Page 970 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 69 Inflammation and Atherothrombosis 937

responsible for coronary instability are multiple and insufficiently the cause of coronary instability in all patients. However, about
understood. 40% of ACS patients have low or very low levels of high-sensitivity
C-reactive protein (hs-CRP), a very sensitive marker of inflam-
ROLE OF INFLAMMATION IN THE PATHOGENESIS mation. Coronary angiography fails to demonstrate obstructive
4
OF ACUTE CORONARY SYNDROMES atherosclerosis in up to one-third of patients with symptoms
suggestive of an ACS along with raised troponin levels and/or
Experimental models of atherogenesis have provided a growing ischemic-like ST segment changes, suggesting that functional
body of information about molecular mechanisms of plaque alterations of epicardial arteries and/or of coronary microcircula-
growth; however, transition from coronary stability to instability tion may also play an important pathogenetic role. 5
is less well understood due to lack of animal models reflective We have recently proposed a pathogenetic classification of
1
of human disease. The abrupt clinical presentation of ACS gives ACS: (i) patients with plaque fissure and systemic inflammation;
a strong signal of discontinuity in the natural history of athero- (ii) patients with plaque fissure without systemic inflammation;
thrombosis. When primary prevention of atherosclerosis fails, (iii) patients with plaque erosion; and (iv) patients with smooth
the progression of coronary atherosclerosis can remain clinically plaques and functional alterations in the coronary circulation
silent for years, decades, or even for life, as indicated by the high (Fig. 69.2). For the first group, multiple studies have highlighted
prevalence of coronary atherosclerosis in subjects dying of the prominent role of inflammation in generating plaque instabil-
noncardiac causes. In contrast, some patients at a certain point ity, with three main features characterizing these ACS patients:
in their lives exhibit acute coronary instability, followed by a (i) the widespread involvement of epicardial arteries, coronary
period of stability that can be short or last for years or decades. microcirculation, and myocardium; (ii) the activation of innate
These simple clinical observations suggest that the mechanisms immunity; and (iii) the activation of adaptive immunity, with
responsible for plaque growth and for plaque instability are a consequent dysbalance between antiinflammatory and proin-
different and that the causes and mechanisms of plaque instability flammatory immune responses.
are multiple. Accordingly, the paradigm that implies a single In patients in whom plaque rupture and coronary instability
type of culprit coronary plaque as a cause for instability does occur in the absence of systemic evidence of inflammation, the
1
not adequately fit the findings of postmortem studies. The precise causes of instability are still poorly understood. However,
concept that inflammatory cell activation plays a key role in the mechanisms such as extreme emotional disturbance, intense
pathogenesis of ACS is now commonly accepted, and it is believed physical exertion, and local mechanical stress at the level of the
that activation of inflammatory cells in the culprit stenosis is artery wall are likely to play a key pathogenetic role.

ACUTE CORONARY SYNDROMES

A B
• SMCs hyperreactivity • Local thrombogenic stimuli
• Proximal and/or distal spasm • Monocytes/PMN
recruitment
White/red
thrombus

Smooth plaque Plaque erosion

C D
NO EVIDENCE OF EVIDENCE OF
SYSTEMIC SYSTEMIC
INFLAMMATION INFLAMMATION
• Local or systemic stressors Plaque fissure • Innate immunity activation
• Adaptive immunity activation

FIG 69.2 Pathogenetic Classification of Acute Coronary Syndromes. In patients with a similar
clinical presentation, mechanisms responsible for coronary instability can be significantly different.
The figure shows optical coherence tomography (OCT) images of different plaques and the
proposed pathogenetic classification of acute coronary syndromes (ACS). This classification is
based on the mechanisms responsible for coronary instability in homogeneous groups of patients:
(D) patients with plaque fissure and systemic inflammation; (C) patients with plaque fissure
without systemic inflammation; (B) patients with plaque erosion; (A) patients with functional
defects in coronary circulation. PMN, Ppolymorphonuclear neutrophil; SMCs, smooth muscle
cells (SMCs).