Page 971 - Clinical Immunology_ Principles and Practice ( PDFDrive )

938 Part seven Organ-Specific Inflammatory Disease

The mechanisms of plaque erosion are still largely unknown, perfused by the culprit artery. This event appears unrelated to
although increasing evidence suggests that local neutrophil coronary atherosclerosis or recurrent ischemia, as it is not
activation possibly plays a role. observed in patients with chronic SA and multivessel coronary
11
Among the majority of patients who present with ACS in the disease or in patients with vasospastic angina. Widespread acute
absence of obstructive atherosclerosis, functional alterations of coronary inflammation is, therefore, the likely cause of multiple
epicardial coronary arteries or of coronary microcirculation are complex stenoses, multiple thrombi, and multiple fissured plaques
the likely cause of instability. involving different coronary artery branches observed in clinical
6
studies in ACS, based on angiography and intravascular imaging.
The number of disrupted coronary plaques correlates with
PLAQUE FISSURE WITH SYSTEMIC systemic hs-CRP levels. The notion of widespread coronary
INFLAMMATION inflammation is confirmed by postmortem studies. 1

Plaque fissure is caused by the combined action of metallopro- Activation of Innate Immunity
teinases, which digest the intercellular matrix and reduce collagen The notion that innate immunity plays an important role in
synthesis. This results in the exposure of the highly thrombogenic ACS is supported by the demonstration of activated monocytes,
content of the underlying lipid plaque that triggers occlusive or polymorphonuclear neutrophils (PMNs), eosinophils, and mast
subocclusive thrombus formation. cells not only at the site of plaque rupture but also in the whole
1
coronary circulation of patients with ACS (Fig. 69.3). High
Plaque Fissure: Pathological and Clinical Findings telomerase activity in PMNs has been reported coming from
The role played by plaque fissure was initially established in the culprit coronary plaque of patients with ACS, but not from
postmortem studies and then confirmed in vivo by using plaque of patients with SA or in PMNs from the peripheral
angioscopy, intravascular ultrasound, and, more recently, optical blood. Telomerase activity is normally absent in differentiated
coherence tomography (OCT), a light-based imaging technique cells such as PMNs. The only predictor of telomerase reactivation
with high spatial resolution. OCT allows the detection of intra- in coronary plaques of ACS patients was a short time interval
coronary thrombi and the precise measurement of fibrous cap from symptom onset to PMN sampling. Neutrophil apoptosis
thickness and plaque components such as lipid core, calcium has been identified as one of the key mechanisms to switch off
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nodules, and microvessels. OCT has been used in clinical studies inflammation. Accordingly, delayed apoptosis of peripheral PMNs
to obtain more detailed information about the vulnerable plaque in ACS patients has been demonstrated. 12
and to find specific features to differentiate between erosion-prone Macrophages account for the majority of leukocytes in
and rupture-prone plaques. In particular, the high resolution of plaques. Plaque-resident macrophages differentiate from
OCT has recently clarified that in vivo plaque rupture is associated monocytes recruited from circulating blood. However, monocytes
with ACS in about half of patients. It is worth noting that fissures represent a heterogeneous cell population, exemplified by the
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do not necessarily lead to ACS, as asymptomatic plaque fissure differential expression of CD14 and CD16. Human coronary
is a frequent event leading to plaque progression. Yonetsu et al. artery lesions contain macrophage subpopulations with different
using OCT found that about 15% of patients with SA presented gene-expression patterns. Patients with coronary atherosclerosis
+
+
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with plaque fissure. A larger plaque burden, a thinner fibrous have higher numbers of circulating CD14 CD16 monocytes than
lo
hi
cap, and a smaller lumen size appear to predispose to thrombus healthy subjects. Finally, peak levels of CD14 CD16 monocytes
formation and ACS. 8 after acute MI correlate negatively with the recovery of left
Among the several inflammatory biomarkers tested in ACS, ventricular ejection fraction 6 months after MI. Noninvasive
levels of hs-CRP are typically elevated, in line with CRP’s high imaging technologies have now been developed to follow and
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sensitivity and wide dynamic range. However, it is difficult to quantify subpopulations of monocytes and macrophages in vivo.
establish a cutoff at the present time. Whereas in primary preven- Monocytes accumulated within thrombi, obtained during
tion hs-CRP levels ≥2 mg/L (and even ≥1 mg/L) might be recom- primary PCIs, specifically overexpress Toll-like receptor 4 (TLR4),
mended, in ACS patients two different cutoffs have been suggested together with specific patterns of locally expressed chemokines
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as clinically useful: an admission value ≥10 mg/L and a discharge and cytokines compared with circulating monocytes. TLR are
value ≥3 mg/L. These cutoffs, although confirmed in larger studies, key pattern-recognition receptors expressed by innate immunity
have not yet led to a general consensus. 4,10 cells that recognize a large number of pathogen-associated
Experimental studies have clarified the molecular mechanisms molecular patterns (PAMPs). Interestingly, Niessner et al. dem-
through which activation of inflammatory cells in the plaque can onstrated that interferon (IFN)-α produced by plasmacytoid
trigger thrombus formation. Inflammatory responses increase the dendritic cells in atherosclerotic plaques could enhance TLR4
fragility of the fibrous cap as well as the thrombogenic potential signaling by sensitizing these cells to lipopolysaccharide and other
of the plaque. The main mediators of inflammation-induced microbial molecules as well as to (modified) endogenous
activation of coagulation are proinflammatory cytokines. molecules, all abundantly present in the atherosclerotic lesion
Several studies have shown the importance of IL-6 in the initia- microenvironment. These sensitized antigen-presenting cells
tion of coagulation activation and the role of tumor necrosis (APCs) strongly upregulate the production of cytokines such as
factor-α (TNF-α) and IL-1 in the modulation of anticoagulant TNF-α, IL-12, IL-23, and matrix metalloproteinase-9 (MMP-9),
pathways. thus enhancing plaque instability. 15
It has been demonstrated that human platelets express
Widespread Coronary Inflammation functional TLRs capable of recognizing bacterial components.
In patients with ACS and systemic evidence of inflammation, TLR activation directly induces platelet aggregation and increased
widespread coronary inflammation is suggested by transcardiac platelet adhesion to collagen under flow conditions. Moreover,
neutrophil activation in the effluent of myocardial regions not stimulation of TLR, in particular TLR2, induces a significant