Age-dependence of risk factors for carotid stenosis: an observational study among candidates for coronary arteriography

Transcription

1 Atherosclerosis 159 (2001) Age-dependence of risk factors for carotid stenosis: an observational study among candidates for coronary arteriography Marco Zimarino a, *, Lucia Cappelletti b, Vincenzo Venarucci b, Sabina Gallina a, Maurizio Scarpignato b, Nadia Acciai b, Antonio Maria Calafiore a, Antonio Barsotti a, Raffaele De Caterina a a Department of Cardiology and Cardiac Surgery, Uni ersity of Chieti, Chieti, Italy b Cardiac Catheterization Laboratory, R. Calai Hospital Gualdo Tadino, Italy Received 4 August 2000; received in revised form 20 December 2000; accepted 14 February 2001 Abstract In order to identify subjects at higher risk for carotid stenosis and to provide insights into mechanisms of disease development at different age-intervals, a color duplex ultrasound of extracranial arteries was performed in 624 consecutive patients (mean age , 483 males) undergoing coronary angiography. Significant carotid atherosclerosis ( 50% stenosis) was documented in 87 patients (14%): the disease was moderate (50 69% stenosis) in 51 patients (8%), severe ( 70% stenosis) in 36 patients (6%). Age (P ), smoking (P ), diabetes (P=0.0002), renal dysfunction (P=0.0119) and hypertension (P=0.0202) were independent predictors of significant carotid atherosclerosis; age (P=0.0001), smoking (P=0.0009) and diabetes (P=0.0201) were independent predictors of severe disease. Among 262 candidates for cardiac surgery, significant carotid artery disease was identified in 57 cases (2.63 Relative Risk, 95% Confidence Intervals: ). Correlation and regression tree analysis demonstrated that diabetes was associated with greater severity of carotid stenosis in younger patients and hypertension in older ones. In conclusion age is the primary determinant of carotid artery disease; diabetes and smoking accelerate progression of atherosclerosis in younger patients, hypertension and smoking in older ones. Among patients undergoing coronary angiography, carotid ultrasonography should be recommended in high risk subgroups of patients Elsevier Science Ireland Ltd. All rights reserved. Keywords: Aging; Carotid arteries; Coronary disease; Risk factors 1. Introduction Interest in screening for carotid atherosclerosis has increased after the publication of studies demonstrating that carotid endarterectomy can prevent stroke even in asymptomatic patients with extracranial artery stenosis [1 4]. Moreover, there is growing evidence about the safety and effectiveness of the percutaneous treatment of carotid stenosis [5]. Carotid ultrasound examination is extremely useful in candidates for coronary artery bypass grafting (CABG), since various surgical strategies can be chosen to reduce adverse cerebral outcomes * Corresponding author. Present address: Via Milano, 75, Pescara, Italy. Tel.: ; fax: address: emosax@yahoo.com (M. Zimarino). in subjects with extracranial artery disease [6,7]. Determination of carotid intima-media thickness has been widely used as an indicator of early atherosclerosis and has been advocated as an additional tool in predicting the extent and severity of coronary artery disease (CAD), even if only a weak relationship has been documented between the two [8 10]. Intima media thickness reflects the consequences of previous longterm exposure to risk factors and has been strongly associated with cardiovascular events [11,12]. This measurement allows an insight into the extent of the disease, whereas measurement of the severity of carotid artery plaques has a more immediate clinical relevance, since it can mandate an interventional strategy [1 3]. Age is the most relevant risk factor for atherosclerosis: the association between other risk factors and vas /01/$ - see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S (01)

2 166 M. Zimarino et al. / Atherosclerosis 159 (2001) cular disease grows weaker in the elderly, and there is conflicting information on how the strength of the relation between risk factors and the development of the disease varies with age [13 18]. The present study was, therefore, designed to assess the prevalence of clinically relevant carotid atherosclerosis in patients with suspected CAD as a function of age, and to provide insights into mechanisms promoting extracranial artery stenosis at different age intervals. 2. Methods 2.1. Patients We studied 989 consecutive patients admitted for coronary angiography as part of an evaluation for CAD. Reasons for angiographic evaluation were: suspected CAD in 869 cases (88%), valvular heart disease in 101 cases (10%), congenital heart disease in 19 cases (2%). Subjects were excluded from the present analysis if they were 30 years old (n=13, 1%), outpatients (n=214, 22%), or if they were clinically unstable (admitted for urgent coronary angiography during acute myocardial infarction and/or unstable angina resistant to intravenous therapy) (n=73, 7%). Additionally, ten patients (1%) refused the informed consent, 21 patients (2%) were excluded from the study for unavailability of complete documentation, and 31 patients (3%) because of a temporary unavailability of the ultrasound equipment. For the purpose of the study, three patients (0.3%) with previous carotid endarterectomy were excluded. Therefore, the study population consisted of 624 patients. The day before cardiac catheterization, written informed consent was obtained and subjects were interviewed using a standardized questionnaire. Information regarding heart and vascular disease status (symptoms of angina, history of myocardial infarction or cerebrovascular accidents), medications and prior diagnostic evaluations were obtained. The study protocol was approved by the local ethical committee Risk factor assessment Body mass index (BMI) was derived from height and weight measurements. A family history of ischemic heart disease was defined as a history of CAD in any first-degree relative 55 years old. Patients who had ever smoked were classified as smokers; smoking was measured in pack-years smoked. Hypertension was defined by a history of the disease or a systolic blood pressure 140 mmhg or a diastolic blood pressure 90 mmhg upon at least three repeated measurements. The presence of diabetes mellitus was defined by a repeated fasting glucose level 7.8 mmol/l (140 mg/dl), the use of antidiabetic drugs or both. Renal dysfunction was defined as a serum creatinine 2 mg/dl. Blood was drawn for direct laboratory measurement of the following: total, HDL cholesterol and triglycerides. Total cholesterol and triglyceride levels were determined enzymatically; HDL cholesterol was also measured enzymatically after dextran sulfate magnesium precipitation. LDL cholesterol was calculated using Friedewald s formula [19]. Dyslipidemia was defined by the use of lipid-lowering medications, a fasting total plasma cholesterol 220 mg/dl, a total cholesterol/hdl cholesterol ratio 5, or an LDL cholesterol 130 mg/dl Carotid ultrasound examination An ultrasonographic evaluation of the extracranial arteries was performed the day before angiography by two experienced operators using a Toshiba SSA270 A color duplex scanner with a 7.5 MHz probe. Concordance between independent readings by the two operators was previously tested (k=0.91). Short segments of real-time scanning and Doppler waveforms were recorded on videotape. Transverse and longitudinal scans were obtained on the common carotid artery, carotid bifurcation, internal and external carotid arteries. Doppler recordings were obtained from the common carotid artery at the base of the neck and just proximal to the carotid bifurcation; internal carotid artery waveforms were obtained from within the bulb and the proximal, mid- and distal segments; external carotid artery waveforms were routinely recorded at the origin of the external carotid artery. Peak systolic and end-diastolic velocities were measured at each location maintaining a Doppler angle of 60 during the examination [20]. Each carotid artery segment was assigned a degree of stenosis based on Strandness criteria [21,22]. The maximal percent stenosis of the two arteries was used for the analysis Coronary angiography Selective coronary angiography was performed in each patient using the Judkins technique. After intracoronary injection of nitroglycerin (0.2 g), a minimum of five projections for the left coronary artery and three projections for the right coronary artery were obtained with a pixels matrix (Toshiba Angiorex DFP-60A) at 25 frames/s. The angiograms were reviewed by two observers. Quantitative angiographic analysis was performed using the single view that identified the most severe stenosis for each vessel.

3 M. Zimarino et al. / Atherosclerosis 159 (2001) Single vessel disease was considered to be present when there was a 50% diameter stenosis of a major epicardial artery; for double- and triple-vessel disease, a 50% diameter stenosis of one or two additional arteries was required. Patients with a 30% left main lumen narrowing were coded as having a three-vessel coronary artery disease Carotid angiography Carotid angiography was performed after coronary arteriography whenever ultrasound study had previously identified a carotid artery stenosis 50%, in cases of discrepancies between the two operators and in cases of aortic valve disease. Carotid angiography was additionally performed in randomly selected cases. Arch aortograms were performed routinely with intra-arterial digital subtraction angiography. Selective carotid artery studies were performed when necessary, with imaging in at least two planes and intracranial views, unless the initial aortic arch injection revealed significant aortic arch disease. The angiograms were reviewed by two observers unaware of the results of carotid ultrasound. The view showing the greatest stenosis was selected for quantitative angiographic analysis. The lumen diameter at the point of maximum stenosis and the diameter of the normal distal internal carotid artery were measured; percent stenosis was then calculated using the method described in the NASCET study [2]. Carotid angiography was performed in 87 patients (14%) with carotid artery disease identified by ultrasound, in 52 patients (8%) with valve heart disease and in 63 other (10%) randomly selected cases: overall 202 (32%) carotid angiographic studies were available. In order to test the reliability of the ultrasound evaluation, duplex ultrasound stenoses were plotted against angiographic results. The correlation coefficient (r) between these two measurements was (P 0.001, SEE=7.23) Statistical analysis Data were processed by the SPSS/Windows statistical package [23]. Continuous variables were expressed as mean S.D. Discrete variables were expressed as percentages. Comparisons between patients admitted and excluded from the study was performed using two-sided unpaired t-test for continuous variables and the Chisquare test (or Fisher s exact test when appropriate) for discrete variables. The associations between carotid atherosclerosis and risk factors was assessed using means with 95% confidence intervals (CI) for continuous variables and relative risk (RR) with 95% CI for discrete variables. Stepwise multiple logistic regression analysis was performed for any significant (stenosis 50%) and severe (stenosis 70%) carotid artery disease as dependent factors, and risk factors significantly associated in univariate analysis were entered as independent variables. The predictive accuracy of the model was assessed by means of the area under Receiver Operating Characteristics (ROC) curve: bootstrapping with the 202 patients who underwent carotid angiography was used for validation of the model. Risk factors identified as independent predictors of carotid artery disease were entered in a Classification and Regression Tree (CART) analysis to allow for risk stratification based on baseline characteristics. The relation between the degree of stenosis determined at duplex ultrasound study and at angiography was analyzed by linear regression; the goodness of fit was evaluated by the k Pearson product moment correlation coefficient. Statistical significance was inferred at P Results Clinical characteristics of subjects excluded from and included in our study were similar, except for family history of ischemic heart disease, which was more frequent among patients included (40 vs 33% in patients excluded, P=0.035) (Table 1). Among the 624 patients studied (mean age years, 77% male) significant coronary artery disease was documented in 497 cases (80%) Distribution of carotid atherosclerosis No signs of extracranial atherosclerosis were detected in 125 patients (20%); a mild ( 50%) carotid artery stenosis was present in 412 patients (66%); significant carotid artery disease ( 50% stenosis) was documented in 87 (14%) subjects: the disease was classified as moderate (50 69% stenosis) in 51 cases (8%) and severe ( 70% stenosis) in 36 cases (6%). Lesion location was as follows: common carotid artery in five cases (6%), carotid bifurcation in ten cases (11%), internal and external carotid artery in 59 (68%) and 13 cases (15%), respectively Risk factors for carotid stenosis Comparisons between patients with normal or mildly diseased extracranial circulation (n=537, 86%), and those with moderate and severe disease are shown in Tables 2 and 3. Subjects with moderate and with severe atherosclerosis were significantly older [mean age 70.3 (95% CI: ) years and 70.8 ( ) years, respectively], when compared to control patients [61.7 ( ) years]. Patients with severe disease were heavier smokers [28.1 ( ) pack-years] than control subjects [14.4 ( ) pack-years].

4 168 M. Zimarino et al. / Atherosclerosis 159 (2001) By univariate analysis, the most potent risk factor for any significant ( 50% stenosis) carotid atherosclerosis was renal dysfunction with a 3.85 RR ( ), followed by diabetes [2.33 ( )] and hypertension [2.05 ( )]. Risk factors for severe ( 70% stenosis) disease were renal dysfunction [6.01 ( )] and diabetes [2.89 ( )]. Patients with multivessel CAD had a 2.02 RR ( ) of severe carotid atherosclerosis; similarly, in candidates for cardiac surgery the risk for any and severe carotid artery disease was, respectively, 2.63 [ ] and 3.68 ( ), respectively, with the highest risk for patients undergoing coronary and valvular surgery [4.08 ( ) and 6.03 ( ), respectively] (Table 4). Age, smoking, diabetes, renal dysfunction and hypertension were identified as independent predictors of any significant carotid atherosclerosis by multivariate analysis; predictors of severe disease paralleled results for any significant disease (Table 5). The area under the ROC curve for the model was Table 1 Characteristics of patients included in and excluded from the study a,b Patients included Patients excluded P n % n % Age (years) Male sex BMI (kg/m 2 ) Family history Diabetes Hypertension Smokers Previous CVA Renal dysfunction Previous MI Previous CABG Angina Indications to angiography: Suspected CAD VHD CHD CAD EF (%) a Data are number and percentages or mean S.D. b BMI, body mass index; CVA, cerebrovascular accident; MI, myocardial infarction; CABG, coronary artery bypass grafting; CAD, coronary artery disease; VHD, valvular heart disease; CHD, congenital heart disease; EF, ejection fraction. Table 2 Means and 95% CI of risk factors for carotid atherosclerosis (CA) a No CA n=537 (86%) Moderate CA n=51 (8%) Severe CA n=36 (6%) Mean CI Mean CI Mean CI Age (years) BMI (kg/m 2 ) Smoking (pack-years) Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Triglycerides (mg/dl) EF (%) a Abbreviations as in Table 1.

5 M. Zimarino et al. / Atherosclerosis 159 (2001) Table 3 RR and 95% CI for carotid atherosclerosis (CA) a No CA Moderate CA Severe CA Any CA Severe CA n % n % n % RR CI RR CI Male sex Family history Diabetes Hypertension Smokers Previous CVA Renal dysfunction Dyslipidemia Previous MI Previous CABG Angina a Abbreviations as in Table 1. Table 4 CAD and Therapeutic Strategy (RR and 95% CI) according to presence/absence of carotid atherosclerosis (CA) a No CA Moderate CA Severe CA Any CA Severe CA n % n % n % RR CI RR CI CAD Therapeutic strategy Medical therapy PTCA , Cardiac surgery CABG Valvular CABG+valvular a Abbreviations as in Table Age-dependence of risk factors The independent predictors of any significant disease derived from the multiple logistic regression model were entered into a CART analysis (Fig. 1); this analysis demonstrates that primarily diabetes and then smoking are associated with carotid atherosclerosis in younger subjects while in older patients hypertension and then smoking again significantly increase the risk of the disease. Age-related distribution of risk factors confirmed that diabetes and smoking were significantly relevant among younger patients with carotid artery disease and hypertension among older subjects (P 0.05, Fig. 2) Therapeutic strategy Among 362 non-surgical candidates, extracranial artery disease was present in 30 cases (8%): endarterectomy was performed alone in eight patients (2%) and after coronary angioplasty in 15 cases (4%), without adverse events. Among 262 surgical candidates, carotid atherosclerosis was identified in 57 subjects (22%): 39 Table 5 Independent predictors of carotid atherosclerosis (CA) by multivariate analysis a Any CA P r Severe CA Age Smoking Diabetes Renal Dysfunction Hypertension Cardiac Surgery CAD a Abbreviations as in Table 1. P r

6 170 M. Zimarino et al. / Atherosclerosis 159 (2001) Fig. 1. Graph presenting the CART model constructed with the independent risk factors for any significant ( 50% stenosis) carotid atherosclerosis. The area of the pie is proportional to the size of the subgroup and the black area is proportional to the prevalence of carotid artery disease, indicated within the circle in percent for the given subdivision. The analysis identifies at each level two subgroups with a statistically significant difference in the prevalence of carotid atherosclerosis. Fig. 2. Bars presenting age-adjusted distribution of hypertension, diabetes and smoking among patients with significant carotid atherosclerosis. Diabetes and smoking are more prevalent among younger subjects, hypertension among the older ones. patients (15%) underwent combined coronary and carotid surgery, eight patients (3%) underwent staged surgery. Beating heart CABG was performed in 26 cases (10%): during combined surgery in 13 cases, after carotid endarterectomy in four cases and alone in nine subjects. Among surgical candidates, three adverse events (1%) occurred: one patient died during combined surgery, one patient, planned for staged surgery, died during urgent CABG following carotid endarterectomy and one patient with mild atherosclerosis of extracranial arteries experienced a non-fatal stroke 15 days following CABG.

7 M. Zimarino et al. / Atherosclerosis 159 (2001) Discussion Although other studies have examined the relationship between various risk factors and the development of carotid plaque [13 17], our report is the first showing a clear-cut age-dependence of risk factors for vascular disease Pre alence of carotid stenosis The present study shows that significant carotid atherosclerosis is present in about 14% of patients with suspected CAD. These results are consistent with those of unselected population: a 50% carotid stenosis was identified in 8% of the 1090 survivors from the original cohort of the Framingham Heart Study [13]. This finding is particularly relevant because of the very low prevalence of patients symptomatic for cerebrovascular disease in our series (3%), in accordance with data from the literature [17] Role of risk factors Carotid and coronary circulations are differently associated with some of the traditional vascular risk factors, with carotid lesions appearing later in life than coronary lesions. This finding slightly differs from that obtained in community-based studies, where hypertension, smoking and diabetes were all associated with carotid atherosclerosis, even after age-adjusted analysis [13 17]. Useful information is provided by our CART analysis: not unexpectedly, age was the major determinant of extracranial artery disease. Age influences the pathogenesis of atherosclerosis both by inducing physiological vascular changes and by increasing the exposure to traditional risk factors [13,24]. In the older subgroup of our population, hypertensive patients exhibited an increased prevalence (30%) of carotid artery disease, with smoking as an additional factor in disease progression. Diabetes is associated with atherosclerosis in younger patients: diabetic subjects 65 years old showed a prevalence of the disease (15%) comparable with older, normotensive patients (16%). The very low-risk subgroup is clearly identified by young, non diabetic patients who never smoked or smoked 15 pack-years or less, with a 1% prevalence of extracranial artery disease. Age-dependence of risk factors for stroke has been previously reported by the Prospective Study Collaboration [25]. In this study, the relevance of hypertension varied significantly with age, with a steeper gradient for younger patient subgroups. In this report, however, only fatal strokes were taken into account, regardless of their ischemic or hemorragic nature; additionally, only diastolic blood pressure was considered, perhaps flawing the relevance of hypertension in the elderly. The present study failed to identify any association between dyslipidemia and the risk of carotid atherosclerosis. A potential source of bias may be related to the study design, since lipid lowering therapy was not recorded and taken into account. However, even if there is evidence of a direct relationship between cholesterol levels and carotid wall thickness [26], most reports show no clear association between cholesterol and stroke mortality [25,27]. Indeed, there is evidence that the effects of lipids on cerebro vascular disease wane after 50 years of age and almost disappear after 60, while they persist with respect to CAD [13]. In our study, renal dysfunction independently predicted the presence of carotid atherosclerosis. Similarly, high serum creatinine has been previously positively correlated with stroke in both normotensives and hypertensives [28]. Cerebral complications after CABG are associated with aortic and extracranial atherosclerosis [4,5], and a preoperative carotid screening simply based on patients history and/or physical examination showed a low accuracy [29] Clinical rele ance of the association between carotid and coronary atherosclerosis Although there is still no clear consensus for what should happen for patients with asymptomatic carotid stenosis [30], the identification of complex atherosclerotic disease is of clinical relevance. In patients with severe extracranial artery disease needing surgical myocardial revascularization a combined carotid/coronary operation is usually recommended [7,31]. In such cases cardiac surgery can be performed with a variety of techniques that decrease the embolic risk, including hypothermic fibrillatory arrest without the clamping of the aorta, arterial conduits to avoid aortic anastomosis and beating-heart CABG [32]. Despite the good correlation between the presence of significant disease of the extracranial circulation and CAD severity, coronary angiography added little information to risk stratification in our model of multivariate analysis. Thus, it would appear that carotid ultrasound should be performed particularly in older subjects, younger diabetic patients, smokers, patients with renal dysfunction and candidates cardiac surgery Study limitations In our study, only patients with suspected CAD were studied; therefore, our findings, which have clinical relevance in this group, may not be applicable to an unselected population. Similar to all currently available clinical studies examining the relationship of carotid and coronary artery disease, we relied on imaging techniques (carotid ultrasound and coronary angiography), as indices of

8 172 M. Zimarino et al. / Atherosclerosis 159 (2001) atherosclerotic extent and severity. Both techniques have limitations: angiography, regardless of the method of analysis, consistently underestimates atherosclerosis severity and only allows an appreciation of lumen reduction. Intravascular ultrasounds might better quantify the overall atherosclerotic burden, especially when compensatory mechanisms such as arterial remodeling come into play, or when diffuse disease is present [33]. A discrete categorization as single- and multi-vessel disease for CAD and as the maximal percent stenosis in the two carotids for carotid artery disease does not take into account plaque extension, and is therefore a rough approximation, although extensively used, of the atherosclerotic involvement. A potential source of bias was the cross-sectional nature of the population: as a common observation, prevalence of diabetes and of smoking is reduced in the oldest age group. Following the study design renal dysfunction was entered into the database as a discrete variable and no serum creatinine values were recorded; probably, the calculated glomerular filtration rate [34] would have increased the value of renal dysfunction. Our study was unable to detect the association between some known risk factors, previously identified as linked to vascular disease progression [13,14]: for example, the study was underpowered to identify the role of male sex, due to the high prevalence of males in our population. No follow-up was available and therefore no inference can be made as to whether patients with combined carotid and CAD are at higher risk for stroke. 5. Conclusions Carotid stenosis is frequent in patients with suspected coronary artery disease. The strength of the relationship between traditional risk factors and vascular disease significantly varies with age: diabetes and hypertension are separately associated with carotid artery disease in younger and older patients, respectively; smoking plays a synergistic role mostly in the former subgroup. Carotid ultrasound has the highest a priori probability to detect carotid atherosclerosis and therefore the highest bayesian yield in older subjects, in younger diabetic patients, in smokers, in patients with renal dysfunction and in candidates for cardiac surgery. Acknowledgements The authors wish to thank Professor Attilio Maseri for his careful review. References [1] Hobson RW, Weiss DG, Fields WS, Goldstone J, Moore WS, Towne JB, Wright CB. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. New Engl J Med 1993;328: [2] Barnett HJM, Taylor W, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. New Engl J Med 1998;339: [3] Donnan GA, Davis SM, Chambers BB, Gates PC. Surgery for prevention of stroke. Lancet 1998;351: [4] The European Carotid Surgery Trialists Collaborative Group. Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 1995; 345, [5] Brown MM. Results of the carotid and vertebral artery transluminal angioplasty study. Br J Surg 1999;86:710 1 For the Carotid and Vertebral Artery Transluminal Angioplasty Study Investigators (CAVATAS). [6] Roach GW, Kanchuger M, Mora Mangano C, et al. Adverse cerebral outcomes after coronary bypass surgery. New Engl J Med 1996;335: [7] Wareing TH, Davila-Roman VG, Daily BB, Murphy SF, Schechtman KB, Barzilai B, Kouchoukos NT. Strategy for the reduction of stroke incidence in cardiac surgical patients. Ann Thor Surg 1993;58: [8] Crouse JR, Craven TE, Hagaman AP, Bond G. Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery. Circulation 1995;92: [9] Adams MR, Nakagomi A, Keech A, et al. Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation 1995;92: [10] Zhoury Z, Schwarts R, Gottlieb S, Chenzbraun A, Stern S, Keren A. Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid and femoral arteries evaluated by ultrasound. Am J Cardiol 1997;80: [11] O Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in adults. New Eng J Med 1999;340: [12] Belcaro G., Nicolaides A.N., Laurora G., Cesarone M., De Sanctis M., Incandela L., Barsotti A., Ultrasound morphology classification of the arterial wall and cardiovascular events in a 6-year follow-up study, Arterioscler. Thromb. Vasc. Biol. 1996, [13] Wilson PWF, Hoeg JM, D Agostino RB, et al. Cumulative effects of high cholesterol levels, high blood pressure and cigarette smoking on carotid stenosis. New Engl J Med 1997;337: [14] Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M, Alzola C. Carotid atherosclerosis measured by M-mode ultrasound in populations: association with cardiovascular risk factors in the ARIC study. Am J Epidemiol 1991;134: [15] Rfolsom AR, Eckfeldt JH, Weitzman S, et al. Relation of carotid artery wall thickness to diabetes mellitus, fasting glucose and insulin, body size and physical activity. Stroke 1994;25: [16] O Leary DM, Polar JF, Kronmal RA, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. Stroke 1992;23: [17] Fabris F, Zanocchi M, Bo M, et al. Carotid plaque, aging and risk factors. Stroke 1994;25: [18] D Apolito G, Zimarino M, Soccio M, et al. Incidenza dei fattori di rischio tradizionali nella patologia aterosclerotica dei distretti coronarico e carotideo. G Ital Cardiol 1999;29: [19] Friedwald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma,

9 M. Zimarino et al. / Atherosclerosis 159 (2001) without the use of the preparative ultracentrifuge. Clin Chem 1972;18: [20] Zimarino M, Soccio M, Scarpignato M, et al. Usefulness of color duplex scanning for the identification of extracranial atherosclerosis in patients with suspected coronary artery disease. Cardiologia 1999;44: [21] Strandness DE Jr. Duplex Scanning in Vascular Disorders. New York: Raven Press, 1990: [22] Neale ML, Chambers JF, Kelly AT, Connard S, Lawton MA, Roche J, Appleberg M. Reappraisal of duplex criteria to assess significant carotid stenosis with special reference to reports from the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial. J Vasc Surg 1994;20: [23] SPSS for Windows, release 8.0. Chicago: SPSS, [24] Stevens J, Jianwen C, Pamuk ER, Williamson DF, Thun MJ, Wood JL. The effect of age on the association between bodymass index and mortality. New Engl J Med 1998;338:1 7. [25] Prospective Study Collaboration: Cholesterol, diastolic blood pressure and stroke: strokes in people in 45 prospective cohorts, Lancet 1995; 346, [26] Mac Mahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis. Circulation 1998;97: On behalf of the LIPID Trial Research Group. [27] Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study, Lancet 1994; 344, [28] Wannamethee SG, Sharper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke 1997;28: [29] Walker WA, Harvey WR, Gaschen JR, Appling NA, Pate JW, Weiman DS. Is routine carotid screening for coronary surgery needed? Am Surg 1996;62: [30] Warlow C. Carotid endarterectomy for asymptomatic carotid stenosis. Better data, but the case is still not convincing. Br Med J 1998;317:1468. [31] Trachiotis GD, Pfister AJ. Management strategy for simultaneous carotid endarterectomy and coronary revascularization. Ann Thorac Surg 1997;64: [32] Calafiore AM, Di Giammarco G, Teodori G, et al. Midterm results after minimally invasive coronary surgery (LAST operation). J Thorac Cardiovasc Surg 1998;115: [33] Mintz GS, Painter JA, Pichard AD, et al. Atherosclerosis in angiographically normal coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J Am Coll Cardiol 1995;25: [34] Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31 41.