Page 976 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 69 Inflammation and Atherothrombosis 943

that endogenous as well as infectious factors may operate to CLINICAL PERSPECTIVE
promote atherothrombosis through this mechanism.
Endothelial erosion occurs on plaques scarcely calcified, less Precision medicine does not generally imply the creation of drugs
prone to expansive remodeling, and only sparsely inflamed. or medical devices that are unique to a single patient. Instead,
However, neutrophil infiltration that typically follows plaque precision medicine signifies the ability to classify individuals into
erosion is considered a hallmark of this distinct morphology of subpopulations that differ in their susceptibility to a particular
vulnerable plaques. No specific morphological features have been disease, in the biology and/or prognosis of those diseases they
identified to distinguish eroded plaques from stable plaques and may develop, or in their response to a specific treatment. Pre-
rupture-prone plaques, and both the limitation of imaging ventive or therapeutic interventions can then be concentrated
techniques and the relative lack of animal models have hampered on those who will benefit, sparing expense and side effects for
progress in this field. those who will not. Indeed, coronary thrombosis is the final
common pathway leading to ACS. More potent antithrombotic
regimens have recently been found to increase the risk of major
KeY COnCePts bleedings, which are associated in turn with a higher risk of
epidemiology of Ischemic Heart Disease mortality. Although the early outcome of ACS has consider-
• Main cause of morbidity and mortality ably improved in the past decade, cardiovascular diseases still
• Recurrence of ACS eventually leads to the pandemics of heart failure represent the main cause of morbidity and mortality overall.
and sudden cardiac death The rate of death, MI, and recurrent ACS at 1-year follow-up in
• Need for a reappraisal of the mechanisms responsible for coronary contemporary NSTE-ACS registries is still very high, approaching
instability and for innovative preventive and therapeutic strategies about 25%. Furthermore, recurrent ACS heralds a progressive
30
impairment of myocardial function leading to chronic heart
Current Concepts on atherosclerosis and Chronic Inflammation failure. Importantly, ischemic heart disease is by far the most
• Atherosclerosis is a chronic non-resolving inflammatory disease important cause of heart failure and thus a public health problem
• Atherosclerotic plaques can remain stable indefinitely
• The mechanisms responsible for coronary instability are multiple of pandemic proportions. Thus the best prevention of heart failure
is the prevention of recurrent episodes of coronary instability
Pathogenic Classification of acute Coronary syndromes (Table 69.4).
• Plaque fissure with systemic inflammation
• Plaque fissure without systemic inflammation
• Plaque erosion CLInICaL reLevanCe
• Functional alterations of coronary circulation (epicardial or microvascular
spasm) • Different mechanisms and triggers are involved in ACS. The pathogenic
classification of ACS might be a useful tool to select the best approach
Main Feature of Inflammation and Immunity associated With for different patients
Plaque Fissure • Histological studies have shown that ACS could be initiated by different
types of unstable plaque
• Often associated with systemic inflammation • Plaque fissure is strictly associated with systemic and coronary
• Widespread coronary inflammation inflammation, with an altered cross-talk between innate and adaptive
• Innate immunity activation (monocytes, neutrophils, Pattern Recognition immunity leading to the unbalance between pro- and anti-inflammatory
Receptors) stimuli
• Adaptive immunity alterations (unbalances between pro-inflammatory • Plaque erosion rely on less clear mechanisms, however an inflammatory
and anti-inflammatory activity)
trigger might be also involved, with different triggers as compared
with plaque fissure, such as hyaluronan exposure and PMN
Main Feature of Inflammation and Immunity associated With recruitment.
Plaque erosion
• Neutrophil accumulation
• Hyaluronan accumulation
• TLR2 activation Plaque Fissure With Systemic Inflammation
The experience gained in the diagnosis, risk stratification, and
management of chronic inflammatory diseases may provide
FUNCTIONAL ALTERATIONS OF important clues to the management of atherothrombosis. Exten-
CORONARY CIRCULATION sive studies regarding helper T-cell subset dysregulation in ACS
strongly support the notion that adaptive immunity is critically
Epicardial coronary vasospasm is a possible cause of ACS when involved in the disease process. Investigating the mechanisms
coronary angiography fails to demonstrate the presence of an underlying T-cell dysregulation is pivotal to identifying new clini-
1
obstructive atherosclerotic plaque. The mechanisms underlying cal biomarkers and potential therapeutic targets in the subset of
coronary spasm are multifold and may involve enhanced Rho ACS patients in whom a T cell–dependent inflammatory outburst
kinase activity in smooth muscle cells. is the likely cause of coronary instability. In this subset of ACS
Vasoconstriction causing ACS can be located also at the patients, raised levels of hs-CRP or of other soluble markers of
4,10
microvascular level. In particular, intense coronary microvascular inflammation are associated with a worse outcome. A specific
vasoconstriction plays an important role in the pathogenesis of adaptive immune system signature proved to be more predictive
Takotsubo syndrome, which is diagnosed by ischemic pain at than biomarkers in the identification of homogeneous subsets
16
rest, ischemic ST-segment changes, and rise in cardiac enzymes. of patients at higher risk for acute coronary event recurrence.
The syndrome also is characterized by a regional akinesia that A change of focus from soluble markers of inflammation to
more frequently affects distal myocardial regions but also is markers of adaptive immunity regulation, such as the molecules
associated with hypercontractility of the remaining regions. involved in TCR signaling, might be more rewarding.