Combined Measurement of Carotid Stiffness and Intima-Media Thickness Improves Prediction of Complex Aortic Plaques in Patients With Ischemic Stroke

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1 Combined Measurement of Carotid Stiffness and Intima-Media Thickness Improves Prediction of Complex Aortic Plaques in Patients With Ischemic Stroke Andreas Harloff, MD; Christoph Strecker; Matthias Reinhard, MD; Marc Kollum, MD; Michael Handke, MD; Manfred Olschewski; Cornelius Weiller, MD; Andreas Hetzel, MD Background and Purpose We hypothesized that for the prediction or exclusion of aortic thrombi or plaques 4 mm, the combination of intima-media thickness (IMT) and distensibility (DC) of the common carotid arteries would be superior to the measurement of IMT alone. Methods We prospectively included 208 stroke patients (mean age, 60 years) undergoing transesophageal echocardiography for screening of aortic plaques. IMT and DC were determined by ultrasound, and DC was quantified by measuring blood pressure and the common carotid arteries diameter change on M-mode ultrasound during the cardiac cycle. Results Negative predictive values of IMT 0.9 mm and DC /kpa for the exclusion of aortic atheroma 4 mm were similar (92.0% and 91.7%, respectively). However, negative predictive values increased to 98.2% and to 100.0% for the exclusion of aortic thrombi when both parameters were combined. Positive predictive values of IMT 0.9 mm and DC 24 were lower (46.3%, 41.1%; respectively), but they also increased in combination (54.3%). Conclusions Our findings suggest that IMT and DC represent different vessel wall properties and that measuring both parameters provides optimized characterization of carotid atherosclerosis. Combining IMT and DC increases the predictive power of carotid ultrasound, making transesophageal echocardiography dispensable for assessment of the aorta for those with normal carotid arteries and indispensable for those patients with carotid atherosclerosis. (Stroke. 2006;37: ) Key Words: aortic plaques carotid arteries distensibility intima-media thickness transesophageal echocardiography Carotid intima-media thickness (IMT) and distensibility (DC) represent structural and functional vessel wall properties, but the pathophysiological mechanism of their correlation is unclear: a strong linkage of the 2 markers as well as the possibility of 2 independent processes have been discussed. 1 Increased IMT and decreased DC are correlated with generalized atherosclerosis, 1,2 and both of them are strong predictors of ischemic stroke. 3 5 In the Rotterdam study, carotid stiffness and IMT were furthermore related to aortic plaque thickness. 1 However, in that population-based study with a high mean age, aortic plaques were judged by abdominal x-ray, thus detecting only advanced stages of atherosclerosis. To date, only a few studies have addressed the link between carotid and aortic atherosclerosis by ultrasound techniques in detail and have investigated the predictive values derived from the easily accessible carotid arteries. In a previous study, we demonstrated that a normal carotid IMT excluded aortic high-risk sources of cerebral embolism, such as thrombi or plaques 4 mm, thus making transesophageal echocardiography (TEE) dispensable for assessment of the aorta. 6 However, in concordance with others, 7 positive predictive values were low. The aim of this study was thus (1) to evaluate the predictive power of carotid DC for complex aortic plaques, ie, aortic thrombi or plaques 4 mm, and (2) to investigate whether the combination of DC and IMT would increase the predictive values compared with IMT measurement alone. Subjects and Methods Study Population and Cardiovascular Risk Factors Patients (N 208) with acute cerebral ischemia admitted to our stroke unit fulfilled the 3 inclusion criteria, ie, age 18 to 85 years, presence of acute brain ischemia, and performance of TEE, and were prospectively included. The indication for TEE was derived from recommendations of a previous study. 8 TEE was scheduled when Received March 28, 2006; final revision received May 12, 2006; accepted June 14, From the Departments of Neurology and Clinical Neurophysiology (A.H., C.S., M.R., C.W., A.H.) and of Cardiology and Angiology (M.K., M.H.), and the Institute of Medical Biometrics and Statistics (M.O.), University of Freiburg, Freiburg, Germany. Correspondence to Andreas Harloff, MD, Department of Neurology and Clinical Neurophysiology, Albert-Ludwigs Universität Freiburg, Breisacher Strasse 64, D Freiburg, Germany. harloff@nz.ukl.uni-freiburg.de 2006 American Heart Association, Inc. Stroke is available at DOI: /01.STR dc 2708

Harloff et al Carotid IMT and Elasticity Predict Aortic Plaques 2709 Figure 1. Longitudinal view of the CCA in M-mode. Measurement of wall excursions over 3 heart cycles.

2 Harloff et al Carotid IMT and Elasticity Predict Aortic Plaques 2709 Figure 1. Longitudinal view of the CCA in M-mode. Measurement of wall excursions over 3 heart cycles. Dd indicates maximal diastolic diameter, and Ds, maximal systolic diameter. routine diagnostic tests (eg, transthoracic echocardiography, ECG, extracranial/intracranial ultrasound) could not clarify the stroke etiology. On an individual basis, patients with equivocal etiology after routine diagnostic tests (eg, moderate internal carotid artery stenosis) also underwent TEE. The local ethics committee approved the study, and all patients gave written, informed consent. Cardiovascular risk factors were prospectively documented and defined as described previously. 7 Infarct etiology was classified according to the Trial of Org in Acute Stroke Treatment (TOAST) criteria in each patient after completion of the diagnostic work-up. 9 Duplex Sonography of Carotid Arteries Intima-Media Thickness Carotid arteries were assessed by duplex ultrasound with a 7- to 12-MHz linear-array scanner (ATL, HDI 5000) by 1 trained sonographer. The subject was examined in the supine position. When an optimal longitudinal image of the common carotid artery (CCA) was obtained, it was frozen in magnification on the R-wave of the ECG and stored on S-VHS videotape. The IMT was measured 4 times on the far wall 4 cm and 4 times 1 cm proximal to the bifurcation on both sides of the CCA at a plaque-free site. For each individual, the common carotid IMT was defined as the overall mean IMT of 16 IMT measurements. Patients were classified into the following categories: 1, IMT mean 0.9 mm; 2, IMT 0.9 mm to 1.05 mm; and 3, IMT 1.05 mm. TABLE 1. Baseline s of the Study Population and the 4 Subgroups Distensibility Coefficient CCA stiffness (ie, DC) was determined in M-mode by assessing the maximal change in diameter during systole and diastole as DC (2 d/dd)/ P (10 3 /kpa), where d is the change in diameter, Dd the end-diastolic diameter, and P the pulse pressure (Figure 1). Measurement was performed 2 cm proximal to the carotid bifurcation at a plaque-free site. Arterial blood pressure was obtained noninvasively and simultaneously with a Dinamap blood pressure measuring device. Pulse pressure ( P) was calculated as the difference between maximal systolic and diastolic blood pressures derived from the average of 4 measurements. A DC of /kpa was chosen as the cutoff between normal and decreased DC because it represented the average value of all included patients. Patients were further subcategorized into 4 groups: 1, normal IMT and DC; 2, normal IMT but decreased DC; 3, increased IMT but normal DC; and 4, increased IMT and decreased DC. Quantitative measurements of IMT and DC were performed offline. The readers of ultrasound images from the videotape were blinded to patient demographics and the results of TEE examinations. Transthoracic and Transesophageal Echocardiography The protocol for echocardiography has been described previously. 8 In brief, the ultrasound system (ATL, HDI 3500) and a 5-MHz transducer were used for the TEE examinations. The ascending aorta and the aortic arch, including the outlet of the left subclavian artery, were examined by TEE with respect to aortic plaques defined as an irregular, intimal thickening with increased echogenicity. The thickest plaque was considered for classification. Aortic thrombus was defined as a laminated deposit along the intimal surface, with variable echogenicity, and which might be associated with mobile lesions. According to the results of a previous study, 3 patients with an aortic wall thickness (AWT) 1 mm were in group 1, those with an AWT 1 to 3.9 mm were in group 2, and those with an AWT 4 mm were in group 3. Aortic thrombi superimposed on plaques or aortic atheroma 4 mm thick were defined as complex plaques. Echocardiograms were stored on videotape, and the cardiologist was blinded to the duplex sonography findings and the patients demographic data. Statistical Analysis Data are presented as the mean and SD for continuous variables and as absolute and relative frequencies for categorical variables. To detect statistically significant relations between categorical variables, Fisher s exact test was used. For continuous variables, t tests or Wilcoxon tests were applied as appropriate. For comparison of 2 groups, a 1-way ANOVA was used. Correlations of selected vari- All Patients, Group 1, n 57 Group 2, n 43 Group 3, n 27 Group 4, n 81 P Age, y 60 ( 13.3) 46.6 ( 11.1) 60.5 ( 13.6) 62.1 ( 8.2) 68.7 ( 6.9) Female sex, No. (%) 95 (45.7) 30 (52.6) 20 (46.5) 6 (22.2) 39 (48.1) Hypertension, No. (%) 138 (66.3) 20 (35.1) 29 (67.4) 19 (70.4) 71 (87.7) Diabetes, No. (%) 44 (21.2) 1 (1.8) 11 (25.6) 8 (29.6) 24 (29.6) Hyperlipidemia, No. (%) 77 (37.0) 10 (17.5) 20 (46.5) 11 (40.7) 37 (45.7) Smoking, No. (%) 58 (27.9) 25 (43.9) 11 (25.6) 9 (33.3) 13 (16.0) Coronary heart disease, No. (%) 39 (18.8) 5 (8.8) 8 (18.6) 8 (29.6) 18 (22.2) Peripheral artery disease, No (%) 12 (5.8) 0 (0.0) 1 (2.3) 2 (7.4) 9 (11.1) Stroke/transient ischemic attack, No. (%) 23 (11.1) 1 (1.8) 6 (14.0) 2 (7.4) 14 (17.3) Systolic blood pressure, mm Hg 137 ( 21.3) 121 ( 15.7) 140 ( 17.6) 127 ( 11.8) 149 ( 20.4) Diastolic blood pressure, mm Hg 73 ( 9.7) 70 ( 8.4) 76 ( 10.6) 71 ( 6.9) 74 ( 10.3) Subgroups are defined in text. Values are SD.

3 2710 Stroke November 2006 TABLE 2. Ultrasound Measurements of IMT and AWT DC 24 (10 3 /kpa), n 124 DC 24 (10 3 /kpa), n 84 P IMT mm, n (48.1%) to 1.05 mm, n (26.4%) mm, n (25.5%) AWT mm, n (13.5%) mm, n (58.2%) mm, n (28.4%) 51 8 P values are the results from the corresponding tests of characteristics for patient groups with DC 24 (10 3 /kpa) and DC 24 (10 3 /kpa). We tested 3 2 tables for IMT and AWT each with 3 categories for DC 24 (10 3 /kpa) and DC 24 (10 3 /kpa). ables were estimated by Pearson s correlation coefficient. Carotid artery ultrasonographic data and corresponding TEE data were compiled on a 2 2 contingency table to allow calculation of predictive values. Multivariate analyses were performed by means of ANCOVA for continuous dependent variables (IMT and DC) and by multiple logistic regression for dichotomized dependent variables (AWT 4 mm versus AWT 4 mm). All significance tests were 2 sided and used a significance level of 5%. We report nominal probability values not adjusted for multiple comparisons. All analyses were performed with the SAS statistical package (version 6.12). Results Baseline s Cardiovascular risk factors of the 208 study participants are shown in Table 1. In patients with both increased IMT and decreased DC (ie, group 4), the prevalence of cardiovascular risk factors such as older age, hypertension, diabetes, peripheral artery disease, and history of stroke was significantly higher compared with that in patients with normal carotid arteries (ie, group 1). Carotid and aortic ultrasound findings are displayed in Table 2 and are shown in relation to the TOAST classification in Table 3. Patients with large-artery atherosclerosis, cardioembolic stroke, and small-vessel disease showed the highest carotid IMT and aortic wall thickness and the lowest DC. Aortic plaques 4 mm were most frequent in patients with cardioembolic stroke. Results of multivariate regression analysis are given in Table 4. Correlation of Carotid and Aortic Atherosclerosis We found a moderate, positive correlation between IMT and AWT (Figure 2A) and a moderate, negative association between CCA DC and both IMT and AWT (Figure 2B and 2C). Combination of IMT and DC and Aortic Findings Figure 3 dichotomizes IMT and DC parameters and shows respective AWT in patients, depending on the combination of IMT and DC. Patients with both a normal IMT and a normal DC (group 1) showed the least aortic atherosclerosis, whereas aortic plaques were most frequent in those with both an increased IMT and a reduced DC of the CCAs (group 4). Predictive Values A given IMT 0.9 mm and a DC /kpa excluded an AWT 4.0 mm with comparable negative predictive values (NPVs) of 92.0% and 91.7%, respectively. However, when both parameters were combined, the NPV increased to 98.2%. Positive predictive values for an IMT 0.9 mm and DC /kpa for the existence of aortic plaques 4.0 mm were lower (46.3% and 41.1%, respectively) but were also increased in combination (54.3%). For the exclusion of aortic thrombi, the NPV for IMT 0.9 mm and a DC /kpa were 97.0% and 98.8%, respectively, whereas the NPV increased to 100% when both parameters were combined. Discussion We present the first prospective investigation of a larger cohort of patients with brain ischemia evaluated by highresolution carotid ultrasound that measured both carotid IMT and DC to provide improved predictive values for aortic atheroma 4 mm thick and aortic thrombi. The impact of IMT and DC was similar, but the most important result of this study was the synergistic effect that could be achieved when both parameters were combined. This finding has not yet been demonstrated. Simons et al 10 found carotid IMT superior to carotid DC in discriminating between low- and high-risk patients in terms of cardiovascular disease, but they neither combined both parameters nor investigated aortic atherosclerosis. Also, in the large Rotterdam study, neither were predictive values of carotid atherosclerosis for aortic atheroma given nor were IMT and DC investigated in combination. 1 The additional determination of CCA DC is reliable 11 and easy to perform in clinical practice with a supplementary expenditure of time of only 5 to 10 minutes for a trained sonographer. The high NPV of the combined measurement can be helpful for assessment of the aorta in patients who refuse TEE or in cases when TEE is not available or contraindicated. On the other hand, patients with carotid atherosclerosis, ie, those with increased IMT and decreased DC, are at high risk for aortic plaques and thrombi and should TABLE 3. Ultrasound Findings in Relation to TOAST Criteria Large-Artery Atherosclerosis Cardioembolism Small-Vessel Disease Other Determined Etiology Undetermined Etiology P n (%) 15 (7.2) 72 (34.6) 22 (10.6) 13 (6.3) 86 (41.3) IMT, mm 1.04 ( 0.22) 1.00 ( 0.20) 0.97 ( 0.21) 0.73 ( 0.14) 0.81 ( 0.17) AWT, mm 3.55 ( 1.91) 4.42 ( 1.80) 2.48 ( 1.06) 1.87 ( 1.13) 2.08 ( 1.16) DC, 10 3 /kpa ( 6.84) ( 9.24) ( 8.02) ( 10.47) ( 11.27) AWT 4 mm, No. (%) 4 (26.7) 48 (66.7) 3 (13.6) 0 (0.0) 4 (4.7) Values are SD.

4 Harloff et al Carotid IMT and Elasticity Predict Aortic Plaques 2711 TABLE 4. Multivariate Regression Analysis of Carotid and Aortic Ultrasound Measurements From Demographic and Clinical Data DC, AWT, AWT 4, mm n 59 DC IMT Systolic blood pressure Diastolic blood pressure Male sex Age 60 y Hypertension Diabetes Hyperlipidemia Smoking Coronary artery disease Peripheral artery disease History of stroke/transient ischemic attack P values for the test of no effect of the corresponding characteristics on the dependent variables are shown. undergo TEE examination to screen for a probable source of cerebral emboli. IMT is widely used as a surrogate end point for determining the success of interventions that lower risk factors for atherosclerosis. 12,13 In contrast, only a few small studies have investigated the effect of statin therapy on carotid DC, and no clinical trials to date have investigated the influence of optimal therapy of cardiovascular risk factors on both carotid IMT and compliance. Our results suggest that measuring both parameters would improve the characterization of atherosclerosis in both the carotid arteries and the aorta and serve as a more sensitive marker of progression and regression of atherosclerosis in clinical trials than IMT measurement alone. Furthermore, measuring both parameters could also help select those patients requiring earlier and more aggressive antiatherogenic treatment. The exact linkage of IMT and DC in the development of atherosclerosis is unknown so far, but several hypothesis have been discussed: (1) The presence of atherosclerosis leads to stiffening of arteries; (2) Increased arterial stiffness causes wall damage and atherosclerosis owing to the loss of shockabsorbing capacity; (3) Both mechanisms apply, leading to a self-perpetuating and reinforcing process; or (4) Atherosclerosis and arterial stiffness are 2 independent processes. 1 The better correlation of AWT with the combination of IMT and DC and the equal predictive values of both parameters suggest 2 independent processes. However, only IMT was an independent predictor of AWT in our study. Future longitudinal studies evaluating the development of IMT increase and the DC decrease over time might clarify this point. The predictive value of IMT found in this study is slightly lower than in our previous study, 6 which might have been attributable to the fact that we performed TEE only in those patients without clarified stroke etiology after routine diagnostic testing; ie, patients with 80% stenosis of the internal Figure 2. A, Correlation between AWT and IMT. B, Correlation between DC and IMT. C, Correlation between DC and AWT. carotid artery or atrial fibrillation were not included. Therefore, a certain number of patients with progressive atherosclerosis of the carotid arteries and the aorta are not represented. Limitations of the Study We did not include stroke patients consecutively, which might have caused a bias in patient selection. Also, we arbitrarily chose the mean value of DC in our cohort as the cutoff for predictive values, because normal values for a larger cohort were unavailable. Therefore, the predictive

5 2712 Stroke November 2006 Figure 3. AWT dependence on the combination of IMT and DC: I, normal IMT and DC; 2, normal IMT but decreased DC; 3, increased IMT but normal DC; and 4, increased IMT but decreased DC. Except for groups 2 and 3, comparison of all other subgroups was significantly different (P 0.001). values of DCs might change with different cutoff values and different study populations. Normal values should be evaluated by high-resolution ultrasound techniques analogous to the determination of IMT in previous studies. 17 Conclusions Carotid IMT and DC seem to represent different atherosclerotic vessel wall properties. Measuring both parameters provides optimal characterization of atherosclerosis and could thus provide a more sensitive surrogate marker of carotid atherosclerosis for future trials investigating the influence of treatment on the progression of atherosclerosis. Also, the combination of IMT and DC of the CCAs increases the predictive power of ultrasound, making TEE dispensable for assessment of the aorta in normal carotid arteries but indispensable in patients with carotid atherosclerosis. References 1. van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman RS, Hoeks AP, van der Kuip DA, Hofman A, Witteman JC. Association between arterial stiffness and atherosclerosis: the Rotterdam Study. Stroke. 2001;32: O Leary DH, Polak JF. Intima-media thickness: a tool for atherosclerosis imaging and event prediction. Am J Cardiol. 2002;90:18L 21L. 3. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. The French Study of Aortic Plaques in Stroke Group. N Engl J Med. 1996;334: Hollander M, Hak AE, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, Witteman JC, Breteler MM. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke. 2003;10: Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, Boutouyrie P. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke. 2003;34: Harloff A, Handke M, Geibel A, Oehm E, Guschlbauer B, Olschewski M, Hetzel A. Do stroke patients with normal carotid arteries require TEE for exclusion of relevant aortic plaques? J Neurol Neurosurg Psychiatry. 2005;76: Fasseas P, Brilakis ES, Leybishkis B, Cohen M, Sokil AB, Wolf N, Dorn RL, Roberts A, VanDecker W. Association of carotid artery intima-media thickness with complex aortic atherosclerosis in patients with recent stroke. Angiology. 2002;53: Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies following examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke. 2006;37: Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST: Trial of Org in Acute Stroke Treatment. Stroke. 1993;24: Simons PC, Algra A, Bots ML, Grobbee DE, van der Graaf Y. Common carotid intima-media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of ARTerial disease). Circulation. 1999;100: Wada T, Kodaira K, Fujishiro K, Maie K, Tsukiyama E, Fukumoto T, Uchida T, Yamazaki S. Correlation of ultrasound-measured common carotid artery stiffness with pathological findings. Arterioscler Thromb. 1994;14: van der Meer IM, Iglesias del Sol A, Hak AE, Bots ML, Hofman A, Witteman JC. Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study. Stroke. 2003;34: Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35: Ubels FL, Muntinga JH, van Doormaal JJ, Reitsma WD, Smit AJ. Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics. Atherosclerosis. 2001;154: Ferrier KE, Muhlmann MH, Baguet JP, Cameron JD, Jennings GL, Dart AM, Kingwell BA. Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol. 2002;39: Smilde TJ, van den Berkmortel FW, Wollersheim H, van Langen H, Kastelein JJ, Stalenhoef AF. The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia. Eur J Clin Invest. 2000;30: Aminbakhsh A, Mancini GB. Carotid intima-media thickness measurements: what defines an abnormality? a systematic review. Clin Invest Med. 1999;22:

I ncreased carotid intima media thickness (IMT) indicates

I ncreased carotid intima media thickness (IMT) indicates 1654 PAPER Do stroke patients with normal carotid arteries require TEE for exclusion of relevant aortic plaques? A Harloff, M Handke, A Geibel, E Oehm, B Guschlbauer, M Olschewski, A Hetzel... See end