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122 PA R T II / Physiologic and Pathologic Responses

Serum Amyloid A
Serum amyloid A (SAA) proteins, a family of inflammatory Table 5-3 ■ CARDIOVASCULAR RISK FACTORS
apolipoproteins, are major acute-phase reactants that are produced Cardiovascular Risk Factors
in response to various insults. 205 Their concentrations can increase
up to 1,000-fold during inflammation. 206,207 They bind HDL Nonmodifiable Risk Factors
with high affinity after their synthesis and participate in modifying Age Male Gender
cholesterol transport during inflammatory conditions. 205,208 SAA Modifiable Risk Factors
is synthesized primarily in the liver 207 and has been identified in Alcohol intake Hypertension Overweight and obesity
human atherosclerotic plaque. 209 Diabetes Lack of exercise Positive family history
Smoking
Left ventricular
Hypercholesterolemia
The exact role of SAA in atherogenesis has not been fully de- hypertrophy
fined. It is complicated by its role in the metabolism of HDL, in Emerging Risk Factors
which evidence suggests it may act as a signal for redirecting HDL C-reactive protein Hypertriglyceridemia Renin
to sites of tissue destruction and cholesterol accumulation. 210 In Fibrinogen Hyper-Lp(a) Uricemia
Hyperhomocysteinuria
Microalbuminuria
addition, SAA might influence HDL-mediated cholesterol efflux
by displacing apolipoprotein A-I from HDL 211 and by modulat-
ing the activity of lecithin cholesterol acyltransferase. 212 SAA may
contribute further to atherogenesis by participating in the remod- 7,174,228
eling of atherosclerotic plaque by inducing the secretion of colla- disease. Some modifiable risk factors can be altered to de-
genase from smooth muscle cells. 213,214 This in turn affects crease one’s risk of CVD. These factors include hyperlipidemia,
thrombus formation by inhibiting platelet aggregation and adhe- hypertriglyceridemia, hypertension, and cigarette smoking. Other
sion at the endothelial cell surface and increasing the oxidation of modifiable risk factors include diabetes mellitus type 2, obesity,
LDL. This causes adhesion and chemotactic recruitment of in- sedentary lifestyle, and ovarian hormone therapy. These factors re-
flammatory cells to the sites of inflammation in atherosclerotic main controversial in the role of contributing to coronary artery
coronary arteries. 215–217 SAA concentrations parallel those of disease. Nonmodifiable risk factors are variables that cannot be al-
CRP; some studies suggest SAA is a more sensitive marker of in- tered and include age, being male and younger than age 70, ge-
flammatory disease. 205 Concentrations of SAA are increased in netic predisposition, and diabetes mellitus type 1. Nontraditional
patients with CHD and seem to have a useful prognostic utility emerging risk factors include hyperhomocystinemia, hypoal-
with acute coronary syndromes. 169,218–220 Further epidemiologi- phalipoproteinemia, high lipoprotein A, and high iron levels. See
cal studies testing the diagnostic and/or prognostic usefulness of Chapter 32 for a complete overview of coronary risk factors.
SAA are required. Inheritance of CVD has been a subject of discussion for many
years, especially in relation to certain metabolic types and in stud-
von Willebrand Factor ies of families. In the past few years, several researchers have iden-
Factor VIII is one of the plasma proteins important for coagulation. tified gene polymorphisms with central obesity and metabolic
It is a complex of two components, each under independent genetic syndrome in CHD populations. Markers that have been identi-
229
resistin gene varia-
control and with biochemical function: (1) factor VIIIc, a coagula- fied include IL-1 gene polymorphism, 231,232 233
230
tion protein; and (2) factor VIIIvW, a platelet adhesion protein (also tion, a genomic region on chromosome 2 and fam5c.
known as von Willebrand factor [vWF]). vWF is a large protein In addition, inflammatory markers have been investigated with
234
complex necessary for normal platelet adhesion and acts as a bridge coronary disease, IL-6, monocyte chemoattractant protein-1,
between a receptor on the platelet surface and the exposed basement and CRP; albeit controversy still exists regarding the role of in-
membrane or subendothelial collagen. Factor VIIIc forms a com- flammatory mediators in coronary syndrome.
plex with vWF in plasma, with the latter acting as a carrier protein. Inflammation can be present in coronary vasospasm without
vWF, a glycoprotein synthesized in endothelial cells and megakary- significant homodynamic changes associated with coronary artery
ocytes, promotes thrombus formation by mediating platelet adhe- disease. Another genetic area of research with coronary syndrome
sion and aggregation. 221 It is released from endothelial cells and is gene therapy in treatment in coronary syndrome and congestive
platelets after endothelial damage and is a marker of endothelial heart failure. A genome scan in acute coronary syndrome has sug-
dysfunction, which in turn is an indicator of early atherogenesis. 222 gested the involvement of the gene encoding the insulin receptor
Several epidemiological studies have established an independ- substrate-1 gene. Some genes are likely relevant to the process of
ent positive association between vWF and CHD. 223–225 One atherosclerosis and thrombosis. Preliminary research has lead to
compelling report provided evidence of increased risk of reinfarc- targeting the heart with gene therapy-optimized gene delivery. In
tion and mortality in survivors of myocardial infarction with ele- addition, the 719Arg variant of Trp719Arg (rs20455), a polymor-
vated levels of vWF. 226 Initial reports of increased risk of stroke 223 phism in kinesin-like protein 6, is associated with greater risk of
failed to be corroborated in other population studies. 157,223,227 coronary events and has been found to have a greater benefit from
pravastatin as compared to placebo. 235

RISK FACTORS FOR CORONARY
ARTERY DISEASE INCIDENCE OF MYOCARDIAL
ISCHEMIA
Epidemiological studies have identified many important genetic
and environmental risk factors associated with atherosclerosis The incidence of myocardial ischemia is difficult to ascertain be-
(Table 5-3). Cardiac risk factors have been identified that precip- cause patients may have silent ischemia. Ischemic heart disease
itate and exacerbate the development of coronary artery parallels that of CHD, with approximately 1 in 5 deaths per