Dear Ken, interesting paper you presented on your blog today. I did attempt to write a reply but it is long and convoluted and probably not for the average reader….. NO ONE ever said YOU were average!
I have kept up contact with professor Uffe Ravnsjovi (see below) and I value his input. He seriously disagrees with the inflammatory (causitive) theory of heart disease. I am sending you his papers.
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 Ravnskov1 and Kilmer S. McCully2,3
1Independent Investigator, Magle Stora Kyrkogata 9, 22350 Lund, Sweden; 2Pathology and Laboratory Medicine Service, Boston Veterans Affairs Healthcare System, West Roxbury, MA; 3Department 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. 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.
Keywords: vulnerable plaque, lipoprotein aggregates, vasa vasorum, hyperhomocysteinemia, microbial remnants, autoimmunity, oxidized LDL
There 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]. Therefore, 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 .
According to the current view, the first 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, 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 process, probably aggravated by antigens from microbes such as Chlamydia, Herpes simplex and Cytomegalovirus, is followed by smooth muscle cell proliferation and the synthesis of extracellular matrix. The 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 .
This 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. However, it conflicts with many clinical, epidemiological, pathological, and experimental observations.
There are in particular six disturbing facts:
1. The 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 .
2. The concept that endothelial damage leads to influx of LDL cholesterol is unlikely as well, because the atherosclerotic plaques seen in extreme hyperhomocysteinemia 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 .
4. In studies of women and the elderly, hypercholesterolemia is a weak risk factor for cardiovascular disease, or, in most cases, not a risk factor at all , although the large majority of cardiovascular deaths occur in people above 65 years of age.
5. Among individuals with familial hypercholesterolemia (FH) there is no association between LDL-cholesterol and the prevalence or the progress of cardiovascular disease [10-15]. The 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 , an occluding coronary thrombus has never been produced experimentally in rodents by hypercholesterolemia alone , 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.
This 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 . 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. 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 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.
The 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. Thus, Thayer reported a high frequency of arterial lesions in patients who died from typhoid fever and a high prevalence of hardened radial arteries in those who survived .
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 , and Osler described the vulnerable plaque as an atherosclerotic pustule . The following statement by Klotz and Manning is typical for the general view at that time: “There 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” .
The 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 . A third of patients with acute myocardial infarction or stroke have had an infectious disease immediately before onset . Bacteriemia and periodontal infections are associated with an increased risk of cardiovascular disease [30,31]. Serological markers of infection are often elevated in patients with cardiovascular disease and are also risk factors for such diseases. A role of infectious agents is suggested by the narrowing of the coronary arteries seen in children who died from an infectious disease  and from thickening of carotid intima-media on highresolution ultrasound in those who survived .
The 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 . 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 . At the same time, Humphrey discovered that antistreptolysin-S was located within the lipid fraction of the blood .
Stollerman et al identified antistreptolysin-S 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 [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 . 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 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 . 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 . There 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 hexamersthat adhered to the LDL molecules .
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 immunoabsorbence assay, and column chromatography . Superti et al 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 Staphylococcus aureus alpha-toxin , and it inactivated an even larger fraction of bacterial lipopolysaccharide (LPS) . 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 .
On the other hand, hypercholesterolemic mice challenged with LPS or live bacteria had an eightfold increase of LD50, compared with normal mice .
Hudgins et al demonstrated that highmolecular weight lipoproteins not only bind LPS, but lipoproteins disappear from the general circulation in infected human beings . They 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. The 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 LD50 after experimental infection
A semiquantitative review presents the binding and inhibitory effects of low-density (LDL), high-density (HDL), and very lowdensity
(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% (LD50); lipopolysaccharide (LPS); apolipoprotein A1 of high-density lipoprotein (ApoA1).
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 .
Recent reviews [58,59] summarized the evidence that both LPS and lipoteichoic acid (the Grampositive 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 lipoprotein aggregation.
An unsettled question concerns the nature of the process that converts macrophages into lipidladen 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, macrophages also take up aggregated LDL by phagocytosis after modification by vortexing or by digestion with phospholipase C . 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  and also from several periodontal pathogens  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. 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.
They 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. This finding opposes the view that the lipidrich core region of plaques originates primarily from the debris of dead intimal foam cells, but the finding agrees with the spontaneous atherothrombosis observed in genetic double knockout mice . These 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 . Indeed, several HDL processes that are able to convert oxidized LDL cholesterol to free cholesterol have been identified . Also, esterified cholesterol may be converted to free cholesterol by microbial processes  and deposited as extracellular cholesterol crystals found deep within the intima .
Hyperhomocysteinemia and autoimmunity.
Homocysteine thiolactone, the reactive cyclic anhydride of homocysteine, reacts with free amino groups of protein to form peptide-bound homocysteine . The process of homocysteinylation of proteins is termed thiolation, because this reaction produces a free sulfhydryl group within the peptide-bound homocysteine molecule. Homocysteine thiolactone reacts with the free amino groups of apoB protein of LDL . When an increased concentration of homocysteine thiolactone reacts with human LDL, the thiolated LDL becomes aggregated and subject to spontaneous precipitation . 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  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 . Antibodies to N-thiolated serum albumin were demonstrated in patients with coronary heart disease [71,72]. Thiolated LDL is present in human serum at low concentration (0.04-0.1%), but autoantibodies to human thiolated LDL have not been reported .
The 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 . These 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, Creactive protein (CRP), adhesion molecules (Pselectin, E-selectin, ICAM-1), and metalloproteinases (MMP-9). Homocysteine up-regulates reactive oxygen species, leading to NF-kappaB activation . CRP binds oxidized LDL and oxidized phospholipids, enhancing phagocytosis to form foam cells .
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. Therefore, 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 . 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 . This 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. This interpretation may also explain the recent finding that low levels of IgM antibodies against phosphorylcholine, a component of inflammatory phospholipids known to cause OxLDLrelated immune reactions, are associated with a greater risk of ischemic stroke .
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. These products may include living microorganisms, because viable Chlamydia pneumoniae have been cultured from atherosclerotic plaques by Ramirez  and Jackson et al .
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 . The presence of Chlamydia pneumoniae in human coronary plaques was confirmed by electron microscopy [87,88]. These organisms were also demonstrated within adventitia by immunohistochemical staining and polymerase chain reaction (PCR) for microbial DNA, presumably arriving via monocytes migrating from vasa vasorum .
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 microorganisms in the creation of vulnerable plaques was presented by Grattan et al . They 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 microorganisms 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. The 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.
The right capillary represents the situation in a normal healthy artery; there are only a few microbes and the lipoproteins are able to traverse the capillary lumen without adherence or obstruction. The left capillary represents the situation in an artery with a severe microbial invasion; microbial products and autoantibodies stick to the lipoproteins, which aggregate and obstruct the capillary lumen, leading to local ischemia, microbial growth, and inflammation. A monocyte enters the plaque from the arterial lumen by diapedesis between endothelial cells; another monocyte enters the plaque via vasa vasorum, leading to formation of foam cell macrophages within the plaque. In the case of an intact immune system, the inflammatory area heals and becomes converted to a fibrous plaque. In the case of an insufficient immune system, microorganisms escape into the tissue and create a microabscess, the vulnerable plaque.9
Flow chart for development of the vulnerable plaque
Microorganisms and spores continually invade the body through the airways, skin and gastrointestinal 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.
Normal immune system
The foam cells probably move back to the circulation. Before re-entering the arterial lumen, they are seen as fatty streaks just beneath the endothelium. The microorganisms 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 endotoxins enter the dead tissue, the capillaries are damaged, erythrocyte extravasation may occur, and a micro abscess is created.
The vulnerable plaque ruptures. Cholesterol 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, 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. This 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  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.
The 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.
The increased incidence of cardiovascular events
found after treatment with rofecoxib and other
non-steroidal anti-inflammatory drugs 
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. The
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 . The
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 . 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
, contradicting the assumption that their
presence is secondary to rupture.
Our interpretation explains the clinical and
laboratory similarities between myocardial infarction
and myocarditis , and it explains the
frequent occurrence of bacteriemia and sepsis in
myocardial infarction complicated with cardiogenic
shock . 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 finding of polymorphonuclear
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 cardiomyocytes
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
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 . On
average, each patient had microbial remnants from
12 different species; some patients had more, some
had fewer , 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 pneumoniae,
because this species is able to survive inside
living cells, where they are resistant to the effects of
antibiotics . 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 .
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. There 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 , 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 .
The 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 hypercholesterolemia
(FH) was longer than in the general
population . The 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
The lack of an association between the degree
of cholesterol lowering and outcome that were
found in clinical and angiographic trials  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 findings
imply that high cholesterol is protective and that its
lowering therefore counteracts exposure-response.
This view is in accordance with the trial findings
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
. 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 S 12 cience, vol. 39, no. 1, 2009
in all of the arteries than atherosclerotic patients
without cardiovascular events . Foam cells
have been identified adjacent to Bruch´s membrane
of the retina, where their number increases with
the age of patients . 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 .
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. Hyperhomocysteinemia
is found in B vitamin deficiency,
smoking, hypertension, hypothyroidism, renal
failure, and aging, all classical risk factors for
cardiovascular disease . Mental stress, a wellknown
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 homocysteine
in blood [117,118], potentially promoting
aggregation of LDL particles . Many infectious
diseases are more prevalent in smokers and
diabetics. The suggestion that excess iron is a risk
factor for vascular disease  is also in accordance
with our interpretation, because bacterial growth is
stimulated by the presence of free iron .
Therefore, attempts to prevent cardiovascular
disease and prolong life may be more successful if
we understand the fallacies of the lipid hypothesis
 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, normocholesterolemic
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
We thank Charles F. Foltz, Medical Media Service,
VA Medical Center, West Roxbury MA, for
assistance in preparing the figure.
Address correspondence to Kilmer S. McCully, M.D., Veterans Affairs Medical Center, West Roxbury, MA 02132, USA; tel 857 203 5990; fax 857 203 5623; email kilmer. firstname.lastname@example.org.
0091-7370/09/0100-0003. $4.80. © 2009 by the Association of Clinical Scientists, Inc.
Available online at http://www.annclinlabsci.org
Annals of Clinical & Laboratory Science, vol. 39, no. 1, 2009 3
1. Hansson GK, Nilsson J. Introduction: atherosclerosis as
inflammation: a controversial concept becomes accepted. J Int
2. Lusis AJ. Atherosclerosis. Nature 2000;407:233-241.
3. Hansson GK, Heistad DD. Two views on plaque rupture.
Arterioscler Thromb Vasc Biol 2007;27:697.
4. Hansson GK. Inflammation, atherosclerosis, and coronary
artery disease. NEJM 2005;352:1685-1695.
5. Reis SE, Holubkov R, Conrad-Smith AJ, Kelsey SF, Sharaf BL,
Reichek N, Rogers WJ, Merz CN, Sopko G, Pepine CJ.
Coronary microvascular dysfunction is highly prevalent in
women with chest pain in the absence of coronary artery
disease: results from the NHLBI WISE study. Am Heart J
6. McCully KS. Vascular pathology of homocysteinemia: implications
for the pathogenesis of arteriosclerosis. Am J Pathol
7. McCully KS. Hyperhomocysteinemia and arteriosclerosis:
historical perspectives. Clin Chem Lab Med 2005;43:980-
8. Ravnskov U. Is atherosclerosis caused by high cholesterol? Q J
9. Ravnskov U. High cholesterol may protect against infections
and atherosclerosis. Q J Med 2003;96:927-934.
10. Miettinen TA, Gylling H. Mortality and cholesterol metabolism
in familial hypercholesterolemia. Long-term follow-up of 96
patients. Arteriosclerosis 1988;8:163-167.
11. Hopkins PN, Stephenson S, Wu LL, Riley WA, Xin Y, Hunt
SE. Evaluation of coronary risk factors in patients with
heterozygous familial hypercholesterolemia. Am J Cardiol
12. Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and
environmental factors affecting the incidence of coronary
artery disease in heterozygous familial hypercholesterolemia.
Arterioscler Thromb 1991;11:290-297.
13. Ferrières J, Lambert J, Lussier-Cacan S, Davignon J. Coronary
artery disease in heterozygous familial hypercholesterolemia
Vulnerable plaques from lipoprotein aggregates 13
patients with the same LDL receptor gene mutation. Circulation
14. Neil HAW, Seagroatt V, Betteridge DJ, Cooper MP, Durrington
PN, Miller JP, Seed M, Naoumova RP, Thompson GR, Huxley
R, Humphries SE. Established and emerging coronary risk
factors in patients with heterozygous familial hypercholesterolaemia.
Heart 2004; 90:1431-1437.
15. Jansen AC, van Aalst-Cohen ES, Tanck MW, Cheng S,
Fontecha MR, Li J, Defesche JC, Kastelein JJ. Genetic
determinants of cardiovascular disease risk in familial hypercholesterolemia.
Arterioscler Thromb Vasc Biol 2005;25:1475-
16. Sugrue DD, Trayner I, Thompson GR, Vere TV, Dimeson J,
Stirling Y, Meade TW. Coronary artery disease and haemostatic
variables in heterozygous familial hypercholesterolaemia. Br
Heart J 1985;53:265-268.
17. Calara F, Silvestre M, Casanada F, Yean N, Napoli C, Palinski
W. Spontaneous plaque rupture and secondary thrombosis in
apolipoprotein E-deficient and LDL receptor-deficient mice. J
18. Naruszewicz M, Mirkiewicz E, Olszewski AJ, McCully KS.
Thiolation of low-density lipoprotein by homocysteine
thiolactone causes increased aggregation and altered interaction
with cultured macrophages. Nutr Metab Cardiovas Dis
19. Thayer WS. On the cardiac and vascular complications and
sequels of typhoid fever. Bull Johns Hopkins Hosp 1904;
20. Wiesel J. Die Erkrankungen arterieller Gefässe im Verlaufe
akuter Infektionen. II Teil. Z Heilkunde 1906; 27:262-294.
21. Osler W. Diseases of the arteries. In: Modern Medicine: its
Practice and Theory (Osler W, Ed), Lea & Fibiger, Philadelphia,
1908; pp 426-447.
22. Klotz O, Manning MF. Fatty streaks in the intima of arteries.
J Pathol Bacteriol 1911;16:211-220.
23. Grayston JT, Kuo CC, Campbell LA, Benditt EP. Chlamydia
pneumoniae strain TWAR and atherosclerosis. Eur Heart J
24. Melnick JL, Adam E, Debakey ME. Cytomegalovirus and
atherosclerosis. Eur Heart J 1993;Suppl K:30-38.
25. Nicholson AC, Hajjar DP. Herpesvirus in atherosclerosis and
thrombosis. Etiologic agents or ubiquitous bystanders? Arterioscler
Thromb Vasc Biol 1998;18:339-348.
26. Ismail A, Khosravi H, Olson H. The role of infection in atherosclerosis
and coronary artery disease. A new therapeutic target.
Heart Dis 1999;1:233-240.
27. Kuvin JT, Kimmelstiel MD. Infectious causes of atherosclerosis.
Am Heart J 1999;137:216-226.
28. Madjid M, Miller CC, Zarubaev VV, Marinich IG, Kiselev OI,
Lobzin YV, Filippov AE, Casscells SW. Influenza epidemics
and acute respiratory disease activity are associated with a surge
in autopsy-confirmed coronary heart disease death: results
from 8 years of autopsies in 34,892 subjects. Eur Heart J
29. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P,
Vallance P. Risk of myocardial infarction and stroke after
acute infection or vaccination. NEJM 2004;351:2611-2618.
30. Valtonen V, Kuikka A, Syrjanen J. Thrombo-embolic complications
in bacteremic infections. Eur Heart J 1993;14Suppl
31. Spahr A, Klein E, Khuseyinova N, Boeckh C, Muche R, Kunze
M, Rothenbacher D, Pezeshki G, Hoffmeister A, Koenig W.
Periodontal infections and coronary heart disease: role of
periodontal bacteria and importance of total pathogen burden
in the Coronary Event and Periodontal Disease (CORODONT)
study. Arch Intern Med 2006;166:554-549.
32. Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C,
Kopp H, Victor A, Hafner G, Prellwitz W, Schlumberger W,
Meyer J. Impact of infectious burden on progression of carotid
atherosclerosis. Stroke 2002;33:2581-2586.
33. Pesonen E. Infection and intimal thickening: evidence from
coronary arteries in children. Eur Heart J 1994;15Suppl C:57-
34. Liuba P, Persson J, Luoma J, Yla-Herttuala S, Pesonen E. Acute
infections in children are accompanied by oxidative modification
of LDL and decrease of HDL cholesterol, and are
followed by thickening of carotid intima-media. Eur Heart J
35. Todd EW, Coburn AF, Hill AB. Antistreptolysin S titres in
rheumatic fever. Lancet 1939;2:1213-1217.
36. Stollerman GH, Bernheimer AW. Inhibition of streptolysin S
by the serum of patients with rheumatic fever and acute
streptococcal pharyngitis. J Clin Invest 1950;29:1147-1155.
37. Humphrey JH. The nature of antistreptolysin S in the sera of
man and of other species; the lipoprotein properties of
antistreptolysin S. Br J Exp Pathol 1949;30:365-375.
38. Stollerman GH, Bernheimner AW, MacLeod CM. The
association of lipoproteins with the inhibition of streptolysin S
by serum. J Clin Invest 1950;29:1636-1645.
39. Skarnes RC. In vivo interaction of endotoxin with a plasma
lipoprotein having esterase activity. J Bacteriol 1968;95:2031-
40. Shortridge KF, Ho WK, Oya A, Kobayashi M. Studies on the
inhibitory activities of human serum lipoproteins for Japanese
encephalitis virus. Southeast Asian J Trop Med Public Health
41. Whitelaw DD, Birkbeck TH. Inhibition of staphylococcal
delta-hemolysin by human serum lipoproteins. FEMS Microbiology
42. Freudenberg MA, Galanos C. Interaction of lipopolysaccharides
and lipid A with complement in rats and its relation to endotoxicity.
Infect Immun 1978;19:875-882.
43. Ulevitch RJ, Johnston AR, Weinstein DB. New function for
high density lipoproteins. Isolation and characterization of a
bacterial lipopolysaccharide-high density lipoprotein complex
formed in rabbit plasma. J Clin Invest 1981;67:827-837.
44. Bhakdi S, Tranum-Jensen J, Utermann G, Fussle R. Binding
and partial inactivation of Staphylococcus aureus alpha-toxin by
human plasma low density lipoprotein. J Biol Chem 1983;258:
45. Seganti L, Grassi M, Mastromarino P, Pana A, Superti F, Orsi
N. Activity of human serum lipoproteins on the infectivity of
rhabdoviruses. Microbiologica 1983;6:91-99.
46. Van Lenten BJ, Fogelman AM, Haberland ME, Edwards PA.
The role of lipoproteins and receptor-mediated endocytosis in
the transport of bacterial lipopolysaccharide. PNAS USA
47. Huemer HP, Menzel HJ, Potratz D, Brake B, Falke D,
Utermann G, Dierich MP. Herpes simplex virus binds to human
serum lipoprotein. Intervirology 1988;29:68-76.
48. Flegel WA, Wölpl A, Männel DN, Northoff H. Inhibition of
endotoxin-induced activation of human monocytes by human
lipoproteins. Infect Immun 1989;57:2237-2245.
49. Cavaillon JM, Fitting C, Haeffner-Cavaillon N, Kirsch SJ,
Warren HS. Cytokine response by monocytes and macrophages
to free and lipoprotein-bound lipopolysaccharide. Infect
50. Northoff H, Flegel WA, Yurttas R, Weinstock C. The role of
lipoproteins in inactivation of endotoxin by serum. Beitr
51. Superti F, Seganti L, Marchetti M, Marziano ML, Orsi N. SA-
11 rotavirus binding to human serum lipoproteins. Med
Microbiol Immunol 1992;181:77-86.
Annals of Clinical & Laboratory S 14 cience, vol. 39, no. 1, 2009
52. Weinstock C, Ullrich H, Hohe R, Berg A, Baumstark MW,
Frey I, Northoff H, Flegel WA. Low density lipoproteins
inhibit endotoxin activation of monocytes. Arterioscler Thromb
53. Flegel WA, Baumstark MW, Weinstock C, Berg A, Northoff
H. Prevention of endotoxin-induced monokine release by
human low- and high-density lipoproteins and by apolipoprotein
A-1. Infect Immun 1993;61:5140-5146.
54. Feingold KR, Funk JL, Moser AH, Shigenaga JK, Rapp JH,
Grunfeld C. Role for circulating lipoproteins in protection
from endotoxin toxicity. Infect Immun 1995;63:2041-2046.
55. Netea MG, Demacker PNM, Kullberg BJ, Boerman OC,
Verschueren I, Stalenhoef AF, van der Meer JW. Low-density
lipoprotein receptor-deficient mice are protected against lethal
endotoxemia and severe Gram-negative infections. J Clin
56. Hudgins LC, Parker TS, Levine DM, Gordon BR, Saal SD,
Jiang XC, Seidman CE, Tremaroli JD, Lai J, Rubin AL. A
single intravenous dose of endotoxin rapidly alters serum lipoproteins
and lipid transfer proteins in normal volunteers. J
Lipid Res 2003;44:1489-1498.
57. Guyton JR, Klemp KF. Transitional features in human atherosclerosis.
Intimal thickening, cholesterol clefts, and cell loss in
human aortic fatty streaks. Am J Pathol 1993;143:1444-1457.
58. Van Amersfoort ES, Van Berkel TJC, Kuiper J. Receptors,
mediators, and mechanisms involved in bacterial sepsis and
septic shock. Clin Microbiol Rev 2003;16:379-414.
59. Khovidhunkit W, Kim M-S, Memon RA, Shigenaga JK, Moser
AH, Feingold KR, Grunfeld C. Effects of infection and
inflammation on lipid and lipoprotein metabolism: mechanisms
and consequences to the host. J Lipid Res 2004;45:1169-1196.
60. Heinecke JW, Suits AG, Aviram M, Chait A. Phagocytosis of
lipase-aggregated low density lipoprotein promotes macrophage
foam cell formation. Sequential morphological and biochemical
events. Arterioscler Thromb 1991;11:1643-1651.
61. Kalayoglu MV, Indrawati, Morrison RP, Morrison SG, Yuan Y,
Byrne GI. Chlamydial virulence determinants in atherogenesis:
the role of chlamydial lipopolysaccharide and heat shock
protein 60 in macrophage-lipoprotein interactions. J Infect Dis
62. Qi M, Miyakawa H, Kuramitsu HK. Porphyromonas gingivalis
induces murine macrophage foam cell formation. Microb
63. Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW, Litovsky
S. Systemic infections cause exaggerated local inflammation in
atherosclerotic coronary arteries: clues to the triggering effect
of acute infections on acute coronary syndromes. Tex Heart
Inst J 2007;34:11-18.
64. Welch CL, Sun Y, Arey BJ, Lemaitre V, Sharma N, Ishibashi
M, Sayers S, Li R, Gorelik A, Pleskac N, Collins-Fletcher K,
Yasuda Y, Bromme D, D’Armiento JM, Ogltree ML, Tall AR.
Spontaneous thrombosis and medial degeneration in Apo3-/-,
Npc1-/- mice. Circulation 2007;116:2444-2452.
65. Noble NL, Boucek RJ, Kao KY. Biochemical observations of
human atheromatosis: analysis of aortic intima. Circulation
66. Bonnefont-Rousselot D, Therond P, Beaudeux JL, Peynet J,
Legrand A, Delattre J. High density lipoproteins (HDL) and
the oxidative hypothesis of atherosclerosis. Clin Chem Lab
67. Fabricant CG, Krook L, Gillespie JH. Virus-induced cholesterol
crystals. Science 1973;181:566-567.
68. Benesch R, Benesch RE. Thiolation of proteins. PNAS USA
69. Vidal M, Sainte-Marie J, Philippot J, Bienvenue A. Thiolation
of low-density lipoproteins and their interactions with L2C
leukemic lymphocytes. Biochimie 1986;68:723-730.
70. Ferguson E, Parthasarathy S, Joseph J, Kalyanaraman B.
Generation and initial characterization of a novel polyclonal
antibody directed against homocysteine thiolactone-modified
low density lipoprotein. J Lipid Res 1998;39:925-933.
71. Undas A, Jankowski M, Twardowska M, Padjas A, Jakubowski
H, Szczeklik A. Antibodies to N-homocysteinylated albumin
as a marker for early-onset coronary artery disease in men.
Thromb Haemost 2005;93:346-350.
72. Yang X, Gao Y, Zhou J, Yang Y, Wang J, Song L, Liu Y, Xu H,
Chen Z, Hui R. Plasma homocysteine thiolactone adducts
associated with risk of coronary heart disease. Clin Chim Acta
73. Perla-Kajan J, Twardowski T, Jakubowski H. Mechanisms of
homocysteine toxicity in humans. Amino Acids 2007;32:561-
74. Lazzerini PE, Capecchi PL, Selvi E, Lorenzini S, Bisogno S,
Galezzi M, Pasini FL. Hyperhomocysteinemia, inflammation
and autoimmunity. Autoimmun Rev 2007;6:503-509.
75. Chang MK, Binder CJ, Torzewski M, Witztum JL. C-reactive
protein binds to both oxidized LDL and apoptotic cells through
recognition of a common ligand: phosphoryl choline of
oxidized phospholipids. PNAS USA 2002;99:13043-13048.
76. Uusitupa MI, Niskanen L, Luoma J, Vilja P, Mercuri M,
Rauramaa R, Ylä-Herttuala S. Autoantibodies against oxidized
LDL do not predict atherosclerotic vascular disease in noninsulin-
dependent diabetes mellitus. Arterioscler Thromb Vasc
77. Leinonen JS, Rantalaiho V, Laippala P, Wirta O, Pasternack A,
Alho H, Jaakkola O, Ylä-Herttuala S, Koivula T, Lehtimäki T.
The level of autoantibodies against oxidized LDL is not
associated with the presence of coronary heart disease or
diabetic kidney disease in patients with non-insulin-dependent
diabetes mellitus. Free Radic Res 1998;29:137-141.
78. Wilson PW, Ben-Yehuda O, McNamara J, Massaro J, Witztum
J, Reaven PD. Autoantibodies to oxidized LDL and
cardiovascular risk: the Framingham Offspring Study. Atherosclerosis
79. Mayr M, Kiechl S, Tsimikas S, Miller E, Sheldon J, Willeit J,
Witztum JL, Xu Q. Oxidized low-density lipoprotein autoantibodies,
chronic infections, and carotid atherosclerosis in a
population-based study. J Am Coll Cardiol 2006;47:2436-
80. Tsimikas S, Aikawa M, Miller RJ Jr, Miller ER, Torzewski M,
Lentz SR, Bergmark C, Heistad DD, Libby P, Witztum JL.
Increased plasma oxidized phospholipid:apolipoprotein B-100
ratio with concomitant depletion of oxidized phospholipids
from atherosclerotic lesions after dietary lipid-lowering: a
potential biomarker of early atherosclerosis regression.
Arterioscler Thromb Vasc Biol 2007;27:175-181.
81. Schumacher M, Eber B, Tatzber F, Kaufmann P, Halwachs G,
Fruhwald FM, Zweiker R, Esterbauer H, Klein W. Transient
reduction of autoantibodies against oxidized LDL in patients
with acute myocardial infarction. Free Radic Biol Med 1995;
82. Su J, Georgiades A, Wu R, Thulin T, de Faire U, Frostegård J.
Antibodies of IgM subclass to phosphorylcholine and oxidized
LDL are protective factors for atherosclerosis in patients with
hypertension. Atherosclerosis 2006;188:160-166.
83. Sjoberg BG, Su J, Dahlbom I, Gronlund H, Wikstrom M,
Hedblad B, Berglund G, de Faire U, J, Frostegård. Low levels
of IgM antibodies against phosphorylcholine – a potential risk
marker for ischemic stroke in men. Atherosclerosis 2007,
84. Ramirez J. Isolation of Chlamydia pneumoniae from the
coronary artery of a patient with atherosclerosis. Ann Int Med
Vulnerable plaques from lipoprotein aggregates 15
85. Jackson LA, Campbell LA, Kuo CC, Rodriguez DI, Lee A,
Grayston JT. Isolation of Chlamydia pneumoniae from a carotid
endarterectomy specimen. J Infect Dis 1997;176:292-295.
86. Maass M, Bartels C, Engel PM, Mamat U, Sievers HH.
Endovascular presence of viable Chlamydia pneumoniae is a
common phenomenon in coronary artery disease. J Am Coll
87. Kuo C-C, Shor A, Campbell LA, Fukushi H, Patton DL,
Grayston JT. Demonstration of Chlamydia pneumoniae in
atherosclerotic lesions of coronary arteries. J Inf Dis 1993;
88. Campbell LA, O’Brien ER, Capuccio AL, Kuo C-C, Wang SP,
Stewart D, Patton DL, Cummings PK, Grayston JT.
Detection of Chlamydia pneumoniae TWAR in human
coronary atherectomy tissues. J Inf Dis 1995;172:285-288.
89. Vink A, Pasterkamp G, Poppen M, Schonfeld AH, deKleijn
DPV, Roholl PJM, Fontijn J, Plomp S, Borst C. The adventitia
of atherosclerotic coronary arteries frequently contains
Chlamydia pneumoniae. Atherosclerosis 2001;157:117-122.
90. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE,
Stinson EB, Shumway NE. Cytomegalovirus infection is
associated with cardiac allograft rejection and atherosclerosis.
91. Falk E. Plaque rupture with severe pre-existing stenosis
precipitating coronary thrombosis. Characteristics of coronary
atherosclerotic plaques underlying fatal occlusive thrombi. Br
Heart J 1983;50:127-134.
92. Buffon A, Biasucci LM, Liuzzo G, D’Onofrio G, Crea F,
Maseri A. Widespread coronary inflammation in unstable
angina. NEJM 2002;347:5-12.
93. Madjid M, Naghavi M, Malik BA, Litovsky S, Willerson JT,
Casscells SW. Thermal detection of vulnerable plaque. Am J
94. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos
CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara
S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE.
Neutrophil infiltration of culprit lesions in acute coronary
syndromes. Circulation 2002;106:2894-2900.
95. Costantini M, Tritto C, Licci E, Sticchi G, Capone S, Montiaro
A, Bruno A, Nuzzaci G, Picano E. Myocarditis with STelevation
myocardial infarction presentation in young men. A
case series of 11 patients. Int J Cardiol 2005;101:157-158.
96. Kohsaka S, Menon V, Lowe AM, Lange M, Dzavik V, Sleeper
LA, Hochman JS; SHOCK Investigators. Systemic inflammatory
response syndrome after acute myocardial infarction
complicated by cardiogenic shock. Arch Intern Med 2005;
97. Spagnoli LG, Pucci S, Bonanno E, Cassone A, Sesti F, Ciervo
A, Mauriello A. Persistent Chlamydia pneumoniae infection of
cardiomyocytes is correlated with fatal myocardial infarction.
Am J Pathol 2007;170:33-42.
98. Stary HC. Macrophages, macrophage foam cells, and eccentric
intimal thickening in the coronary arteries of young children.
99. Stary HC. Evolution and progression of atherosclerotic lesions
in coronary arteries of children and young adults. Arteriosclerosis
100. Ritman EL, Lerman A. The dynamic vasa vasorum. Cardiovasc
101. Johnsen SP, Larsson H, Tarone RE, McLaughlin JK, Norgard
B, Friis S, Sorensen HR. Risk of myocardial infarction among
users of rofecoxib, celecoxib, and other NSAIDs: a populationbased
case-control study. Arch Intern Med 2005;165:978-984.
102. Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S,
Rehman A, Kuhbacher T, Nikolaus S, Namsolleck P, Blaut M,
Hampe J, Sahly H, Reinecke A, Haake N, Gunther R, Kruger
D, Lins M, Herrmann G, Folsch UR, Simon R, Schreiber S.
Detection of diverse bacterial signatures in atherosclerotic
lesions of patients with coronary heart disease. Circulation
103. Melnick JL, Petrie BL, Dreesman GR, Burek J, McCollum
CH, DeBakey ME. Cytomegalovirus antigen within human
arterial smooth muscle cells. Lancet 1983;2:644-647.
104. Pampou SY, Gnedoy SN, Bystrevskaya VB, Smirnov VN,
Chazov EI, Melnick JL, DeBakey ME. Cytomegalovirus genome
and the immediate-early antigen in cells of different layers of
human aorta. Virchows Arch 2000;436:539-552.
105. Shi Y, Tokunaga O. Chlamydia pneumoniae and multiple
infections in the aorta contribute to atherosclerosis. Pathol Int
106. Gieffers J, Füllgraf H, Jahn J, Klinger M, Dalhoff K, Katus
HA, Solbach W, Maass M. Chlamydia pneumoniae infection in
circulating human monocytes is refractory to antibiotic
treatment. Circulation 2001;103:351-356.
107. Katz JT, Shannon RP. Bacteria and coronary atheroma: more
fingerprints but no smoking gun. Circulation 2006;113:920-
108. Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH,
Smelt AH, Kastelein JJ. Mortality over two centuries in large
pedigree with familial hypercholesterolaemia: family tree
mortality study. Brit Med J 2001;322:1019-1023.
109. Elias ER, Irons MB, Hurley AD, Tint GS, Salen G. Clinical
effects of cholesterol supplementation in six patients with the
Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet
110. Yuan C, Mitsumori LM, Beach KW, Maravilla KR. Carotid
atherosclerotic plaque: noninvasive MR characterization and
identification of vulnerable lesions. Radiology 2001;221:285-
111. Fleiner M, Kummer M, Mirlacher M, Sauter G, Cathomas G,
Krapf R, Biedermann BC. Arterial neovascularization and
inflammation in vulnerable patients: early and late signs of
symptomatic atherosclerosis. Circulation 2004;110:2843-
112. Curcio CA, Millican CL, Bailey T, Kruth HS. Accumulation
of cholesterol with age in human Bruch’s membrane. Invest
Ophthalmol Vis Sci 2001;42:265-274.
113. Schonholzer KW, Waldron M, Magil AB. Intraglomerular
foam cells and human focal glomerulosclerosis. Nephron 1992;
114. Lee HS, Kruth HS. Accumulation of cholesterol in the lesions
of focal segmental glomerulosclerosis. Nephrology 2003;8:224-
115. Crouse JR, Grundy SM, Ahrens EH. Cholesterol distribution
in the bulk tissues of man: variation with age. J Clin Invest
116. McCully KS. Homocysteine, vitamins, and vascular disease
prevention. Am J Clin Nutr 2007;86(Suppl):1563S-1568S.
117. Stoney CM. Plasma homocysteine levels increase in women
during psychological stress. Life Sciences 1999;64:2359-2365.
118. Stoney CM, Engebretson TO. Plasma homocysteine concentrations
are positively associated with hostility and anger. Life
119. Sullivan JL. The iron paradigm of ischemic heart disease. Am
Heart J 1989,117:1177-1188.
120. Bullen JJ, Rogers HJ, Spalding PB, Ward CG. Natural
resistance, iron and infection: a challenge for clinical medicine.
J Med Microbiol 2006;55:251-258.
121. Ravnskov U. The fallacies of the lipid hypothesis. Scand Cardiovasc
Annals of Clinical & Laboratory S 16 cience, vol. 39, no. 1, 2009
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