-C is associated with higher risk of all-cause mortality. The observed association persisted after adjusting for potential confounders. Further studies are warranted to determine the causal relationship between LDL-C level and all-cause mortality.
... Moreover, there is a subset of elderly people with high LDL-C who live longer than those with low levels [4]. Another potential beneficial effect of increased LDL-C is the inactivation of microorganisms which may explain the reduced mortality from respiratory and gastrointestinal diseases [5,6]. High LDL-C may also play a protective role against cancer, as witnessed by lower cancer mortality in patients with familial hypercholesterolemia. ...
Article
Full-text available
Background Life expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival. Methods This was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013–2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed. Results Overall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found. Conclusions This analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.
... The reason why high LDL-C is beneficial is most likely that LDL participates in our immune system by adhering to and inactivating all types of microorganisms and their toxic products, a little-known fact that has been documented in many ways by more than a dozen research groups [5,6]. ...
... However, the potential mechanism remains to be elucidated. Our findings could be explained by the following: Some experiments have shown that LDL-C could play important anti-infective roles and protect against endotoxin-induced tissue damage [31,32]. Furthermore, some studies have suggested that dysbiosis and altered bile acid metabolism [33][34][35][36] as a common mechanism may operate that links low LDL-C concentration to different disease status. ...
Article
Full-text available
Background and aimsAlthough low-density lipoprotein cholesterol (LDL-C) has been considered as a risk factor of atherosclerotic cardiovascular disease, limited studies can be available to evaluate the association of LDL-C with risk of mortality in the general population. This study aimed to examine the association of LDL-C level with risk of mortality using a propensity-score weighting method in a Chinese population, based on the health examination data.Methods We performed a retrospective cohort study with 65,517 participants aged 40 years or older in Ningbo city, Zhejiang. LDL-C levels were categorized as five groups according to the Chinese dyslipidemia guidelines in adults. To minimize potential biases resulting from a complex array of covariates, we implemented a generalized boosted model to generate propensity-score weights on covariates. Then, we used Cox proportional hazard regression models with all-cause and cause-specific mortality as the dependent variables to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs).ResultsDuring the 439,186.5 person years of follow-up, 2403 deaths occurred. Compared with the median LDL-C group (100–130 mg/dL), subjects with extremely low LDL-C levels (group 1) had a higher risk of deaths from all-cause (HR = 2.53, 95% CI:1.80–3.53), CVD (HR = 1.84, 95% CI: 1.28–2.61), ischemic stroke (HR = 2.29, 95% CI:1.32–3.94), hemorrhagic stroke (HR = 3.49, 95% CI: 1.57–7.85), and cancer (HR = 2.12, 95% CI: 1.04–4.31) while the corresponding HRs in LDL-C group 2 were relatively lower than that in group 1.Conclusions Low LDL-C levels were associated with an increased risk of all-cause, CVD, ischemic stroke, hemorrhagic stroke, and cancer mortality in the Chinese population.
... 4 Moreover, the LDL-C of patients with acute myocardial infarction is lower than normal, and the risk increases if it is lowered even more. 2 The reason for these contradictions to the common view about CVD is most likely that LDL is an important participants in the immune system, 5 and there is much evidence that infectious diseases may increase the risk of atherosclerosis. 6 Further evidence that high LDL-C is not inherently atherogenic was provided in a systematic review of 19 follow-up studies on mortality rate in relation to LDL-C levels. ...
Article
Full-text available
Recently, Polychronopoulos and Tziomalos reviewed research on the use of inclisiran and bempedoic acid in the management of cardiovascular disease (CVD) risk in people with familial hypercholesterolemia (FH).1 Their treatment recommendations were based on the general premise that high LDL-cholesterol (LDL-C) is inherently atherogenic, and that low levels of LDL-C need to be achieved to reduce CVD risk in FH individuals. However, their perspective on LDL-C is flawed at two levels of analysis: 1) They ignored the extensive literature demonstrating that CVD is not caused by high LDL-C;2 and 2) they failed to consider CVD treatment strategies that take into account the extensive literature that has shown that coagulation factors are more closely related to coronary events in FH than is LDL-C.3 In the following, we have briefly addressed each of these flaws in their review.
... One study suggested that low total cholesterol levels may be a biomarker for malnutritionrelated illness in older persons [35], while other studies have reported that higher cholesterol levels were associated with better outcomes in late-life physical function and the ability to recover from illnesses [36,37]. Another possible reason of the inverse association between CVD and LDL-C levels is that CVD may be caused by infections, and high LDL-C levels may be beneficial as LDL is involved in the immune system by adhering to and inactivating all kinds of microorganisms and their toxic products [38,39]. Moreover, the mean LDL-C value in the fourth quartile in this study was 161.6 ± 25.0 mg/dL, which was relatively lower than that in the highest quartile in most studies showing no association between high LDL-C levels and CV mortality [10,11,23,26,40] because older adults who had a medical history of dyslipidemia (including those who had received medications for dyslipidemia) were excluded from this study. ...
Article
Full-text available
Background Dyslipidemia is considered an independent health risk factor of cardiovascular disease (CVD), a leading cause of mortality in older adults. Despite its importance, there have been few reports on the association between lipoprotein cholesterol and future CVD and cardiovascular (CV) mortality among elderly Asians aged ≥ 65 years. This study investigated the association between lipoprotein cholesterol and future CVD and CV mortality in an elderly Korean population using a large nationwide sample. Methods From the cohort database of the Korean National Health Insurance Service, 62,604 adults aged ≥ 65 years (32,584 men and 30,020 women) were included. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were categorized by quartiles. Cox proportional hazard models and linear regression analyses were used to assess the association between the quartiles of lipoprotein cholesterol and future CV events or mortality. Results The mean follow-up period was 3.3 years. The incidence rates of ischemic heart disease and ischemic brain disease were 0.97 and 0.61 per 1,000 person-years, respectively, and the mortality rates from these diseases were 0.22 and 0.34 per 1,000 person-years, respectively. In a completely adjusted model, high HDL-C and LDL-C levels were not associated with total CV events and CVD mortality. However, high LDL-C levels were significantly associated with a lower incidence of ischemic brain disease. Furthermore, diabetic patients with high LDL-C levels were more likely to have higher CV mortality, whereas non-smokers with high LDL-C levels were less likely to be at risk of CV events. Conclusions Neither high LDL-C nor HDL-C levels were significantly associated with future CV mortality in older adults aged ≥ 65 years. High LDL-C levels do not seem to be a risk factor for CVD in elderly individuals, and further studies are required.
... Of further importance is the fact that many studies have shown that low cholesterol is associated with increased mortality from infections [23], probably because LDL-C partakes in the immune system by adhering to and inactivating many microorganisms and their toxic product [24]. This fact is not widely recognised, but it has been documented by more than a dozen research groups [25]. ...
Article
Full-text available
Objective: In a previous review of 19 follow-up studies, we found that elderly people with high Low-Density-Lipoprotein Cholesterol (LDL-C) live just as long as or longer than people with low LDL-C. Since then, many similar follow-up studies including both patients and healthy people of all ages have been published. We have therefore provided here an update to our prior review. Methods: We searched PubMed for cohort studies about this issue published after the publication of our study and where LDL-C has been investigated as a risk factor for all-cause and/or Cardiovascular (CVD) mortality in people and patients of all ages. We included studies of individuals without statin treatment and studies where the authors have adjusted for such treatment. Results: We identified 19 follow-up studies including 20 cohorts of more than six million patients or healthy people. Total mortality was recorded in 18 of the cohorts. In eight of them, those with the highest LDL-C lived as long as those with normal LDL-C; in nine of them, they lived longer, whether they were on statin treatment or not. CVD mortality was measured in nine cohorts. In two of them, it was inversely associated with LDL-C; in five of them, it was not associated. In the study without information about total mortality, CVD mortality was not associated with LDL-C. In two cohorts, low LDL-C was significantly associated with total mortality. In two other cohorts, the association between LDL-C and total mortality was U-shaped. However, in the largest of them (n>5 million people below the age of 40), the mortality difference between those with the highest LDL-C and those with normal LDL-C was only 0.04%. Conclusions: Our updated review of studies published since 2016 confirms that, overall, high levels of LDL-C are not associated with reduced lifespan. These findings are inconsistent with the consensus that high lifetime LDL levels promote premature mortality. The widespread promotion of LDL-C reduction is not only unjustified, it may even worsen the health of the elderly because LDL-C contributes to immune functioning, including the elimination of harmful pathogens.