There are hundreds of journal articles demonstrating that infective agents play the key role in atherosclerosis and thus CHD (coronary heart disease). There is strong evidence that besides transport of cholesterol and triglycerides by HDL and LDL, they play important immune functions. This is why LDL and HDL are present in atheroma; there they among other things bond to, and thus disable endotoxins produce by the pathogens in the artery walls. The infective agents also produce a response an immune response by white blood cells, thus their presence in the inflamed atheroma. The strong experimental evidence thus accounts for the presence of both white bloods cells and the lipoproteins. This is contrary to the standard LDL theory where oxidized LDL (no mention of the bacterial and virus vectors or the immune role of HDL and LDL) produces an immune response by macrophages. Since pharma and its opinion leaders can’t refute the infection cause, they simply ignore the issue. Pharma’s oxidation theory makes atherosclerosis an auto-immune disease. A much better explanation based upon experimental evidence is given by Prof. Uffe Ravnskov in his book and journal article of these events and the role of infective agents. In the articles below bacterial living within the middle layer of the artery wall trigger the immune response by T-cells which are further aided by macrophages. The damage caused in this process damage the arteriole (vasa vasorum) which supply blood to the muscle cells in the artery walls. A large body of clinical evidence (see for examples Ignore the Awkward! by Prof. Uffe Ravnskov—notes on this book), and also the notes on Anthony Calpo chapter 21 The Infection Connection, from The great Cholesterol Con, an excellent scholarly source. --jk.

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http://www.ncbi.nlm.nih.gov/pubmed/23431458 J Lipids. 2013;2013:684903 . Jan 30,2013

High-density lipoproteins and the immune system

Abstract

High-density lipoprotein (HDL) plays a major role in vasodilation and in the reduction of low-density lipoprotein (LDL) oxidation, inflammation, apoptosis, thrombosis, and infection; however, HDL is now less functional in these roles under certain conditions. This paper focuses on HDL, its anti-inflammation behavior, and the mechanisms by which HDL interacts with components of the innate and adaptive immune systems. Genome-wide association studies (GWAS) and proteomic studies have elucidated important molecules involved in the interaction between HDL and the immune system. An understanding of these mechanisms is expected to be useful for the prevention and treatment of chronic inflammation due to metabolic syndrome, atherosclerosis, or various autoimmune diseases.

From the complete version http://www.hindawi.com/journals/jl/2013/684903/

5. Conclusions

Accumulating evidence suggests that HDL or a specific apolipoprotein associated with HDL, such as apoA-I, is involved in the innate and adaptive immune responses primarily through the modulation of lipid raft components in monocytes/macrophages, dendritic cells, and T and B lymphocytes. Plasma HDL-C is usually reduced in chronic inflammation. These findings suggest that . However, chronic inflammation modifies HDL from a molecule with anti-inflammatory properties to one with pro-inflammatory properties, which leads to complex interpretation of plasma HDL-C levels. Although recent genetic and proteomic studies have unveiled important molecular players in HDL metabolism and immune activity, the mechanism for HDL regulation by these molecules remains unclear. Additional studies are required to answer several questions about HDL-C and inflammatory disease with regard to reduced plasma HDL-C levels as potential pathogenic cause of inflammatory diseases; HDL-C consumption and its consequences versus benefits for protection against these diseases; and altered HDL function in these diseases.

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http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2008.02031.x/abstract;jsessionid=EC115C50981171B5FF6A56394159C4FA.f02t04?deniedAccessCustomisedMessage=&userIsAuthenticated=false

European Journal of Clinical Investigation; Volume 38, Issue 11, pages 857–862, November 2008

Multiple bacteria contribute to intraplaque T-cell activation in atherosclerosis

J. J. Van Der Meer¹, A. C. Van Der Wal¹, P. Teeling¹, M. M. Idu², A. Van Der Ende³ and O. J. De Boer¹

Abstract

Background Infection with microorganisms is considered a pathogenic factor in atherogenesis. Several studies have shown the presence of a broad spectrum of bacterial species in atherosclerotic plaques, which could trigger local inflammation. Because T cells contribute to atherosclerotic plaque inflammation, we studied the responsiveness of human plaque derived T-cell cultures to bacteria of different species.

Materials and methods Primary polyclonal T-cell cultures were generated from both carotid endarterectomy tissue and peripheral blood of nine patients, and the peripheral blood of eight matched controls. The in vitro proliferative responses of the T-cell cultures against H. pylori, N. meningitidis, N. lactamica, S. aureus, S. pneumoniae, S. epidermidis and E. coli were analysed. T-cell proliferation was measured by ³H-thymidine incorporation and expressed as a stimulation index. Selective outgrowth of intraplaque microbial specific T cells was studied by calculating the ratio of plaque T-cell SI and peripheral blood T-cell SI in each patient.

Results All patients showed T-cell responsiveness to multiple bacteria in their plaque tissue. Stimulation indices were in the range of 0·3–30, and this degree of reactivity with the different species was heterogeneous among patients. Selective outgrowth (plaque/peripheral blood ratio) of T cells against multiple bacteria was observed in six out of nine patients.

Conclusions T cells in atherosclerotic plaques have the capacity to selectively respond to antigens of a wide variety of microbial antigens. This supports the view that such mechanisms could contribute to the atherosclerotic inflammatory response.

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http://journals.lww.com/co-lipidology/Abstract/2009/10000/The_role_of_hypoxia_in_atherosclerosis.9.aspx

Current Opinion in Lipidology: October 2009 - Volume 20 - Issue 5 - p 409–414

The role of hypoxia in atherosclerosis Hultén, Lillemor Mattsson; Levin, Max

Abstract: Purpose of review: It is important to address the factors involved in the progression of atherosclerosis because advanced atherosclerotic lesions are prone to rupture, leading to disability or death. Hypoxic areas are known to be present in human atherosclerotic lesions, and lesion progression is associated with the formation of lipid-loaded macrophages and increased local inflammation. Here we summarize the role of hypoxia in the development of advanced atherosclerotic lesions by promoting lipid accumulation, inflammation, ATP depletion, and angiogenesis.

Recent findings: A recent study clearly demonstrated the presence of hypoxia in macrophage-rich regions of advanced human carotid atherosclerotic lesions. We showed that hypoxia increases the formation of lipid droplets in macrophages and promotes increased secretion of inflammatory mediators, and recent evidence indicates that lipid droplets may play a role in mediating the inflammatory response. Hypoxia also promotes lesion progression by exacerbating ATP depletion and lactate accumulation, and the presence of hypoxia in human carotid atherosclerotic lesions correlates with angiogenesis.

Summary: Recent studies indicate that hypoxia may play a key role in the progression to advanced lesions by promoting lipid accumulation, increased inflammation, ATP depletion, and angiogenesis. Further understanding of the effects of hypoxia in atherosclerotic lesions could indicate potential therapeutic targets.

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http://informahealthcare.com/doi/abs/10.3109/07853890.2010.497767

September 2010, Vol. 42, No. 6 , Pages 394-403 (doi:10.3109/07853890.2010.497767) University of Birmingham Centre for Cardiovascular Sciences

The role of monocytes in atherosclerotic coronary artery disease

Abstract: Inflammation plays a key role in the pathogenesis of atherosclerosis. The more we discover about the molecular pathways involved in atherosclerosis, the more we perceive the importance of monocytes in this process. Circulating monocytes are components of innate immunity, and many pro-inflammatory cytokines and adhesion molecules facilitate their adhesion and migration to the vascular endothelial wall. In addition to the accumulation of lipids and formation of atherogenic ‘foam’ cells, monocytes may promote atherosclerotic plaque growth by production of inflammatory cytokines, matrix metalloproteinases, and reactive oxidative species. However, the contribution of monocytes to atherogenesis is not only limited to tissue destruction. Monocyte subsets are also involved in intraplaque angiogenesis and tissue reparative processes.

The aim of this overview is to discuss the mechanisms of monocyte activation, the pivotal role and importance of activated monocytes in atherosclerotic coronary artery disease, their implication in the development of acute coronary events, and their potential in cardiovascular reparative processes such angiogenesis.

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http://link.springer.com/article/10.1007/s12350-010-9263-x#page-3; ALSO pdf

http://download.springer.com/static/pdf/676/art%253A10.1007%252Fs12350-010-9263-x.pdf?auth66=1414730536_909f4c5f3727da727a6c3247ea617561&ext=.pdf

Journal of Nuclear cardiology, Sept/Oct 2010

Molecular imaging of inflammation and intraplaque vasa vasorum: A step forward to identification of vulnerable plaques?

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis and most likely under influence of hypoxic [lack of oxygen] and inflammatory stimuli. [Then goes on to describe imaging techniques.]

Pathophysiology of the Vulnerable Plaque: Traditionally, the burden of atherosclerotic disease was estimated from the percentage of stenosis detected by angiography. However, it has become apparent [2 decades ago] plaque rupture and consequent cardiovascular events are dependent on the plaque composition rather than stenosis. Analyses of culprit lesions demonstrated that plaque vulnerable to rupture are characterized by active inflammation, a large lipid core with a thin fibrous cap, positive remodeling, intraplaque hemorrhage, and intraplaque neovascularization of the vasa vasorum.

Inflammation: Inflammation is one of the hallmarks of plaque vulnerability. Macrophages are the most prevalent inflammatory cell in the atherosclerotic plaque and play a major role in the pathophysiology of plaque vulnerability. Macrophages secrete proteolytic enzymes, which degrade the extracellular matrix weakening the fibrotic cap structure and ultimately leading to plaque rupture.

Vasa Vasorum Neovascularization: Interruption of the adventitial vasa vasorum results in media necrosis, showing they are critical for nourishment of the media. The vasa vasorum are unevenly distributed along the vessel wall. It has been hypothesized that areas of low vasa vasorum density have less efflux of lipoproteins and are prone to inflammation. A relative hypoxic state… may be the trigger for the formation of atherosclerotic plaque. This hypothesis has been supported by the presence of hypoxic [lack of oxygen] and inflammatory factors….

Clinical applications: Due to the tortuous and ever moving nature of the coronary arteries, imaging of coronary atherosclerotic plaques is a major challenge…. Because atherosclerosis is a systemic inflammatory disease and local changes in macrophage content and vasa vasorum density are often uniformly present in different vascular beds, the presence and composition of atherosclerotic plaques in peripheral arteries can be used as an indication for atherosclerotic disease of the coronary arteries.

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http://jid.oxfordjournals.org/content/180/3/780.short J Infect Dis. (1999) 180 (3): 780-790.

Cellular Oxidation of Low-Density Lipoprotein by Chlamydia pneumoniae

Abstract: A spectrum of clinical and epidemiologic studies implicate infectious agents, including Chlamydia pneumoniae, in the pathogenesis of atherosclerosis. The complexity of atherosclerotic disease necessitates examining the role of infection in the context of defined risk factors, such as high levels of native low-density lipoprotein (LDL). Although native LDL does not have atherogenic properties, cellular oxidation of LDL alters the lipoprotein into a highly atherogenic form. In this report, C. pneumoniae and chlamydial hsp60, an inflammatory antigen that was recently localized to atheromas, were found to induce cellular oxidation of LDL. These data provide initial evidence that an infectious agent can render LDL atherogenic and suggest a mechanism whereby C. pneumoniae may promote atheroma development.

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In one of the 2 best scholarly books on the cholesterol myth, all the important related topics are set out in length. (The other is Ignore the Award, Prof. Uffe Ravnskov, 2010, a shorter work). Both cover the real major cause of CVD, infectious agents within the artery walls. Below are experts from The Great Cholesterol Con, Anthony Colpo, 2006
Chapter 21: The Infection Connection. A rapidly-expanding volume of research is implicating common infectious agents—including the respiratory but Chlamydia pneumoniae, the ulcer-causing Helicobacter pylori bacteria, herpes viruses such as cytomegalovirus, and Herpes simplex and even dental infections—as playing a direct role in the instigation and progression of CHD…. A review of thirteen published studies in which researchers went hunting for the organism [Chlamydia pneumonia] in arterial tissues showed that the organism could be detected in over half of all atheromas, but in only 5 percent of adjacent, lesion-free arterial tissue samples 207-208…. [e]xamined fifty human atheroma specimens, they found that forty-four percent were positive for one or more strains of periodontal bacteria, 2008. Another potentially confounding factor is the fact that total infectious burden… not just the presence of any single bacteria or virus. In a representative study, 233 patients at a Washington DC cardiovascular research unit underwent coronary angiography to determine the presence of coronary artery disease, then were tested for a variety of bacterial and viral antibodies. The prevalence of CAD was 48, 69, and 85 percent in individuals with antibodies to two or less pathogens, to three or four pathogens, and to five pathogens, respectively, 210. There is now compelling evidence to show that low cholesterol levels increase the susceptibility to infectious disease, while high cholesterol levels appear to protect against infection!... The cell membranes of gram-negative organisms contain what is known as endotoxins, or lipopolysaccharide (LPS), while Gram-positive microbes contain lipoteichoic acid (LTA). LPS and LTA are virulent factors that trigger the inflammatory response and cause much of the unpleasant symptoms of infection. In the laboratory experiments, LPS and LTA rapidly bind to and are subsequently inactivated by HDL and /or LDL (36-39). In additions Staphylococcus aureus alpha-toxin, a toxin produced by most strains of Gram-positive Staphylococcus bacteria that causes damage to a wide variety of cells, is bound and almost totally inactivated by LDL, 211. In men with high cholesterol, mononuclear cells (lymphocytes and monocytes) exerted a far more robust immune response than those in men with lower cholesterol level…. 68,400 deaths, found that as total cholesterol went down, mortality from respiratory and gastro-intestinal diseases—most of which are initiated by infectious organisms—went up, 212.