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C HAPTER 5 / Atherosclerosis, Inflammation, and Acute Coronary Syndrome 119
Oxidative the complex participation of proinflammatory mediators in the
stress initiation and progression of CVD. 112
Endothelial Gender Inflammation is a key feature of all stages of atherothromboge-
dysfunction and age nesis. This paradigm shift has prompted the search for inflamma-
tory, as well as hemostatic, markers, which may reflect current risk
or predict future CVD. Their identification is also tantalizing in
their potential to serve as targets for new therapeutic interventions,
or provide more appropriate targeting of established therapies. It is
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present, there remains insufficient evidence to support incorpora-
tion of any of these risk markers into routine clinical practice. A
description of those inflammatory markers with sustained and con-
sistent evidence of a role in CVD is examined below.
Inflammation Insulin
resistance Brain Natriuretic Peptide
Thrombogenesis The heart is an endocrine organ. Natriuretic peptides are neuro-
hormones produced by the heart, which participate in an impor-
■ Figure 5-4 Myriad population studies, animal models of disease
and biochemical studies have demonstrated the participation and tant counter-regulatory system to balance the effects of sympa-
complex interaction of lipid metabolism, endothelial function, carbo- thetic neurohormones. Brain natriuretic peptide (BNP) is a
hydrate metabolism, thrombogenesis, oxidative stress and inflamma- cardiac neurohormone secreted from the ventricles of the heart in
tion in the occurrence of cardiovascular disease. response to ventricular volume expansion and pressure over-
load. 113 BNP is a diuretic, a natriuretic, and a vasorelaxant. 114
Secreted in a precursor form (ProBNP), it is cleaved into two frag-
CVD-related morbidity and mortality, more than 35% of CVD ments: physiologically active BNP and a biologically inactive frag-
occurs among those without any known risk factors. 106 This ob- ment (NTproBNP). 115 NTproBNP has a longer biological half-life
servation motivates a large part of the medical research commu- than BNP, is more stable in serum and plasma, and is a more spe-
nity to identify novel markers of disease, including inflammatory cific marker of cardiac activity than BNP.
markers of CVD. Epidemiologic studies indicate that BNP and NTproBNP are
It is now abundantly clear that CVD is the result of the inter- useful prognostic indicators after the onset of heart failure, 116,117
action of multiple physiological processes. Myriad population transmural myocardial infarction, 118,119 and non-ST segment
studies, animal models of disease, and biochemical studies have elevation acute coronary syndromes. 120 In addition, they appear to
demonstrated the participation and interaction of lipid metabo- be sensitive diagnostic markers of myocardial diseases: hypertrophy
lism, endothelial function, carbohydrate metabolism, thromboge- and ventricular dysfunction. 116,121 Therapy that modifies
nesis, oxidative stress, and inflammation in the occurrence of NTproBNP has been shown to not only reduce total cardiovascu-
CVD (Fig. 5-4). Inflammation is the process by which the body lar events but also delay time to first event. 122 Of particular interest
responds to injury. Laboratory evidence and findings from clinical is the mounting evidence that these biomarkers are effective prog-
and population studies suggest that inflammation plays an impor- nostic indicators of mortality in the general population. 117,123
tant role in all stages of atherosclerosis. 107 The demonstration of
the presence of inflammatory cytokines in patients with heart fail- Circulating Adhesion Molecules
ure immediately sparked interest in the role that these molecules When inflammatory markers come into contact with endothelial
play in regulating cardiac structure and function, particularly with cell membranes, they produce a series of proteins termed adhesion
respect to their potential role in the progression of heart failure. molecules. Activation of endothelial cells and platelets is an im-
The goal of understanding the role of inflammatory mediators portant mediator of atherothrombosis. 124 Adhesion molecules are
in heart failure derives from the observation that many aspects of specific proteins that regulate the different steps of leukocyte mi-
the syndrome of heart failure can be explained in large part by the gration from the blood stream into the vessel wall. 125–127 Markers
biological effects of proinflammatory cytokines. When expressed of endothelial cell and platelet activation, such as soluble adhesion
in the circulation at sufficiently high concentrations, cytokines are molecules, can be measured in plasma. Soluble forms of adhesion
potent enough to recapitulate many facets of heart failure, includ- molecules occur on enzymatic cleavage of membrane-bound mol-
ing progressive left ventricular dysfunction and remodeling, pul- ecules, which serve as markers of endothelial cell activation and in-
monary edema, and cardiomyopathy. 108–110 Growing experimen- flammation. 128 Intracellular adhesion molecule I (ICAM-I), vas-
tal evidence suggests that heart failure progresses in part as a result cular adhesion molecule I (VCAM-I), and E-selectin are three such
of the deleterious effects of cytokines in the heart and peripheral proteins that are expressed in response to inflammatory markers
circulation, thus exacerbating heart failure. 111 What is also clear is such as interleukin 1 (IL-1), TNF- , and interferon- ). 129,130
that the sustained expression (in clinical terms), caused by high- Leukocyte migration is a definitive early event in atherogenesis,
level production of inflammatory mediators inducing maladaptive and expression of these adhesion molecules can be detected in ath-
effects in the heart or cardiovascular system as a whole. erosclerotic plaques. 131–133 Elevated levels of the soluble forms of
Appreciation of the pathophysiological consequences of sus- E-selectin, ICAM-1, and VCAM-1 are found in the plasma of pa-
tained expression of proinflammatory mediators in preclinical and tients with stable angina and acute coronary syndromes. 134
clinical heart failure models has led to a series of multicenter clin- Circulating adhension molecules are independent of other risk
ical trials in patients with moderate to advanced heart failure. The factors. 22 Soluble (s)VCAM-1, sICAM-1, and sE-selectin are cur-
often contradictory outcomes of these clinical trials underscore rently measured by commercial enzyme-linked immunoabsorbent