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2288 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2289

mortality and hypertension. It is supposed that the increase in mor- with CVD have higher titers of antibodies against this pathogen.
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tality was a result of an off-target effect of the drug increasing blood Viruses, such as herpes simplex and cytomegalovirus, also are impli-
pressure and not because of cholesterol ester transfer protein inhibition. cated in human atherosclerotic lesion formation. Gingivitis as a conse-
Clinical trials evaluating the effect of other inhibitors of cholesteryl ester quence of poor dental hygiene or smoking may lead to cellular immune
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transfer protein on atherosclerosis and cardiovascular events have not activation and provoke atherosclerosis by cytokines or antibodies.
shown clinical efficacy thus far. Along similar lines, delivery of a mutant Endogenous proteins, such as heat shock proteins, also are implicated
form of apoA1 (apoA1 Milano) resulted in regression of plaque size as in atherosclerosis. One study showed that progression of carotid disease
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measured by intravascular ultrasound in a small phase II clinical trial. correlated with antibodies against heat shock proteins 65 and 60. 143
However, studies evaluating the effect of apoA1 mimetics on athero-
sclerosis also are have not shown compelling data regarding reducing Splenectomy and Atherosclerosis
plaque size or cardiovascular events. 135
The relationship between the immune system and atherosclerosis is
complex, as evident from an animal study that showed that splenectomy
CD40, CD40 Ligand, and Atherosclerosis of cholesterol-fed apoE–/– mice led to significantly increased athero-
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Studies indicate that human atherosclerotic lesions express the immune sclerosis. This proatherogenic effect was rescued by transfer of either
mediator CD40 and its soluble ligand, sCD40L. Increasing evidence purified B cells or T cells from the spleens of atherosclerotic apoE–/–
indicates that the CD40–sCD40L signaling pathway plays a central role donors. A long-term study of soldiers who underwent splenectomy
in several inflammatory processes, including atherosclerosis and graft after trauma found the soldiers had a twofold increased incidence of
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rejection following transplantation. Interruption of CD40 signaling CAD, providing evidence that the spleen has antiatherogenic activity.
in hyperlipidemic mice reduces the size of aortic atherosclerotic lesions Further studies are needed to determine if splenectomy significantly
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and their lipid, macrophage, and T-lymphocyte content. Atorvastatin, impacts the atherosclerotic process, and if so, by what mechanism.
lovastatin, pravastatin, and simvastatin reduce IFN-γ–induced CD40
expression in a dose-dependent manner. Activation of atheroma-asso- Genetics and Myocardial Infarction
ciated cells with human recombinant sCD40L is reduced when cells are Atherosclerotic disease is a complex human trait involving multiple
treated with statins. In addition, retrospective ex vivo immunostaining genes and environmental factors. Through the study of linkage analysis
of human carotid atherosclerotic lesions of patients treated with sim- of families and sibling pairs as well as candidate genes and genome-wide
vastatin for more than 3 months revealed less CD40 expression and association studies, the genetic predisposition to MI is starting to be
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atheroma-associated cells compared with patients who were not treated understood. The clinical importance of this knowledge is the poten-
with the drug. A reduction in sCD40L is associated with pravastatin or tial identification of markers of disease for risk prediction and potential
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cerivastatin therapy. These findings support the notion that statins are intervention to lower the risk of atherosclerotic-based cardiovascular
antiinflammatory, in addition to their cholesterol-lowering effects. events.
The use of genome-wide linkage analyses of families or sib-pairs
Transforming Growth Factor-β and Atherosclerosis has identified chromosomal loci linked to or genetic variations in the
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Transforming growth factor (TGF)-β is a cytokine secreted by macro- arachidonic 5-lipoxygenase-activating protein gene (ALOX5AP) and
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phages, smooth muscle cells, and the Th3 subset of Th cells that has leukotriene A hydrolase gene (LTA H). The genes are both involved
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multiple regulatory functions. TGF-β is speculated to contribute to in inflammation-related pathway of leukotriene B production. Inter-
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plaque stabilization because it stimulates collagen synthesis and is fibro- estingly, a small molecule inhibitor of ALOX5AP was shown to reduce
genic. One study found that inhibition of TGF-β signaling by neutraliz- leukotriene production and plasma levels of C-reactive protein.
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ing antibodies led to a larger plaque size with an unstable phenotype. Several association studies of unrelated individuals have identified
Further studies are needed to clarify the role of TGF-β in atherosclerotic genetic variations that confer susceptibility to atherosclerotic disease
plaque initiation and growth. and cardiovascular events. Studies using genome-wide linkage analysis
ABO Blood Type and Cardiovascular Risk The ABO blood identified four SNPs on chromosome 9p21.3 that were associated with
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group is determined from presence of A and B antigens on the surface of MI in white cohorts. Other genetic polymorphisms also contribute
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the red blood cells and is thought to confer cardiovascular risk. These to increased risk of CVD through a variety of mechanisms.
antigens are also expressed on the surface of platelets and the endothe-
lium and consist of terminal carbohydrate molecules which are synthe- ATHEROSCLEROTIC PLAQUE
sized by the sequential action of the ABO glycosyltransferases. Genetic Plaque Classification
studies showed that carriers of single nucleotide polymorphisms (SNPs) The American Heart Association classification of atherosclerotic plaques
that mark non-O blood group types have higher levels of plasma VWF into types I through VIII is based on lesion composition and structure
when compared to O individuals. Epidemiologic and genetic studies (Fig. 134–5). Types I through III atherosclerotic plaques have foam
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show that the non-O blood group is associated with adverse cardiovas- cells organized in a fatty streak, ranging from those not visible on close
cular events. One study demonstrated that the SNP rs514659 was asso- examination (type I) to those that are apparent on examination (type III).
ciated with coronary artery diseases (CADs) when complicated by MI Types I through III lesions are small and clinically silent, whereas types
but not with CAD without MI, suggesting that the primary relationship IV through VI lesions may obstruct the lumen and produce a clinical
of ABO to clinical CAD is through modulation of coronary thrombosis event. Type IV lesions contain a confluent pool of lipid and in most
or plaque rupture in patients with established coronary atherosclerosis patients do not cause anginal symptoms because of the ability of the
rather than through primary promotion of atherosclerosis per se. artery to remodel outward. Type V lesions contain a fibromuscular cap
resulting from replacement of tissue disrupted by accumulated lipid and
Infection and Atherosclerosis hematoma or organized thrombotic deposits. Type VI lesions involve
Several infectious agents have been implicated as pathogens in thrombosis that may be either mural or obstructive. Of note, a type IV
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atherosclerosis. A well-studied infectious pathogen is C. pneumoniae. lesion may develop type VI changes without ever passing through a type
Animals infected with this agent develop atherosclerosis, and patients V change and accumulating significant fibrous tissue. Plaques that are

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