Journal of the American College of Cardiology Vol. 41, No.

7, 2003
© 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00
Published by Elsevier Science Inc. doi:10.1016/S0735-1097(03)00088-3

STATE-OF-THE-ART PAPER

Atherothrombosis, Inflammation, and Diabetes

Giuseppe G. L. Biondi-Zoccai, MD, Antonio Abbate, MD, Giovanna Liuzzo, MD,
Luigi M. Biasucci, MD, FACC
Rome, Italy
Diabetes represents a major cause of cardiovascular morbidity and mortality in developed
countries, and atherothrombosis accounts for most deaths among diabetics. Recent evidence
has reliably shown the relevant etiopathogenetic role of inflammation in atherothrombotic
disease. This review summarizes and discusses the possible synergistic effects of diabetes and
inflammation in promoting atherothrombosis and its complications, as well as potential
avenues for diagnostic, preventive, and therapeutic benefits in the modulation of inflamma-
tory mechanisms in diabetic atherothrombotic disease. (J Am Coll Cardiol 2003;41:
1071–7) © 2003 by the American College of Cardiology Foundation

Diabetes mellitus has been recognized as an independent
major cardiovascular risk factor since the publication of the
first large-scale epidemiologic investigations in the 1970s
(1). There are over 100 million people worldwide with
diabetes (5% to 8% of overall population), and this number
is likely to increase significantly in the near future. Accord-
ing to data from clinical studies, most diabetics die of
cardiovascular disease, and atherothrombosis accounts for
about 8 of 10 of all diabetic deaths (2). Diabetes mellitus, in
the absence of previous cardiovascular disease, may confer a
risk of adverse cardiovascular events similar to that faced by
nondiabetic individuals who have already had a previous
myocardial infarction, thus representing a “coronary risk
equivalent” and, therefore, diabetic patients should join
secondary prevention programs, regardless of their cardio-
vascular history (3,4). Moreover, diabetic patients, consti-
tuting about 15% to 20% of patients presenting with acute
coronary syndromes, are at considerably increased risk of
excess morbidity and mortality, as compared with nondia-
betic patients, as diabetics’ risk of adverse events is twice
that of nondiabetics, even in the most recent experimental
or observational clinical studies.
Diabetes and related metabolic diseases, such as hyper-
insulinemia, insulin resistance, and central obesity, are
recognized as major contributors to cardiovascular morbid-
ity and mortality. Interestingly, recent and compelling
evidence has shown the significant and independent role of
systemic and coronary inflammation in the initiation, pro-
gression, and precipitation of atherothrombosis superim-
posed on traditional risk factors (5). Given the increasing
prevalence of diabetes and dysmetabolic syndrome, the
diffuse atherosclerotic burden of diabetics, the possible
synergistic effect of diabetes and inflammation in athero-
sclerosis, as well as the potential for a preventive and
therapeutic benefit in the modulation of inflammation in
diabetics, this review covers the basic epidemiologic and
From the Institute of Cardiology, Catholic University, Rome, Italy.
Manuscript received August 15, 2002; revised manuscript received October 31,
2002, accepted November 19, 2002.
pathophysiologic aspects underlying these two disease pro-
cesses (Fig. 1).
DIABETES MELLITUS,
ATHEROTHROMBOSIS, AND INFLAMMATION
The pathophysiologic process of atherosclerosis has been
schematically summarized in several steps, each of them
characterized by significant involvement of humoral and
cellular inflammatory elements (5). Pathologic, angio-
graphic, and other in vivo studies have shown that diabetes
favors diffuse and accelerated progression of atherosclerosis
(6). Diabetic plaques are also more commonly complicated
and at greater risk of subsequent complications. Moreover,
diabetics who die suddenly show an increased number of
fissured atherosclerotic plaques, as compared with nondia-
betics (7). In fact, the results of angioscopic examination
show that diabetic patients with unstable angina have a
higher incidence of plaque ulceration and intracoronary
thrombus formation than nondiabetic patients, and diabetic
plaques usually have a greater lipid core burden and a richer
inflammatory component and are more commonly compli-
cated by overlying thrombosis (8).
Genetic abnormalities. Several genetic abnormalities in
glycemic metabolism have been associated with the devel-
opment of diabetes, diabetic complications, or aspects of the
dysmetabolic syndrome. All of these derangements could be
also involved in atherogenesis. Transcription factors, such as
peroxisome proliferator-activated receptor (PPAR)-alpha
and -gamma, are now being intensively studied. Whereas
PPAR-alpha primarily stimulates the beta-oxidative degra-
dation of fatty acids, PPAR-gamma promotes lipid storage
by regulating adipocyte differentiation. Peroxisome
proliferator-activated receptor-alpha is the molecular target
of lipid-lowering drugs such as fibrates, and PPAR-gamma
interacts with insulin-sensitizer drugs such as thiazo-
lidinediones, and they may significantly modulate athero-
genicity and inflammation. In particular, mutations in the
PPAR-gamma gene have recently been shown to be asso-
1072 Biondi-Zoccai et al. JACC Vol. 41, No. 7, 2003
Atherothrombosis, Inflammation, and Diabetes April 2, 2003:1071–7

ciated with diabetes, glucose intolerance, and hypertension

Abbreviations and Acronyms (9).
AGEP ⫽ advanced glycation end products The role of transcription factors in homeostasis and
CRP ⫽ C-reactive protein disease is quite complex and still unclear, owing to the
HDL ⫽ high-density lipoprotein
ICAM-1 ⫽ intercellular adhesion molecule-1
heterogenicity, cell specificity, and pleiotropy of their ef-
I-kappa-B ⫽ NF-kappa-B–inhibiting protein fects. However, substantial evidence has shown that
IL ⫽ interleukin PPARs often interact intracellularly with another tran-
LDL ⫽ low-density lipoprotein scription factor, nuclear factor-kappa-B (NF-kappa-B),
NF-kappa-B ⫽ nuclear factor-kappa-B
NO ⫽ nitric oxide
whose activities are mainly proinflammatory and prolifera-
PAI-1 ⫽ plasminogen activator inhibitor-1 tive. Peroxisome proliferator-activated receptor-alpha–
PPAR ⫽ peroxisome proliferator-activated receptor deficient mice show a prolonged systemic acute-phase
TNF-alpha ⫽ tumor necrosis factor-alpha response and a local innate and immune inflammatory
VCAM-1 ⫽ vascular cell adhesion molecule-1
reaction to common noxious stimuli, whereas PPAR-alpha

Figure 1. The pathogenetic mechanisms involved in the initiation of subclinical atherosclerosis and progression to atherosclerotic clinical events in diabetic
patients include infection, inflammation, hyperglycemia, insulin resistance, dyslipidemia, and thrombosis. AGE ⫽ advanced glycation end products; CRP ⫽
C-reactive protein; HDL ⫽ high-density lipoprotein; HTN ⫽ hypertension; IL-6 ⫽ interleukin-6; LDL ⫽ low-density lipoprotein; PAI-1 ⫽ plasminogen
activator inhibitor-1; SAA ⫽ serum amyloid A protein; TF ⫽ tissue factor; TG ⫽ triglycerides; tPA ⫽ tissue-type plasminogen activator.
JACC Vol. 41, No. 7, 2003
April 2, 2003:1071–7
activation appears to decrease vascular cell adhesion
molecule-1 (VCAM-1) expression by activated endothelial
cells, thereby switching off the proatherogenic-activated
endothelium (10). Moreover, PPAR-alpha selectively
downregulates human aortic smooth muscle cell secreting
and proliferating activities (11). In particular, ligands of this
transcription factor inhibit interleukin (IL)-1–induced pro-
duction of IL-6 and prostaglandin and expression of
cyclooxygenase-2 in endothelial cells. In hyperlipidemic
patients, fenofibrate-dependent PPAR-alpha activation de-
creases levels of IL-6, fibrinogen, and C-reactive protein
(CRP) (11). On the other hand, thiazolidinedione-activated
PPARs inhibit both the proliferation and migration of
vascular smooth muscle cells. In endothelial cells, the
PPAR agonist troglitazone markedly attenuates tumor
necrosis factor-alpha (TNF-alpha)–induced expression
of VCAM-1 and intercellular adhesion molecule-1
(ICAM-1), whereas apolipoprotein E-deficient mice
treated with troglitazone show reduced monocyte/
macrophage homing to atherosclerotic plaques (12). Finally,
the combined activation of PPAR-alpha and -gamma
appears to decrease CRP-mediated production of monocyte
chemoattractant protein-1 by human endothelial cells, an
effect similar to that achieved by simvastatin. Moreover,
type 2 diabetic patients treated with troglitazone have
increased levels of NF-kappa-B–inhibiting protein
(I-kappa-B) and reduced NF-kappa-B activity, as well as
systemic levels of reactive oxygen species, plasminogen
activator inhibitor-1 (PAI-1), and CRP (13). Accordingly,
the human promoter polymorphism 174 G/C of the IL-6
gene has been associated with an increased risk of cardio-
vascular disease and hypertension (14).
Dyslipidemic abnormalities. Diabetics usually show de-
creased high-density lipoprotein (HDL) cholesterol levels
and increased low-density lipoprotein (LDL) cholesterol
and triglyceride levels. Diabetes is most often associated
with smaller, denser LDL that is more susceptible to
oxidation and thus has greater atherogenicity (5). Even if
diabetic patients with good glycemic control may have LDL
levels similar to or slightly lower than those of nondiabetic
individuals, fasting and postprandial levels of triglyceride-
rich lipoproteins, especially very-low-density lipoprotein,
are higher and those of HDL are lower than those of
nondiabetics (15). In addition, glycation of LDL and other
lipoproteins is quite common in diabetes, thus making the
lipoproteins of diabetic patients more susceptible to oxida-
tion and more atherogenic. Finally, several clinical studies
have shown the benefit of lipid-lowering strategies in
diabetics, even in cases of modestly increased or normal
cholesterol levels, and these benefits are often greater than
those found in nondiabetic patients (16).
Oxidative stress. Diabetics have decreased antioxidant ac-
tivity and increased oxidative burden (17), and hyperglyce-
mia increases the production of reactive oxygen species.
These may shift the oxidant-antioxidant balance toward
nonenzymatic oxidation of lipoproteins, thus contributing
Biondi-Zoccai et al. 1073
Atherothrombosis, Inflammation, and Diabetes
to atherogenic processes. It has also been hypothesized that
reactive carbonyl groups may overwhelm the antioxidant
mechanism of diabetic patients, leaving them unprotected
to common oxidative stressors such as smoking.
Advanced glycation end products (AGEP). Diabetic hy-
perglycemia characteristically leads to nonenzymatic glyca-
tion of common macromolecules, as usually assessed
through hemoglobin A1c (18). Nonenzymatic macromolec-
ular glycation leads to the production of biomacromolecular
aggregates known as AGEP. Glycated molecules as well as
AGEP have been implicated in LDL modification, accu-
mulation, and inflammatory activation. Oxidation of AGEP
seems to play an important and perhaps primary role in
initiating and amplifying lipid oxidation, thus contributing
to the atherogenic profile of diabetics (19). Macromolecular
glycated complexes increase arterial intimal noncellular
growth and may involve proteins, nucleic acids, and lipid
structures. The formation of complex and less degradable
macromolecular aggregates and the impairment of scaven-
ger cells cause quantitative imbalances in lipid levels and
abnormal vascular clearance of proatherosclerotic lipids
(20). Specific receptors for AGEP have been described, and
their modulation has shown antiatherosclerotic effects in
mice, whereas in normal rabbits, AGEP induces endothelial
VCAM-1 and ICAM-1 expression and promotes atheroma
formation (21).
Prothrombotic and antifibrinolytic abnormalities.
Diabetes has several prothrombotic effects possibly involved
in the initiation of atherosclerotic plaque, its progression,
and complication. Diabetic rats show increased platelet
adhesiveness and aggregability after common platelet-
activating stimuli, such as adenosine and collagen (22).
Platelet dysfunction is probably due in part to increased
catabolism of arachidonic acid and increased production of
thromboxanes. Diabetes is also associated with increased
levels of fibrinogen, von Willebrand factor, factor VII,
factor VIII, platelet factor 4, and PAI-1 levels. Peroxisome
proliferator-activated receptor-alpha dysfunction or de-
creased activity seems to play a role in hyperfibrinogenemia
(11), and fibrates may determine a reduction in fibrinogen
levels through PPAR-alpha activation. Diabetic and hyper-
insulinemic patients typically exhibit increased production
of PAI-1 from visceral abdominal adipocytes. Finally, it is
likely that elevated levels of tissue factor and PAI-1 and
reduced levels of tissue-type plasminogen activator are
associated with increased IL-6 production from adipocytes
(according to the hypothesis of obesity as an inflammatory
disease).
Dysmetabolic syndrome. The concept of dysmetabolic
syndrome (metabolic syndrome X or insulin resistance
syndrome) stands at the crossroads of hyperglycemia, overt
type 2 diabetes mellitus, inflammation, and atherosclerosis
(Fig. 2) (23). It is defined as a condition characterized at
least in part by one or more of the following: glucose
intolerance, relative hyperinsulinemia, peripheral insulin
resistance, visceral or abdominal obesity, increased serum
1074 Biondi-Zoccai et al.
Atherothrombosis, Inflammation, and Diabetes
Figure 2. Reciprocal interplay between inflammation and diabetes mellitus in the pathogenesis of atherothrombosis, with emphasis on both the role of
inflammation in the development of overt diabetes mellitus and the proinflammatory action of hyperglycemia and insulin resistance. Potential or established
modulating agents are shown by dashed arrows. ACEi ⫽ angiotensin-converting enzyme inhibitors; ARB ⫽ angiotensin receptor blockers; PPAR ⫽
peroxisome proliferator-activated receptor.
triglyceride concentrations, hyperuricemia, microalbumin-
uria, hypertension, and endothelial dysfunction. All of these
entities have in common the same final effect of hyperinsu-
linemia, low-grade inflammation, and metabolic dysfunc-
tion. However, diabetes and the dysmetabolic syndrome
seem to have both an independent detrimental effect on
cardiovascular outcomes, as shown by studies that adjusted
for insulin levels, diabetic status, and glycemic control (24).
Hyperinsulinemia is also an independent and significant risk
factor for coronary heart disease development in apparently
healthy subjects. The overwhelming prevalence of this
syndrome has prompted the proposal of the so-called
“thrifty gene hypothesis,” according to which in relatively
early times, the ability to store fat may have conferred
survival advantage, thus enriching ethnic groups of genes
facilitating fat storage without negative feedback control
(25). Several pathophysiologic mechanisms have been pro-
posed, including abnormalities in leptin gene expression,
decreased activity of PPAR-alpha, and primary inflammatory
or infective processes. Nonetheless, the concept of the dys-
metabolic syndrome has re-emphasized the metabolic and
inflammatory role of adipocytes. In fact, among the several
cellular elements involved in vascular inflammation, adipocytes
merit great interest, as dysfunction in lipid metabolism is
characteristic of diabetes, and as adipocytes have recently been
shown able to produce IL-6 and TNF-alpha (26).
Role of inflammation in development of diabetes mellitus.
Although it is plausible to accept diabetes as a trigger for
vascular inflammation, the converse is also true, as substan-
tial evidence has shown that low-grade inflammation is an
important pathogenetic determinant of type 2 diabetes. In
the West of Scotland Coronary Prevention Study, increased
CRP levels significantly predicted the risk of later develop-
ing type 2 diabetes, and this risk was independent of body
JACC Vol. 41, No. 7, 2003
April 2, 2003:1071–7
mass index, fasting triglyceride or glucose levels, or statin
use (27). Moreover, a high white blood cell count was an
independent predictor of a worsening insulin action and the
development of type 2 diabetes in Pima Indians (28), as well as
in U.S. adult women (29). Increased levels of other markers of
inflammation, such as sialic and orosomucoid acid, are also
associated with the later occurrence of diabetes (30).
More recently, an abundance of clinical evidence has
confirmed the pathogenetic role of inflammation in the
onset of diabetes, showing that anti-inflammatory agents,
such as statins (31), PPAR agonists (32), and other drugs,
including angiotensin-converting enzyme inhibitors (33),
may prevent or delay the onset of diabetes in high-risk
subjects. Trials are currently underway to further validate
this exciting hypothesis.
Role of nitric oxide (NO) in inflammation. Nitric oxide
has several pleiotropic functions in the vascular milieu,
beyond its well-known vasodilating capabilities. In vitro,
NO selectively inhibits IL-1–induced VCAM-1 expression
on endothelial cells. This inhibition is paralleled by reduced
monocyte adhesion to endothelial monolayers. Nitric oxide
also decreases the endothelial expression of other leukocyte
adhesion molecules (E-selectin and, to a lesser extent,
ICAM-1) and secretable cytokines (IL-6 and -8). Molecu-
lar assays indicate that NO represses VCAM-1 gene tran-
scription, in part by inhibiting NF-kappa-B (34). The
expression of macrophage colony-stimulating factor in en-
dothelial cells, an important regulating factor of
macrophage-derived foam cells in atherosclerotic lesions, as
induced by oxidized LDL or TNF-alpha, is significantly
downregulated by NO through inhibition of NF-kappa-B
(35). The precise mechanisms of NO-mediated NF-kappa-B
inhibition are probably the induction and stabilization of
I-kappa-B-alpha.
JACC Vol. 41, No. 7, 2003
April 2, 2003:1071–7
Role of cytokines and infectious agents. Experimental
observations have demonstrated the central mechanistic
relevance of several cytokines and chemokines networks in
atherosclerotic processes (5). In this regard, diabetes, insulin
resistance, and glucose intolerance all seem to have impor-
tant modulating effects, with global proatherosclerotic ac-
tivity. At least partly as a consequence of hyperglycemia and
imbalances in insulin homeostasis, diabetes commonly in-
duces abnormalities in the expression and activity of various
cytokines and vasoactive peptides, such as TNF-alpha,
IL-6, angiotensin II, and endothelin-1 (36). Serum levels of
TNF-alpha, IL-6, and several adhesion molecules are sig-
nificant predictors of future cardiovascular events in healthy
subjects as well as diabetics, and in diabetic patients,
increased VCAM-1 levels are independently associated with
cardiovascular mortality (37). Interleukin-1 and TNF-alpha
are produced by inflammatory cells in the atherosclerotic
plaque and induce the release of IL-6 from several cell types,
including smooth muscle cells. Furthermore, circulating
IL-6 stimulates the hypothalamic-pituitary-adrenal axis,
activation of which is associated with central obesity, hy-
pertension, and insulin resistance (38). Thus, it is intriguing
that overweight and obese individuals have increased serum
levels of CRP, IL-6, TNF-alpha, and leptin. Actually, it has
been recently shown that IL-6 levels decrease in obese
women after significant weight loss (39).
Hyperglycemic patients demonstrate a significant pro-
duction of AGEP, which are specifically recognized by
inflammatory cells in atherosclerotic plaque, and induce the
release of inflammatory cytokines. These mediators stimu-
late endothelial and smooth muscle proliferation, endothe-
lial activation, and collagen overproduction, thus contribut-
ing to plaque growth and progression. C-reactive protein, a
nonspecific marker of inflammation that also has a direct
inflammatory activity in atherosclerosis, has been associated
for a decade with adverse cardiovascular outcomes in pa-
tients with coronary artery disease as well as in healthy
subjects (40,41). Interestingly, levels of CRP are higher in
diabetics than in nondiabetics. Although elevated CRP
levels in diabetics may depend on adipocyte activation or
dysfunction, an additional hypothesis is that elevation of
CRP might be associated with a low-grade inflammatory
response driven by invading pathogens, as infections are
very common in diabetics (42). The role of infectious agents
in the pathogenesis of atherothrombosis might indeed be
greater in diabetics than in nondiabetics, given the increased
pathogen burden and decreased defense mechanisms of the
former. Among the putative organisms, possible culprits
include Chlamydia pneumoniae, Helicobacter pylori, cytomeg-
alovirus, and herpes simplex virus (43). Diabetes may affect
several steps of the host-infectious organism interaction.
Poor glycemic control may lead to excessive AGEP produc-
tion, vascular inflammation, and increased endothelial per-
meability, thus permitting bacterial or viral infiltration and
infection of fatty streaks and, later, atheromatous plaques.
Moreover, micro-organisms may contain molecules capable
Biondi-Zoccai et al. 1075
Atherothrombosis, Inflammation, and Diabetes
of eliciting host dysimmune responses through molecular
mimicry (44). This may occur more often in an individual
with greater global inflammatory burden and reactivity, as
well as inflammatory dysfunction, such as in a diabetic.
Individuals infected with multiple pathogens such as
herpes viruses, cytomegalovirus, Helicobacter pylori, and
hepatitis A virus have higher CRP levels and the greatest
relative risk of coronary artery disease. Thus, pathogens
might contribute to the atherosclerotic process by promot-
ing inflammatory responses, whereas infection may promote
vessel wall injury initiated by oxidized lipids, smoking-
derived oxidants, hypertensive shear, glycooxidized mole-
cules, or a combination of these factors.
Among the putative cytokines involved in atherosclerosis,
IL-6 appears to link local and systemic inflammation and
the hepatic acute-phase response, acting as a messenger
molecule, causing rises in CRP, serum amyloid A protein,
and fibrinogen, as well as a decrease in albumin. Notwith-
standing the role of inflammation in diabetic atherosclero-
sis, there is a strong and suggestive association between
typical characteristics of insulin resistance and chronic
low-grade inflammation. For instance, in nondiabetic sub-
jects, levels of CRP and concentrations of the proinflam-
matory cytokines IL-6 and TNF-alpha are related to obe-
sity. Moreover, CRP concentrations are related to insulin
resistance, as calculated from the homeostasis assessment
model, blood pressure, HDL, and triglycerides, and to
markers of endothelial dysfunction. Similar conclusions
have been reached, even by the assessment of noncoronary
atherosclerosis, as CRP levels are partially associated with
dysmetabolic syndrome markers and, together with them,
predict carotid artery atherosclerosis (45). These data seem
to indicate that adipose tissue is an important determinant
of a low-level, chronic inflammatory state, as reflected by
levels of IL-6, TNF-alpha, and CRP, thus supporting the
hypothesis that such a low-level, chronic inflammatory state
may induce insulin resistance and endothelial dysfunction
and, therefore, link the latter phenomena with obesity and
cardiovascular disease (46).
INFLAMMATORY MARKERS,
DIABETES MELLITUS, AND RISK PREDICTION
A decade ago, elevated systemic markers of inflammation
were found for the first time to predict adverse events in
patients with severe unstable angina (40). Since then, the
concept of predicting cardiac events by means of plasma
markers has been proposed and, at the same time, chal-
lenged in several studies in both primary and secondary
prevention. These data suggest an important independent
prognostic value of CRP in predicting adverse outcomes in
the short- and long-term follow-up of patients presenting
with acute coronary syndromes and also in apparently
healthy individuals (47,48).
In consideration of the overlap between inflammatory
status and diabetic derangements, some authors have also
1076 Biondi-Zoccai et al.
Atherothrombosis, Inflammation, and Diabetes
looked at the association between these two conditions.
Among 917 patients with acute coronary syndromes, dia-
betes and admission CRP levels were both independent
predictors of long-term outcome (49). Other prospective
studies considering CRP levels have confirmed the prog-
nostic role of diabetic status (50,51). However, although the
FRagmin during InStability in Coronary artery disease
(FRISC) cohort has shown that diabetes plays a prognostic
role independent of CRP levels (49), several other smaller
studies have shown that diabetes acts as a significant
predictor on univariate but not multivariate analysis. Inter-
estingly, in some series, the presence of diabetes was
associated, independent of the prognosis, with elevated
CRP levels (50,52), whereas in other studies, the two
parameters appeared to be independent (53,54). After per-
cutaneous coronary interventions, the baseline CRP level
was shown to be a predictor of events (including target
vessel revascularization), independent of diabetic status (a
condition associated with a significantly increased risk of
recurrence after revascularization procedures) (55–58).
Primary prevention studies among apparently healthy
men (41) and women (59) have shown significant cardiac
risk prediction by means of elevated CRP levels. In these
data, no correlation between CRP levels and diabetes was
described, and although diabetes was shown to be signifi-
cantly associated with increased cardiac risk, CRP levels
were still independent markers of prognosis. The MONI-
toring trends and determinants in CArdiovascular disease
(MONICA) Augsburg cohort study was the first study to
evaluate the prospective value of CRP levels in primary
prevention (60). Many baseline clinical variables, including
a history of diabetes, were found to be associated with
higher CRP levels, and during follow-up, CRP remained an
independent predictor of adverse cardiovascular events. The
independent prognostic role of CRP has also been reported
in patients with peripheral artery disease (61).
In conclusion, these data appear to demonstrate that
CRP levels predict cardiac risk independent of diabetic
status. However, the fact that diabetics tend to have higher
CRP levels and that, in some clinical studies, diabetes still
remained a significant independent predictor suggests that
inflammation and metabolic derangements may represent two
different aspects of the same process and thus both could be
considered as independent predictors of cardiac risk. To the
best of our knowledge, no study to date has thoroughly looked
at the prognostic value of CRP between diabetics and nondia-
betics separately. Therefore, these conclusions need further
confirmation. In addition, the relative role of cytokines (IL-6,
TNF-alpha), oxidized LDL, fibrinogen, and other markers of
risk prediction require further investigation.
Reprint requests and correspondence: Dr. Luigi M. Biasucci,
Institute of Cardiology, Catholic University, Largo A. Gemelli 8,
00168 Rome, Italy. E-mail: lmbiasucci@virgilio.it.
JACC Vol. 41, No. 7, 2003
April 2, 2003:1071–7
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