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Atherosclerosis 211 (2010) 672675

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Atherosclerosis
j our nal homepage: www. el sevi er . com/ l ocat e/ at her oscl er osi s
Insulin resistance and acute coronary syndrome
G. Caccamo, F. Bonura, F. Bonura

, G. Vitale, G. Novo, S. Evola, G. Evola, M.R. Grisanti, S. Novo


Division of Cardiology, Department of Internal Medicine, Cardiovascular and Nephro Urological Disease, Italy
a r t i c l e i n f o
Article history:
Received 12 January 2010
Received in revised form 7 February 2010
Accepted 25 March 2010
Available online 4 April 2010
Keywords:
Atherosclerosis
Hyperinsulinemia
Coronary artery disease
HOMA index
Inammation
a b s t r a c t
Background: Insulin resistance (IR), which can be quantied by HOMA index (fasting glucose X fasting
insulin/22.5), is considered the primum movens for the development of Metabolic Syndrome. Many
authors have suggested that insulin resistance could raise both incidence and mortality of coronary heart
disease (CHD). IR is also associated with important predictors of cardiovascular disease, as increased
concentration of LDL or triglyceride, decreased concentration of HDL, high systolic blood pressure, vis-
ceral obesity. There is accumulating evidence that chronic sub-clinical inammation, as measured by
inammatory markers as C-reactive protein (CRP) and brinogen, is related with insulin resistance.
Aim of the study: To clarify if insulin resistance would predict cardiovascular disease independently of
the other risk factors, such as hypertension, visceral obesity or dyslipidemia, by focusing our attention
on the relation between Acute Coronary Syndrome (ACS) and high HOMA index.
Methods: We evaluatedglucose andinsulinlevels at baseline andpost-prandial phase, inorder toestimate
HOMA index in both the conditions; we related the data obtained with the incidence of cardiovascular
events, also investigating traditional cardiovascular risk factors. The cohort included 118 patients with a
clinical diagnosis of ACS and excluded those with type 1 diabetes, acute inammatory diseases, hepatic
or renal failure, disreactive disorders, autoimmunity and cancer.
Subjects: Subjects were followed-up for a period of 1 year, being subdivided in three groups: (1) subjects
at elevated HOMA (HOMA 6); (2) subjects at intermediate HOMA (HOMA <6 and 2); (3) subjects at
lowHOMA (HOMA 2). We considered as end points newcardiovascular events, cerebrovascular events
(both TIA and stroke), procedures of revascularization with angioplasty or surgery, cardiovascular death,
sudden death.
Results: Patients with elevated HOMA have a higher incidence of previous cardio- and cerebrovascu-
lar events (p=0.03), myocardial infarction without ST elevation (p=0.005), unstable angina (p=0.01),
asymptomatic carotid plaques (p=0.05), depressed systolic function (p=0.05); we found, also, a signi-
cant statistic correlation between HOMA index and high levels of CRP, brinogen, serum creatinine and
TnI. Cardiovascular and cerebrovascular events were registered in 61% of patients with elevated HOMA
during the followup, despite of 25% registered in the control group: so we could consider HOMA index as
a negative prognostic variable, also in virtue by the statistic correlation with the inammatory markers,
whose power of prediction is already known.
Conclusions: Beyond traditional cardiovascular risk factors, insulin resistance quantied by HOMA index
seems to signicantly have an important prognostic role, both in primary and secondary prevention in
patients with Acute Coronary Syndrome.
2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Cardiovascular disease (CVD) has a great clinical relevance, rep-
resenting the main cause of disability and death in industrialized
countries. In USA about 12 millions of patients suffer from Coro-
nary Artery Disease (CAD), 6 millions for Effort Angina and over 7
millions for acute myocardial infarction [1].

Corresponding author. Tel.: +39 0916552986; fax: +39 0916554301.


E-mail addresses: bonuraff@libero.it, capiuc@libero.it (F. Bonura).
Data fromWHO estimate that in 2020 the world mortality from
CAD will grow from 7.1 to 11.1 millions per year [2].
Atherosclerosis, whose development and progression represent
the starting points for clinical manifestations such as Transient
Ischemic Attack (TIA), Ischemic Stroke, claudication, critical leg
ischemia, is the main cause of ischemic cardiac events as angina
pectoris, acute myocardial infarction, cardiac failure, arrhythmias
and sudden cardiac death.
Regarding the risk factors for cardiovascular disease, observa-
tional and epidemiological studies have suggested the predictive
andprognostic roles of brinogenandC-reactive protein; therefore
their dose could support patients stratication with CAD.
0021-9150/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2010.03.033
G. Caccamo et al. / Atherosclerosis 211 (2010) 672675 673
Moreover, recent data demonstrate that the condition of insulin
resistance plays a primary role both in the pathogenesis of
Metabolic Syndromeandinthepredictionof cardiovascular events;
thus the dose of fasting glycaemia, post-prandial glycaemia and
insulin may be correlated positively with the incidence of newcar-
diac events in patients with Acute Coronary Syndrome (ACS) [3],
with or without a previous diagnosis of diabetes [4].
Several studies have suggested that although insulin resistance
is associated with traditional risk factors as low levels of high den-
sity lipoproteins cholesterol (HDL-c), high levels of low density
lipoproteins cholesterol (LDL-c) or triglycerides, hypertension, vis-
ceral obesity, it may inuence independently the progression of
coronary atherosclerotic plaques inasymptomatic patients [5], also
in virtue of the correlation with the endothelial dysfunction [6].
The aim of our study was to evaluate the potential relations
betweenAcute Coronary Syndrome andhighlevels of HOMAindex,
surrogate measure of insulin resistance.
2. Methods
We studied118subjects, 84males and34females, all referredto
our Unit of Cardiovascular Care for Acute Coronary Syndrome, from
April 2008 to June 2009. We dened Effort Angina, Acute Myocar-
dial Infarction with and without ST elevation as Acute Coronary
Syndrome. Effort Angina was characterizedbythe presence of chest
pain on walking that was relieved within 10min after stopping or
by ST segment of ECG down sloping in a standard 12-lead elec-
trocardiogram during chest pain or by positive stress testing; AMI
was characterized by a pronged episode of chest pain with electro-
cardiogram and/or specic myocardial markers changes, involving
hospitalization.
The project designincludeda medical examination, biochemical
analyses and instrumental exams as echocardiography, coronary
angiography, Ecocolor Doppler of carotid arteries.
Subjects were excluded from the study if they had type I
diabetes, acute inammatory diseases, hepatic or renal failure, dis-
reactive disorders, autoimmunity and cancer. Among the main
cardiovascular risk factors, the presence of hypertension, type
II diabetes, hypercholesterolemia, hypertriglyceridemia, smoking
habits, visceral obesity were considered.
Total cholesterol, HDL and LDL cholesterol, triglycerides, b-
rinogen and CRP, ESR (erythrocyte sedimentation rate), troponin
I were dosed; moreover HOMA index was calculated, accord-
ing to the Matthews formula [7] [insulin (IU/mL) glycaemia
(mmol/L)]/22.5], bydosingfastingandpost-prandial glycaemia and
insulin. Haemolysed blood samples were excluded because of the
presence of inactivating insulin enzymes. Since insulin therapy
or oral diabetes medications could inuence serum insulin levels,
patients had to stop them at least 1 day before the blood sample.
It was basic to know also serum creatinine levels to estimate
creatinine clearance rate, through MDRD [8] formula, given the
correlations between ACS and renal dysfunction [9,10].
Echocardiography was included in this study, in order to dis-
cern systolic and diastolic functions through the evaluation of the
Ejection Fraction (EF) and the transmitral ow prole (measure-
ments of E and A waves); we evaluated also coronary angiographic
results, arterial wall thickness in the carotid arteries using Ecocolor
Doppler Examination, statintherapy, medications withantiplatelet
drugs at the admission in hospital.
Subjects were divided into three groups, according to the distri-
butionintertiles of the HOMAindex values: (1) subjects at elevated
HOMA (HOMA 6); (2) subjects at intermediate HOMA (HOMA<6
and 2); (3) subjects at low HOMA (HOMA 2), which represents
the control group [11].
In consideration of the prevalence of type II diabetes, we distin-
guished diabetic patients and non-diabetic ones; furthermore the
same classication in three groups according to the HOMA values
was made in diabetic subjects, so to apply them stratication.
We performed a 1 year follow up study in all of the patients
to estimate the incidence of new cardiovascular events, as Angina
Pectoris, Acute Myocardial Infarction or Re-acute Myocardial
Infarction, cardiac failure, arrhythmias, coronary revascularization
with CABG (Coronary Artery By pass Grafting) or PTCI (Percuta-
neous Transluminal Coronary Intervention).
Table 1
Group A (HOMA 2) Group B (HOMA between 2 and 6) Group C (HOMA 6) p value
Patients 52 (43%) 48 (41%) 18 (15%)
Male 37 (71%) 34 (71%) 13 (72%) 0.92
Age 66.613 6412 679 0.14
STEMI 16 (30.7%) 15 (31%) 6 (33%) 0.94
NSTEMI 6 (11.5%) 15 (31%) 9 (50%) 0.005
Effort angina 28 (54%) 18 (38%) 3 (17%) 0.01
Currant smoker 19 (36; i%) 15 (31%) 6 (33%) 0.69
Hypertension 38 (73%) 37 (77%) 14 (78%) 0.54
Diabetes 20 (33%) 27 (56%) 10 (56%) 0.05
IMT >1.5mm 12 (23%) 15 (31%) 12 (66%) 0.05
Previous vascular events 17 (33%) 19 (40%) 13 (72%) 0.03
Total cholesterol 16938 171.258 168.550 0.77
HDL cholesterol 44.512 39.212 4018 0.22
LDL cholesterol 9834 10552 9642 0.72
CRP 1.11.4 1.72 4.36 0.04
ESR 13: 411 2320 26.719 0.02
Fibrinogen 35079 396108 415.7112 0.05
Troponin I 49 1929 14.224 0.014
Creatinine 1.030.3 1.52 2.23 0.001
Cr. clearance 7928.9 83.832 64.835.5 0.02
Fasting glucose 11332 130.844 17658 <0.001
Post-prandial Glucose 132.749 134.845 40.152 0.61
Fasting insulin 4.82 11.94 40.117 <0.001
Post-prandial insulin 2117 34.735 3017 0.05
HOMA-IR 1.30.5 3.61 1830 0.03
HbAlc 6.21.4 71.5 70.8 0.05
Systolic function EF >55%=36 (69%) EF >55%=25 (52%) EF >55%=7 (39%) 0.05
EF <55%=15 (25%) EF >55%=22 (46%) EF <55%=9 (50%)
674 G. Caccamo et al. / Atherosclerosis 211 (2010) 672675
3. Statistical analysis
Statistical analysis was performed using the Med Calc Program.
We applied Students T and
2
tests in order to analyse quantitative
and qualitative variables respectively. A linear regression analysis
was assessed to evaluate the association between insulin resis-
tance, quantied by HOMA-IR, inammation and renal function.
Independent associations of the studied variables with the clinical
events registered during the follow up were assessed by multiple
regression analysis.
p values lower than 0.05 were considered statistically signi-
cant.
4. Results
Subdividing our population according to the distribution in ter-
tiles of HOMA index values, we found that patients with elevated
HOMA have an higher incidence of previous cardiovascular and
cerebrovascular events (p=0.03), myocardial infarction without ST
elevation (p=0.005), effort angina (p=0.01), asymptomatic carotid
plaques or IntimaMedia Thickness major of 1.5mm, according to
the guidelines of the European Society of Cardiology [12] (p=0.05),
low systolic function (p=0.05); we found, also, a signicant statis-
tic correlation between higher HOMA index values and high levels
of CRP, brinogen, serum creatinine, creatinine clearance and TnI.
These data are shown in Table 1. We can observe also that some
variables such as age, male sex, total cholesterol, LDL cholesterol
Table 2
Total cholesterol LDL cholesterol HDL cholesterol
HOMA-IR p=0.68 p=0.76 p=0.51
and HDL cholesterol, are homogeneously distributed among the
three groups of patients.
A linear regression analysis demonstrated that HOMA-IR is
related to markers of inammation as CRP (p=0.04), brinogen
(p=0.05) and ESR (p=0.02), serum creatinine (p=0.001) and tro-
ponin I (p=0.014); in order to validate our results, we applied a
regressionanalysis to CRP andbrinogen: we foundthat these vari-
ables are statistically correlated, as several studies have already
demonstrated [13] (Fig. 1).
Although several studies have conrmed a correlation between
insulin resistance and dyslipidemias [14] (both high levels of LDL
cholesterol and low levels of HDL cholesterol), we did not nd any
signicant statistical association involving HOMA index and tra-
ditional lipid risk factors, probably because about 80% of patients
underwent statintherapybefore the admissioninhospital (pvalues
are showed in Table 2).
In consideration of the prevalence of type II diabetes, we distin-
guished diabetic patients and non-diabetic ones; we found that in
diabetic group coronary atherosclerosis involved a major number
of arteries, as angiographic data demonstrated; moreover serum
levels of markers of inammation were higher than control group.
Fig. 1. Regression analysis (HOMA index and hs-CRP, brinogen, ESR, troponin and creatinine).
G. Caccamo et al. / Atherosclerosis 211 (2010) 672675 675
As regards diabetic subjects, after subdividing them according
to the distribution in tertiles of HOMA index values, we found a
signicant relation between insulin resistance and renal function
measured by serum creatinine (p<0.001).
At the end of the 1 year follow up, we found that both the inci-
dence of intra-hospital and extra-hospital events was higher in
subjects belonging to group C, characterized by a major insulin
resistance measured by HOMA index. Focusing our attention to
mortality, it was not registered in the control group, but it com-
plicated the follow up of subjects with HOMA index levels greater
than 2. Eventually the global incidence of new cardiovascular and
cerebrovascular events grewfromGroup A, characterized by lower
HOMA-IR, to Group C, with higher HOMA-IR (25% despite 61%
respectively), so insulin resistance may inuence prognosis.
We assessed by multiple regression analysis that there was no
statistic correlationbetweenhighlevels of HOMA-IRandthe occur-
rence of global events (p=0.19); a signicant association, instead,
linked the occurrence of new intra-hospital events with high lev-
els of CRP (p=0.007), Troponin I (p=0.04), creatinine (p=0.02), ESR
(p=0.02) and low systolic function (p=0.0008), while a border-
line statistic association existed between the occurrence of new
intra-hospital events and HOMA-IR (p=0.06).
Intra-hospital mortality seemed to be signicantly related to
high levels of CRP (p<0.0001) and troponin I (p<0.04); HOMA
index, also in this case, did not reach a statistical signicance
(p=0.07). Although there was not any statistic correlation between
high levels of HOMA-IR and global mortality, because of the small
sample size andthe short followup, we demonstratedthat the inci-
dence of new events (%) grows contemporary to the increasing of
HOMA-IR, so it may play a prognostic role.
5. Conclusions
Beyondtraditional cardiovascular risk factors, insulinresistance
quantied by HOMA index seems to signicantly be an inde-
pendent cardiovascular risk factor; it is certainly associated with
markers of inammation such as hs-CRP and brinogen, whose
predictive power known [15], and it also play a considerable role
in the pathogenesis of endothelial dysfunction [16]. In our evi-
dences a signicant associationlinks insulinresistance withcarotid
atherosclerosis, measured by Ecocolor Doppler examination, and
renal dysfunction, measured by serum creatinine and creatinine
clearance: these data conrm that atherosclerosis is a progressive
multifocal process.
The utility of CRP in the prevention of cardiovascular risk and its
prognostic role are unchallenged; because of the signicant rela-
tionship between insulin resistance and inammation, HOMA-IR
seems to signicantly have an important prognostic role, both in
primary and secondary prevention in patients with Acute Coronary
Syndrome.
Further studies need to be conducted to evaluate the implica-
tions of these results.
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