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].
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]. 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