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Chapter 144 Atherothrombosis 2131

coagulation systems serves to enhance each other and to promote posttranscriptional mechanisms. Dozens of specific MiRs have been
atherosclerosis. identified that are expressed in highly regulated tissue-specific
Not surprisingly, patients with systemic autoimmune inflamma- manners, and that regulate expression of genes involved in all
tory disorders, including rheumatoid arthritis, Wegener’s granuloma- aspects of atherosclerosis, including hepatic lipoprotein homeostasis;
tosis, and lupus erythematosus have been shown to have accelerated macrophage, endothelial cell, and smooth muscle cell functions;
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atherosclerosis, as assessed by biomarkers, such as ultrasound evidence mechanosensory functions; and cytokine expression. Therapeutic
of carotid artery intima-medial thickening, as well as major cardio- interventions based on specific MiRs are under development, includ-
vascular events. Obesity, a risk factor for atherosclerosis, is now also ing, as noted previously, an inhibitor of MiR-33 to raise HDL levels
known to be a systemic inflammatory disorder, with evidence of and promote RCT. Unbiased “omics” studies to identify expression
inflammation readily detectable within obese central adipose tissue. levels of MiR–mRNA pairs that associate with cardiovascular risk or
Obese patients also have elevated, circulating levels of coagulation with circulating lipoprotein levels also show promise for both bio-
and inflammation biomarkers, including plasminogen activator marker development and therapeutic target discovery.
inhibitor-1 (PAI-1). Another very promising avenue of research in atherothrombosis
Given these observations, there has been renewed interest in is the gut microbiome. Elegant studies using mouse models and
exploring the use of antiinflammatory agents and antithrombotic human subjects have identified a “metaorganismal” pathway that
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agents to slow the progress of atherosclerosis. The approach has contributes both to the development of plaque and to the pro-
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been tempered by clinical studies showing small increases in ath- thrombotic state associated with atherosclerosis. Diets rich in
erosclerotic complications in patients taking cyclooxygenase (COX) phosphatidyl choline, choline, and carnitine (which are present in
inhibitors (especially those with preferential activity against COX2), meats, eggs, and cheese) can be metabolized in the gut by specific
but this may relate to the specific target and the complication of genera of microbes to generate trimethyl amine (TMA). TMA enters
altered eicosanoid production, perhaps changing the balance away the circulation and is then converted to trimethyl amine oxide
from antiatherothrombotic end products, such as prostacyclin and (TMAO) in the liver by flavin monooxidase enzymes. TMA and
resolvins, towards proatherothrombotic products, such as thrombox- TMAO levels in blood associate strongly with both risk of cardiovas-
ane, HETE, and lipoxins. Also, although aspirin and ADP receptor cular disease and arterial thrombosis in human subjects, and TMAO
antagonists definitively reduce risk for major cardiovascular events, was shown to promote platelet activation in vitro and thrombosis in
no studies have shown an impact on burden of atheroma. Nev- vivo in animal models. Importantly, the constitution of the gut
ertheless, novel agents targeted to more specific atherothrombotic microbiome can be influenced by diet, and thus the ability to generate
pathways, such as chemokines, LDL oxidation, SRs, lipoxygen- TMA and TMAO can also be influenced by diet. Human subjects
ases, phospholipase 2, leukotrienes, selectins, and IL-1 are being on vegan diets have much less ability to generate TMA/TMAO than
considered. 29 do carnivores and omnivores, and this could be restored simply by
adding back meat, eggs, or carnitine to the diet. Interestingly, athero-
thrombotic risk in mice could be transmitted from susceptible to
PLAQUE REGRESSION resistant strains by fecal microbiome transplant, and resistant strains
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could be converted to susceptible by antibiotic or dietary manipula-
Finding pharmacologic approaches to decrease the amount of arterial tion of the microbiome. These studies suggest that microbial enzymes
plaque has proved to be an elusive goal. Intravenous ultrasound has and/or ecosystems could be targeted for atherothrombosis treatment
shown that very aggressive lowering of LDL cholesterol with high- and prevention strategies.
dose statins and extremely rigorous dietary alterations can halt plaque Finally, although B cells are not prominent cellular constituents of
4
progression and, in some cases, cause some regression. As noted plaque, B1 subclass cells responsible for innate antibody generation
previously, strategies to enhance RCT or to induce macrophage are present in plaque from humans and experimental animals. These
emigration from plaque are being developed, and strategies to stabilize cells produce innate IgM antibodies, including a prevalent species
plaque by targeting the neovasculature, cellular apoptosis, and effe- called E06 that reacts with oxLDL. E06 and other autoantibodies
rocytosis are being considered. Specific antioxidant approaches based against plaque constituents may be protective, perhaps by facilitating
on fundamental understanding of the oxidation processes relevant to clearance of oxLDL via pathways that do not lead to foam cell
atherosclerosis remain viable as well, and much effort is being put formation, and/or by interfering with oxLDL-mediated activation
15
into developing new animal models to study plaque regression. of circulating monocytes and platelets. Based on these observa-
tions, passive immunization strategies against oxLDL are also being
considered.
ADDITIONAL FUTURE DIRECTIONS
Initial enthusiasm for large-scale genome-wide association studies
(GWAS) as discovery platforms to identify novel genes and pathways REFERENCES
that could be targeted with therapeutic or preventive effect has waned
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large genomic region on chromosome 9p21 as a risk site, but iden- Circulation 133:e38–e360, 2015.
tification of specific genes has not yet been accomplished with cer- 2. Libby P, Ridker PM, Hansson GK: Progress and challenges in translating
tainty. More recently, approaches moving beyond GWAS have the biology of atherosclerosis. Nature 473:317–325, 2011.
coupled whole-genome or whole-exome sequencing of highly selec- 3. Plump AS, Smith JD, Hayek T, et al: Severe hypercholesterolemia and
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high or low lipoprotein levels) followed by deep sequencing of specific recombination in ES cells. Cell 71:343–353, 1992.
candidate genes in larger cohorts. This approach has yielded new data 4. Nicholls SJ, Ballantyne CM, Barter PJ, et al: Effect of two intensive
identifying potential novel antiatherothrombosis targets; for example, statin regimens on progression of coronary disease. N Engl J Med
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of potential relevance to atherosclerosis diagnostics and therapeutics 6. Undurti A, Huang Y, Lupica JA, et al: Modification of high density
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