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Association of ischemic stroke to coronary artery disease using computed tomography coronary angiography
International Journal of Cardiology 160 (2012) 171–174
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Association of ischemic stroke to coronary artery disease using computed tomography coronary angiography Jesper K. Jensen a,⁎, Hector M. Medina b, Bjarne L. Nørgaard a, Kristian A. Øvrehus a, Jesper M. Jensen a, Lene H. Nielsen a, Pal Maurovich-Horvat b, Leif-Christopher Engel b, James L. Januzzi c, Udo Hoffmann b, Quynh A. Truong b,c a b c
Department of Cardiology, Vejle Hospital, Denmark Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, USA Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, USA
a r t i c l e
i n f o
Article history: Received 17 December 2010 Received in revised form 11 March 2011 Accepted 14 April 2011 Available online 4 May 2011 Keywords: Acute ischemic stroke Coronary atherosclerosis Coronary CT angiography
a b s t r a c t Background: While patients with coronary artery disease (CAD) and cerebrovascular disease share similar risk factor profiles, data on whether IS can be considered a “CAD equivalent” are limited. We aimed to determine whether ischemic stroke is an independent predictor of CAD by using cardiac computed tomography angiography (CTA). Methods: We analyzed the CTA in 392 patients with no history of CAD (24 patients with acute IS and 368 patients with acute chest pain). Extent of plaque burden was additionally dichotomized into 0–4 versus N4 segments. Results: Patients with IS had a near 5-fold increase odds of having coronary artery plaque (odds ratio [OR] 4.9, P b 0.01) as compared to those without IS. After adjustment for age, gender, and traditional cardiac risk factors, there remained a near 4-fold increase odds for coronary plaque (adjusted OR 3.7, P = 0.04). When stratified by extent of plaque, patients with IS had over 18-fold increase odds of having N 4 segments of plaque than 0–4 segments as compared to patients without stroke (OR 18.3, P b 0.01), which remained significantly associated in adjusted analysis (adjusted OR 12.1, P b 0.001). Conclusion: Acute IS is independently associated with higher risk and greater extent of CAD compared to patients with acute chest pain at low-to-intermediate risk for acute coronary syndrome. © 2011 Elsevier Ireland Ltd. All rights reserved.
Stroke and myocardial infarction are leading causes of morbidity and mortality in industrialized countries [1]. The mechanism that links cerebrovascular and cardiovascular diseases has been suggested by studies in stroke patients with provocative functional tests (i.e., exercise testing or myocardial perfusion imaging). The American Heart Association/American Stroke Association practice guidelines suggest that stroke patients with significant carotid disease and risk assessment based on Framingham Risk Score to be considered for non-invasive testing for coronary artery disease (CAD) [2]. However, data about the prevalence of CAD in the patients with acute ischemic stroke (IS) remain limited [3–6]. This is relevant, as (outside of those with stroke due to carotid artery disease) patients with acute IS represent an under-represented population in current consensus guidelines for lipid management [7]. Determining IS as a “CAD equivalent”, similar to what has been shown in patients with diabetes mellitus, may have tremendous significance in patient management.
⁎ Corresponding author at: Department of Cardiology, Odense University Hospital, DK-5000 Odense C, Denmark. Tel.: + 45 6017 7420; fax: + 45 6312 0854. E-mail address: [email protected] (J.K. Jensen). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.04.006
Cardiac computed tomography angiography (CTA) is a wellvalidated state-of-the-art non-invasive imaging modality for accurate assessment of CAD [8–10]. Because CTA is performed non-invasively, this technique represents an attractive tool to determine if patients with acute IS have co-existing CAD. Thus, we aimed to determine the relation of acute IS to the presence and extent of CAD. 1. Methods A total of 392 patients without known CAD were included in the analysis and derived by combining 2 cohorts (24 patients with acute IS and 368 patients with acute chest pain). Patients with acute IS were enrolled from May 2008 to December 2008 at the Department of Neurology, Vejle Hospital, Denmark between weekday hours of 7 AM and 3 PM. Intra-cerebral or subarachnoid haemorrhage was ruled out by computed tomography at the time of admission. Patients with history of myocardial infarction, stable or unstable angina pectoris, history of coronary angioplasty or coronary bypass surgery were excluded (n = 21); those with onset of stroke symptoms N 7 days before admission (n = 11) and those with lack of compliance, unwillingness to participate and renal insufficiency (Creatinine N 1.9 mg/dL) (n = 71) were also excluded. None of the patients were treated with thrombolysis due to late presence of symptoms. For comparison, we examined results of CTA from patients with acute chest pain, enrolled from the Rule Out Myocardial Infarction Using Computer Assisted Tomography (ROMICAT) trial [11]. Briefly, these patients presented to the emergency department with acute chest pain and had low-to-intermediate likelihood for acute
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coronary syndrome with normal initial biomarkers and negative or inconclusive electrocardiogram. The study was approved by both the local ethics committees.
Table 1 Baseline characteristics of all patients.
1.1. Cardiac CT imaging protocol
Characteristics
Patients without stroke Patients with stroke P value (n = 368) (n = 24)
CTA imaging of the patients was performed using standard retrospectively-gated coronary artery imaging protocol with a 64-slice dual-source CT scanner (Somatom definition, Siemens Medical Solutions; Forcheim, Germany) for the acute IS patients and a 64-slice MDCT scanner (Siemens Sensation 64; Forchheim, Germany) for the acute chest pain patients. In preparation for the scan, patients with IS were not treated with betablockers or nitroglycerin for safety reasons. CTA examinations were performed during the first 5 days of admission for the acute IS patients and prior to hospital admission for the acute chest pain patients. The parameters for the dual-source CT scanner were as follows: spiral mode with 330 ms rotation time, 64× 0.6 mm collimation, tube voltage 120 kVp for both tubes, current 560 mA with tube modulation and full current between 25% and 80% of the RR interval, and pitch 0.20–0.44 according to the heart rate. The parameters for the MDCT scanner are as follows: spiral mode with 330 ms rotation time, 32 × 0.6 mm collimation, tube voltage of 120 kVp, and maximum effective tube current-time product of 850 mA s, adjusted to the subjects body habitus, tube modulation was employed when possible, and pitch dependent on heart rate. A test bolus scan followed by contrast agent (Iomeron 350 mg/cm3 or Iodixanol 320 mg/cm3) injection rate of 5 mL/s for total contrast volume dependent on scan range. Transaxial images were reconstructed using a singlesegment algorithm with 0.75 mm slice thickness, 0.4–0.5 mm increment, and a medium sharp kernel (B26) with at least one diastolic and one systolic phase dataset. All reconstructions were transferred to an offline workstation for analysis. The interpreters were blinded to patient clinical data.
Age (yrs)⁎ (mean ± SD) Male gender, n (%)
53 ± 12 226 (61)
70 ± 11 13 (54)
b0.001 0.521
Past medical history Diabetes, n (%) High lipids, n (%) Hypertension, n (%) Smoking, n (%)
40 (11) 135 (37) 145 (39) 93 (25)
3 (13) 12 (50) 14 (58) 11 (46)
0.737 0.199 0.086 0.033
Vital signs, admission Heart rate⁎, bpm 77 ± 16 Body mass index⁎, kg/m2 29 ± 6 ¶SSS score⁎ – LACI, n (%) – PACI/TACI, n (%) – POCI, n (%) –
78 ± 14 26 ± 6 44 ± 10 9 (38) 13 (54) 2 (8)
0.760 0.023 – – – –
Laboratory Creatinine⁎ (mg/dL)
0.95 ± 0.18
0.93 ± 0.34
0.680
56 (15)
7 (29)
0.084
103 (28) 84 (23) 117 (32)
10 (42) 5 (21) 10 (42)
0.166 1.000 0.396
1.2. Coronary artery plaque assessment Coronary artery calcium (CAC) scores were measured according to the method described by Agatston et al. [12]. All CTA evaluations were made on a separate workstation (Leonardo, Siemens Medical Solutions) independently by two experienced observers blinded to patient history. The presence and extent of calcified, mixed, and non-calcified coronary plaque were determined for each subject and evaluated according to the modified American Heart Association classification with 17-coronary segments [13]. Details on plaque detection and characterization have been previously described and validated [14]. The presence of coronary artery stenosis was defined as a luminal obstruction N50% diameter in any coronary segment. 1.3. Covariates and risk factor assessment Patient demographics, clinical characteristics and medical history were obtained from the patients, his/her relatives, and/or from hospital records. The presence of cardiovascular risk factors was established from actual measurements obtained during index hospitalization. Diabetes was defined as a fasting plasma glucose N 126 mg/dL or treatment with a hypoglycaemic agent. Hyperlipidemia was defined as total cholesterol of N 200 mg/dL or treatment with a lipid lowering medication. Measurement of lipids was performed the next morning after the stroke event. Hypertension was defined as systolic blood pressure N 140 mm Hg or diastolic blood pressure N 90 mm Hg or current antihypertensive treatment. Hypertension in the stroke population was defined as current antihypertensive treatment. Subjects were classified as smokers if they had smoked at least one cigarette per day for at least the past 6 months. Body mass index (BMI) was defined as weight (in kilograms) divided by the height squared (in meters). Severity of the index stroke was assessed using the Scandinavian Stroke Scale (SSS) [15]. Stroke subtypes were classified according to the Oxfordshire Community Stroke Project [16]. 1.4. Statistical analysis Continuous variables were reported as mean ± SD or median with interquartile range [IQR], when appropriate. CAD categories were stratified into no CAD, nonobstructive CAD, and stenosis. The extent of coronary plaque was dichotomized into 0– 4 versus N4 coronary segments. To compare differences between groups, we used Fisher's exact test, Wilcoxon rank sum test and Student's t-test as appropriate. We used logistic regression analysis to determine the associations of stroke to the presence of any plaque, extent of plaque (0–4 versus N 4 coronary segments), and type of plaque (calcified, mixed and non-calcified). Multivariable analyses included stroke and were adjusted for potential confounders based on a priori knowledge, which included age N 75 years, gender, and traditional cardiovascular risk factors of BMI, hypertension, hyperlipidemia, diabetes and smoking. A two-tailed P value b0.05 was considered to be statistically significant. All analyses were performed using STATA/SE 10.0 (StataCorp LP, College Station, TX).
2. Results Table 1 summarizes the patient demographics of the two cohorts. Patients with stroke were older than those without stroke, and the BMI was lower than those without stroke. Of the combined cohorts, 205 patients (52%) had presence of coronary artery plaque. Of 17
Medication Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, n (%) Lipid lowering drugs, n (%) Beta-blockers, n (%) Aspirin, n (%)
¶ Scandinavian Stroke Scale. LACI, Lacunaria infarction. TACI, Total anterior circulation infarction. PACI, Partial anterior circulation infarction. POCI, Posterior circulation infarction. ⁎ means (mean +/- SD).
segments, there was a median of 1 [IQR 0 to 5] coronary segments with plaque per subject. 2.1. Stroke and presence of coronary artery disease The presence of coronary plaque was more frequently seen in patients with stroke than those without (83.3% versus 50.3%, P b 0.001) (There was no difference in the frequency of obstructive CAD between the two groups. Table 2 summarizes the CTA findings. As compared to patients without stroke, patients with IS had a near 5-fold increase odds of having any coronary plaque (odds ratio [OR] 4.9, P b 0.001). After adjustment for age N 75 years, gender, and traditional cardiovascular risk factors, this increase remained (OR 3.7, P = 0.04) (Table 3). 2.2. Stroke and extent of coronary plaque Patients with stroke had a greater extent of coronary plaque than subjects without stroke (7 [IQR 5 to 8] versus 1 [0 to 4] segments with any plaque, P b 0.001). When stratified by extent of plaque, patients with stroke had over 18-fold increase odds of having N4 segments of plaque than 0–4 segments as compared to patients without stroke (OR 18.3, P b 0.01), which remained significantly associated in adjusted analysis (adjusted OR 20.0, P b 0.001) (Table 3). 2.3. Stroke and coronary plaque composition Calcified plaque was present in 185 patients (47%) whereas 147 (38%) had non-calcified plaque, and 130 (33%) had mixed plaque. The median number of segments of plaque per patient was 0 [IQR 0 to 3] for calcified plaque, 0 [IQR 0 to 1] for mixed plaque, and 0 [IQR 0 to 1] for non-calcified plaque. Patients with stroke were more likely to demonstrate mixed (79% versus 30%, P b 0.01) and calcified plaque (71% versus 46%, P = 0.02) whereas there was no difference between
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Table 2 Comparison of CTA findings between patients admitted without and with stroke. CTA findings
All patients n = 392
Patients without stroke n = 368
Patients with stroke n = 24
No CAD Non-obstructive CAD Stenosis (N 50% luminal narrowing) Non-obstructive plaque or no CAD Agatston scorea
187 131 74 318 –
183 117 68 300 –
4 (17%) 14 (58%) 6 (25%) 18 (75%) 255 (68–736)
By plaque morphologya Segments with any plaque Segments with any calcified plaque Segments with any non-calcified plaque Segments with any mixed plaque
(48%) (33%) (19%) (81%)
1 (0–5) 0 (0–3) 0 (0–1) 0 (0–1)
(50%) (32%) (18%) (82%)
1 (0–4) 0 (0–3) 0 (0–1) 0 (0–1)
7 (5–8) 3 (0–4) 0 (0–1) 3 (2–5)
P value 0.001 0.012 0.423 0.423 –
b0.001 0.068 0.684 b0.001
CAD, Coronary Artery Disease. a Median (IQR).
the two groups when stratified by non-calcified plaque (38% versus 38%, P = 1.00). In unadjusted analysis, patients with IS had 3-fold increase odds of having any calcified plaque (OR 2.9, P = 0.02) and a 9-fold increase of having any mixed plaque (OR 8.8, P b 0.01) when compared to those with acute chest pain. After adjustment for age, gender, and traditional risk factors, these increased risks of plaques remained significant for mixed plaque (OR 7.4, P b 0.01), but were attenuated for calcified plaque (OR 1.6, P = 0.37). There was no difference in OR for noncalcified plaque between patients with and without stroke. 3. Discussion In this study, we found a high prevalence of coronary artery plaque burden by CTA in patients with acute IS despite lack of symptoms or history of ischemic heart disease. Patients with acute IS had a 4-fold increased risk of having any coronary plaque as compared to a population of patients with acute chest pain at low-to-intermediate risk for acute coronary syndrome. This association was independent of age, gender, and traditional cardiovascular risk factors. When stratifying into the different subtypes of plaque, there was a significant association between ischemic stroke and the presence of mixed coronary plaque. The association of IS with coronary artery plaque is presumably due to shared risk factors [17]. Because of its overlap with risk factors of cardiovascular disease, IS has been suspected to be associated with CAD, and risk of cardiovascular events. This hypothesis is supported by previous studies demonstrating an association of IS with coronary calcification [18], which represents a part of the spectrum of CAD [19,20]. These studies have demonstrated a high prevalence of CAD (47.1%) in IS as well as significant CAD (18%) [3–6]. However, these studies did not provide information whether stroke per se is associated with CAD. The composition of plaque subtype has recently be evaluated by Yoon et al [5]. The prevalence of plaque subtype in this study was Table 3 Uni and multivariable analysis for the presence of any plaque in all patients. Odds ratio
Age N 75 years Gender (male) Diabetes High lipids Hypertension Smoking BMI Creatinine Stroke
Any plaque Uni-variable OR (95% CI)
P value
Multi-variable OR (95% CI)
P value
14.6 1.7 2.0 3.6 3.2 1.0 1.0 3.0 4.9
b 0.01 0.01 0.04 b 0.01 b 0.01 0.89 0.60 0.04 b 0.01
12.1 (2.3–56.8) 2.2 (1.3–3.9) 0.9 (0.4–2.4) 3.0 (1.9–5.0) 2.6 (1.6–4.3) 1.3 (0.8–2.1) 1.0 (1.0–1.0) 1.5 (0.3–6.4) 3.7 (1.1–12.8)
b 0.01 b 0.01 0.85 b 0.01 b 0.01 0.36 0.94 0.60 0.04
(3.4–62.3) (1.1–2.5) (1.0–4.0) (2.3–5.6) (2.1–5.0) (0.7–1.6) (1.0–1.0) (1.1–8.5) (1.7–14.8)
very different compared to our results perhaps due to different scanners (single vs. dual source), patients (cardio-embolic vs. no overt ischemic heart disease) and the fact that plaque subtypes only were evaluated in significant lesions (≥50% stenosis). Furthermore, despite the fact that IS significantly adds over traditional risk factors when predicting cardiovascular events [21], current consensus guidelines do not list IS as a “CAD equivalent”. Our data extend the findings of previous studies by demonstrating that patients with IS had an increased risk of having any plaque and mixed plaques as compared to a cohort of patients with acute chest pain and thus further support the argument that IS may be considered as a CAD equivalent similar to peripheral artery disease or diabetes mellitus [22]. Recently, several papers have suggested that mixed plaques by CTA are associated with outcomes. Interestingly in our study, mixed plaques were independently associated with IS and may be associated with outcome. Thus, both the assessment of stenosis and the presence and composition of non-obstructive plaque may be important for risk stratification of patients with IS and no known CAD [23–26]. Prolonged follow-up of patients surviving cerebrovascular disease indicates that coronary artery disease is the main course of long-term mortality [27]. Thus, primary or secondary prevention of CAD may be equally or more important than prevention of recurrent stroke in these patients. The American Heart Association/American Stroke Association statement recommends risk assessment notably on Framingham Risk Score to identify stroke patients for non-invasive testing of CAD [2]. Thus, only a part of patients with IS are routinely screened for CAD. In addition, the sensitivity and specificity for classic non-invasive tests in detecting CAD are low [28,29].The newest CT technology permits the assessment of CAD with a low radiation scan (b5 mSv) in most patients. Several limitations of this study should be noted. First, the study is a cross-sectional analysis with a small subgroup of patients with IS and does not allow assessment of causality or whether assessment of CAD indeed will improve prognosis of patients with IS. In addition, due to the small number of patients with acute IS the results need to be confirmed in larger patient cohorts. While two different CT scanners were used, both 64-slice MDCT and dual-source CT have comparable spatial resolution. The lack of using beta-blockers in the stroke population may have influenced the image quality, but CT interpretations were performed at a single core laboratory by highly experienced readers. In conclusion, acute IS is independently associated with higher risk and greater extent of subclinical CAD compared to symptomatic patients with acute chest pain at low-to-intermediate risk for ACS. Larger prospective studies are needed to establish ischemic stroke as a CAD equivalent and to establish whether these patients may benefit from medical therapy for CAD; nonetheless in the absence of clear contraindication, logic would dictate a benefit would be expected from aggressive secondary prevention measures.
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Acknowledgments We are greatly indebted to Jens O. Kjaersgaard for helping with the clinical evaluation of the patients. This project was supported with grants from P.A Messerschmidt Foundation, Copenhagen, Familien Hede Nielsens Foundation, Horsens, The Danish Medical Association, Copenhagen and Kirsten Anthonius Foundation, Aarhus. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [29]. References [1] Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart Disease and Stroke Statistics— 2010 Update. A Report from the American Heart Association. Circulation 2010;121(7):e46–e215. [2] Adams RJ, Chimowitz MI, Alpert JS, et al. Coronary risk evaluation in patients with transient ischemic attack and ischemic stroke: a scientific statement for healthcare professionals from the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke Association. Stroke 2003;34(9): 2310–22. [3] Calvet D, Touze E, Varenne O, Sablayrolles JL, Weber S, Mas JL. Prevalence of asymptomatic coronary artery disease in ischemic stroke patients: the PRECORIS study. Circulation 2010;121(14):1623–9. [4] Jin GY, Jeong SK, Lee SR, Kwon KS, Han YM, Cho YI. Screening strategies for the diagnosis of coronary artery stenosis in patients with cerebral infarction using dual-source spiral CT. J Neurol Sci 2009;284(1–2):129–34. [5] Yoon YE, Chang HJ, Cho I, et al.: Incidence of subclinical coronary atherosclerosis in patients with suspected embolic stroke using cardiac computed tomography. Int J Cardiovasc Imaging 2010. [6] Hoshino A, Nakamura T, Enomoto S, et al. Prevalence of coronary artery disease in Japanese patients with cerebral infarction: impact of metabolic syndrome and intracranial large artery atherosclerosis. Circ J 2008;72(3):404–8. [7] Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):227–39. [8] Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52(21):1724–32. [9] Achenbach S, Ropers U, Kuettner A, et al. Randomized comparison of 64-slice single- and dual-source computed tomography coronary angiography for the detection of coronary artery disease. JACC Cardiovasc Imaging 2008;1(2):177–86. [10] Gaudio C, Mirabelli F, Pelliccia F, et al. Early detection of coronary artery disease by 64-slice multidetector computed tomography in asymptomatic hypertensive high-risk patients. Int J Cardiol 2009;135(3):280–6. [11] Hoffmann U, Bamberg F, Chae CU, et al. Coronary computed tomography angiography for early triage of patients with acute chest pain: the ROMICAT (Rule Out Myocardial Infarction using Computer Assisted Tomography) trial. J Am Coll Cardiol 2009;53(18):1642–50. [12] Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte MJr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15((4):827–32.
[13] Raff GL, Abidov A, Achenbach S, et al. SCCT guidelines for the interpretation and reporting of coronary computed tomographic angiography. J Cardiovasc Comput Tomogr 2009;3(2):122–36. [14] Bamberg F, Dannemann N, Shapiro MD, et al. Association between cardiovascular risk profiles and the presence and extent of different types of coronary atherosclerotic plaque as detected by multidetector computed tomography. Arterioscler Thromb Vasc Biol 2008;28(3):568–74. [15] Multicenter trial of hemodilution in ischemic stroke—background and study protocol. Scandinavian Stroke Study Group. Stroke 1985;16(5):885–90. [16] Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991;337(8756):1521–6. [17] Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002;106(3):388–91. [18] Vliegenthart R, Hollander M, Breteler MM, et al. Stroke is associated with coronary calcification as detected by electron-beam CT: the Rotterdam Coronary Calcification Study. Stroke 2002;33(2):462–5. [19] Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995;92(8): 2157–62. [20] Sangiorgi G, Rumberger JA, Severson A, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 1998;31(1):126–33. [21] Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. Jama 2004;291(2):210–5. [22] Smith Jr SC, Blair SN, Bonow RO, et al. AHA/ACC Scientific Statement: AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease: 2001 update: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 2001;104(13):1577–9. [23] Mitsutake R, Miura S, Zhang B, Saku K. HDL-associated factors provide additional prognostic information for coronary artery disease as determined by multi-detector row computed tomography. Int J Cardiol 2010;143(1):72–8. [24] Pundziute G, Schuijf JD, Jukema JW, et al. Evaluation of plaque characteristics in acute coronary syndromes: non-invasive assessment with multi-slice computed tomography and invasive evaluation with intravascular ultrasound radiofrequency data analysis. Eur Heart J 2008;29(19):2373–81. [25] Henneman MM, Schuijf JD, Pundziute G, et al. Noninvasive evaluation with multislice computed tomography in suspected acute coronary syndrome: plaque morphology on multislice computed tomography versus coronary calcium score. J Am Coll Cardiol 2008;52(3):216–22. [26] Funabashi N, Asano M, Komuro I. Predictors of non-calcified plaques in the coronary arteries of 242 subjects using multislice computed tomography and logistic regression models. Int J Cardiol 2007;117(2):191–7. [27] Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology 2006;66(5):641–6. [28] Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362(10):886–95. [29] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Association of ischemic stroke to coronary artery disease using computed tomography coronary angiography Jesper K. Jensen a,⁎, Hector M. Medina b, Bjarne L. Nørgaard a, Kristian A. Øvrehus a, Jesper M. Jensen a, Lene H. Nielsen a, Pal Maurovich-Horvat b, Leif-Christopher Engel b, James L. Januzzi c, Udo Hoffmann b, Quynh A. Truong b,c a b c
Department of Cardiology, Vejle Hospital, Denmark Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, USA Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, USA
a r t i c l e
i n f o
Article history: Received 17 December 2010 Received in revised form 11 March 2011 Accepted 14 April 2011 Available online 4 May 2011 Keywords: Acute ischemic stroke Coronary atherosclerosis Coronary CT angiography
a b s t r a c t Background: While patients with coronary artery disease (CAD) and cerebrovascular disease share similar risk factor profiles, data on whether IS can be considered a “CAD equivalent” are limited. We aimed to determine whether ischemic stroke is an independent predictor of CAD by using cardiac computed tomography angiography (CTA). Methods: We analyzed the CTA in 392 patients with no history of CAD (24 patients with acute IS and 368 patients with acute chest pain). Extent of plaque burden was additionally dichotomized into 0–4 versus N4 segments. Results: Patients with IS had a near 5-fold increase odds of having coronary artery plaque (odds ratio [OR] 4.9, P b 0.01) as compared to those without IS. After adjustment for age, gender, and traditional cardiac risk factors, there remained a near 4-fold increase odds for coronary plaque (adjusted OR 3.7, P = 0.04). When stratified by extent of plaque, patients with IS had over 18-fold increase odds of having N 4 segments of plaque than 0–4 segments as compared to patients without stroke (OR 18.3, P b 0.01), which remained significantly associated in adjusted analysis (adjusted OR 12.1, P b 0.001). Conclusion: Acute IS is independently associated with higher risk and greater extent of CAD compared to patients with acute chest pain at low-to-intermediate risk for acute coronary syndrome. © 2011 Elsevier Ireland Ltd. All rights reserved.
Stroke and myocardial infarction are leading causes of morbidity and mortality in industrialized countries [1]. The mechanism that links cerebrovascular and cardiovascular diseases has been suggested by studies in stroke patients with provocative functional tests (i.e., exercise testing or myocardial perfusion imaging). The American Heart Association/American Stroke Association practice guidelines suggest that stroke patients with significant carotid disease and risk assessment based on Framingham Risk Score to be considered for non-invasive testing for coronary artery disease (CAD) [2]. However, data about the prevalence of CAD in the patients with acute ischemic stroke (IS) remain limited [3–6]. This is relevant, as (outside of those with stroke due to carotid artery disease) patients with acute IS represent an under-represented population in current consensus guidelines for lipid management [7]. Determining IS as a “CAD equivalent”, similar to what has been shown in patients with diabetes mellitus, may have tremendous significance in patient management.
⁎ Corresponding author at: Department of Cardiology, Odense University Hospital, DK-5000 Odense C, Denmark. Tel.: + 45 6017 7420; fax: + 45 6312 0854. E-mail address: [email protected] (J.K. Jensen). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.04.006
Cardiac computed tomography angiography (CTA) is a wellvalidated state-of-the-art non-invasive imaging modality for accurate assessment of CAD [8–10]. Because CTA is performed non-invasively, this technique represents an attractive tool to determine if patients with acute IS have co-existing CAD. Thus, we aimed to determine the relation of acute IS to the presence and extent of CAD. 1. Methods A total of 392 patients without known CAD were included in the analysis and derived by combining 2 cohorts (24 patients with acute IS and 368 patients with acute chest pain). Patients with acute IS were enrolled from May 2008 to December 2008 at the Department of Neurology, Vejle Hospital, Denmark between weekday hours of 7 AM and 3 PM. Intra-cerebral or subarachnoid haemorrhage was ruled out by computed tomography at the time of admission. Patients with history of myocardial infarction, stable or unstable angina pectoris, history of coronary angioplasty or coronary bypass surgery were excluded (n = 21); those with onset of stroke symptoms N 7 days before admission (n = 11) and those with lack of compliance, unwillingness to participate and renal insufficiency (Creatinine N 1.9 mg/dL) (n = 71) were also excluded. None of the patients were treated with thrombolysis due to late presence of symptoms. For comparison, we examined results of CTA from patients with acute chest pain, enrolled from the Rule Out Myocardial Infarction Using Computer Assisted Tomography (ROMICAT) trial [11]. Briefly, these patients presented to the emergency department with acute chest pain and had low-to-intermediate likelihood for acute
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J.K. Jensen et al. / International Journal of Cardiology 160 (2012) 171–174
coronary syndrome with normal initial biomarkers and negative or inconclusive electrocardiogram. The study was approved by both the local ethics committees.
Table 1 Baseline characteristics of all patients.
1.1. Cardiac CT imaging protocol
Characteristics
Patients without stroke Patients with stroke P value (n = 368) (n = 24)
CTA imaging of the patients was performed using standard retrospectively-gated coronary artery imaging protocol with a 64-slice dual-source CT scanner (Somatom definition, Siemens Medical Solutions; Forcheim, Germany) for the acute IS patients and a 64-slice MDCT scanner (Siemens Sensation 64; Forchheim, Germany) for the acute chest pain patients. In preparation for the scan, patients with IS were not treated with betablockers or nitroglycerin for safety reasons. CTA examinations were performed during the first 5 days of admission for the acute IS patients and prior to hospital admission for the acute chest pain patients. The parameters for the dual-source CT scanner were as follows: spiral mode with 330 ms rotation time, 64× 0.6 mm collimation, tube voltage 120 kVp for both tubes, current 560 mA with tube modulation and full current between 25% and 80% of the RR interval, and pitch 0.20–0.44 according to the heart rate. The parameters for the MDCT scanner are as follows: spiral mode with 330 ms rotation time, 32 × 0.6 mm collimation, tube voltage of 120 kVp, and maximum effective tube current-time product of 850 mA s, adjusted to the subjects body habitus, tube modulation was employed when possible, and pitch dependent on heart rate. A test bolus scan followed by contrast agent (Iomeron 350 mg/cm3 or Iodixanol 320 mg/cm3) injection rate of 5 mL/s for total contrast volume dependent on scan range. Transaxial images were reconstructed using a singlesegment algorithm with 0.75 mm slice thickness, 0.4–0.5 mm increment, and a medium sharp kernel (B26) with at least one diastolic and one systolic phase dataset. All reconstructions were transferred to an offline workstation for analysis. The interpreters were blinded to patient clinical data.
Age (yrs)⁎ (mean ± SD) Male gender, n (%)
53 ± 12 226 (61)
70 ± 11 13 (54)
b0.001 0.521
Past medical history Diabetes, n (%) High lipids, n (%) Hypertension, n (%) Smoking, n (%)
40 (11) 135 (37) 145 (39) 93 (25)
3 (13) 12 (50) 14 (58) 11 (46)
0.737 0.199 0.086 0.033
Vital signs, admission Heart rate⁎, bpm 77 ± 16 Body mass index⁎, kg/m2 29 ± 6 ¶SSS score⁎ – LACI, n (%) – PACI/TACI, n (%) – POCI, n (%) –
78 ± 14 26 ± 6 44 ± 10 9 (38) 13 (54) 2 (8)
0.760 0.023 – – – –
Laboratory Creatinine⁎ (mg/dL)
0.95 ± 0.18
0.93 ± 0.34
0.680
56 (15)
7 (29)
0.084
103 (28) 84 (23) 117 (32)
10 (42) 5 (21) 10 (42)
0.166 1.000 0.396
1.2. Coronary artery plaque assessment Coronary artery calcium (CAC) scores were measured according to the method described by Agatston et al. [12]. All CTA evaluations were made on a separate workstation (Leonardo, Siemens Medical Solutions) independently by two experienced observers blinded to patient history. The presence and extent of calcified, mixed, and non-calcified coronary plaque were determined for each subject and evaluated according to the modified American Heart Association classification with 17-coronary segments [13]. Details on plaque detection and characterization have been previously described and validated [14]. The presence of coronary artery stenosis was defined as a luminal obstruction N50% diameter in any coronary segment. 1.3. Covariates and risk factor assessment Patient demographics, clinical characteristics and medical history were obtained from the patients, his/her relatives, and/or from hospital records. The presence of cardiovascular risk factors was established from actual measurements obtained during index hospitalization. Diabetes was defined as a fasting plasma glucose N 126 mg/dL or treatment with a hypoglycaemic agent. Hyperlipidemia was defined as total cholesterol of N 200 mg/dL or treatment with a lipid lowering medication. Measurement of lipids was performed the next morning after the stroke event. Hypertension was defined as systolic blood pressure N 140 mm Hg or diastolic blood pressure N 90 mm Hg or current antihypertensive treatment. Hypertension in the stroke population was defined as current antihypertensive treatment. Subjects were classified as smokers if they had smoked at least one cigarette per day for at least the past 6 months. Body mass index (BMI) was defined as weight (in kilograms) divided by the height squared (in meters). Severity of the index stroke was assessed using the Scandinavian Stroke Scale (SSS) [15]. Stroke subtypes were classified according to the Oxfordshire Community Stroke Project [16]. 1.4. Statistical analysis Continuous variables were reported as mean ± SD or median with interquartile range [IQR], when appropriate. CAD categories were stratified into no CAD, nonobstructive CAD, and stenosis. The extent of coronary plaque was dichotomized into 0– 4 versus N4 coronary segments. To compare differences between groups, we used Fisher's exact test, Wilcoxon rank sum test and Student's t-test as appropriate. We used logistic regression analysis to determine the associations of stroke to the presence of any plaque, extent of plaque (0–4 versus N 4 coronary segments), and type of plaque (calcified, mixed and non-calcified). Multivariable analyses included stroke and were adjusted for potential confounders based on a priori knowledge, which included age N 75 years, gender, and traditional cardiovascular risk factors of BMI, hypertension, hyperlipidemia, diabetes and smoking. A two-tailed P value b0.05 was considered to be statistically significant. All analyses were performed using STATA/SE 10.0 (StataCorp LP, College Station, TX).
2. Results Table 1 summarizes the patient demographics of the two cohorts. Patients with stroke were older than those without stroke, and the BMI was lower than those without stroke. Of the combined cohorts, 205 patients (52%) had presence of coronary artery plaque. Of 17
Medication Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, n (%) Lipid lowering drugs, n (%) Beta-blockers, n (%) Aspirin, n (%)
¶ Scandinavian Stroke Scale. LACI, Lacunaria infarction. TACI, Total anterior circulation infarction. PACI, Partial anterior circulation infarction. POCI, Posterior circulation infarction. ⁎ means (mean +/- SD).
segments, there was a median of 1 [IQR 0 to 5] coronary segments with plaque per subject. 2.1. Stroke and presence of coronary artery disease The presence of coronary plaque was more frequently seen in patients with stroke than those without (83.3% versus 50.3%, P b 0.001) (There was no difference in the frequency of obstructive CAD between the two groups. Table 2 summarizes the CTA findings. As compared to patients without stroke, patients with IS had a near 5-fold increase odds of having any coronary plaque (odds ratio [OR] 4.9, P b 0.001). After adjustment for age N 75 years, gender, and traditional cardiovascular risk factors, this increase remained (OR 3.7, P = 0.04) (Table 3). 2.2. Stroke and extent of coronary plaque Patients with stroke had a greater extent of coronary plaque than subjects without stroke (7 [IQR 5 to 8] versus 1 [0 to 4] segments with any plaque, P b 0.001). When stratified by extent of plaque, patients with stroke had over 18-fold increase odds of having N4 segments of plaque than 0–4 segments as compared to patients without stroke (OR 18.3, P b 0.01), which remained significantly associated in adjusted analysis (adjusted OR 20.0, P b 0.001) (Table 3). 2.3. Stroke and coronary plaque composition Calcified plaque was present in 185 patients (47%) whereas 147 (38%) had non-calcified plaque, and 130 (33%) had mixed plaque. The median number of segments of plaque per patient was 0 [IQR 0 to 3] for calcified plaque, 0 [IQR 0 to 1] for mixed plaque, and 0 [IQR 0 to 1] for non-calcified plaque. Patients with stroke were more likely to demonstrate mixed (79% versus 30%, P b 0.01) and calcified plaque (71% versus 46%, P = 0.02) whereas there was no difference between
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Table 2 Comparison of CTA findings between patients admitted without and with stroke. CTA findings
All patients n = 392
Patients without stroke n = 368
Patients with stroke n = 24
No CAD Non-obstructive CAD Stenosis (N 50% luminal narrowing) Non-obstructive plaque or no CAD Agatston scorea
187 131 74 318 –
183 117 68 300 –
4 (17%) 14 (58%) 6 (25%) 18 (75%) 255 (68–736)
By plaque morphologya Segments with any plaque Segments with any calcified plaque Segments with any non-calcified plaque Segments with any mixed plaque
(48%) (33%) (19%) (81%)
1 (0–5) 0 (0–3) 0 (0–1) 0 (0–1)
(50%) (32%) (18%) (82%)
1 (0–4) 0 (0–3) 0 (0–1) 0 (0–1)
7 (5–8) 3 (0–4) 0 (0–1) 3 (2–5)
P value 0.001 0.012 0.423 0.423 –
b0.001 0.068 0.684 b0.001
CAD, Coronary Artery Disease. a Median (IQR).
the two groups when stratified by non-calcified plaque (38% versus 38%, P = 1.00). In unadjusted analysis, patients with IS had 3-fold increase odds of having any calcified plaque (OR 2.9, P = 0.02) and a 9-fold increase of having any mixed plaque (OR 8.8, P b 0.01) when compared to those with acute chest pain. After adjustment for age, gender, and traditional risk factors, these increased risks of plaques remained significant for mixed plaque (OR 7.4, P b 0.01), but were attenuated for calcified plaque (OR 1.6, P = 0.37). There was no difference in OR for noncalcified plaque between patients with and without stroke. 3. Discussion In this study, we found a high prevalence of coronary artery plaque burden by CTA in patients with acute IS despite lack of symptoms or history of ischemic heart disease. Patients with acute IS had a 4-fold increased risk of having any coronary plaque as compared to a population of patients with acute chest pain at low-to-intermediate risk for acute coronary syndrome. This association was independent of age, gender, and traditional cardiovascular risk factors. When stratifying into the different subtypes of plaque, there was a significant association between ischemic stroke and the presence of mixed coronary plaque. The association of IS with coronary artery plaque is presumably due to shared risk factors [17]. Because of its overlap with risk factors of cardiovascular disease, IS has been suspected to be associated with CAD, and risk of cardiovascular events. This hypothesis is supported by previous studies demonstrating an association of IS with coronary calcification [18], which represents a part of the spectrum of CAD [19,20]. These studies have demonstrated a high prevalence of CAD (47.1%) in IS as well as significant CAD (18%) [3–6]. However, these studies did not provide information whether stroke per se is associated with CAD. The composition of plaque subtype has recently be evaluated by Yoon et al [5]. The prevalence of plaque subtype in this study was Table 3 Uni and multivariable analysis for the presence of any plaque in all patients. Odds ratio
Age N 75 years Gender (male) Diabetes High lipids Hypertension Smoking BMI Creatinine Stroke
Any plaque Uni-variable OR (95% CI)
P value
Multi-variable OR (95% CI)
P value
14.6 1.7 2.0 3.6 3.2 1.0 1.0 3.0 4.9
b 0.01 0.01 0.04 b 0.01 b 0.01 0.89 0.60 0.04 b 0.01
12.1 (2.3–56.8) 2.2 (1.3–3.9) 0.9 (0.4–2.4) 3.0 (1.9–5.0) 2.6 (1.6–4.3) 1.3 (0.8–2.1) 1.0 (1.0–1.0) 1.5 (0.3–6.4) 3.7 (1.1–12.8)
b 0.01 b 0.01 0.85 b 0.01 b 0.01 0.36 0.94 0.60 0.04
(3.4–62.3) (1.1–2.5) (1.0–4.0) (2.3–5.6) (2.1–5.0) (0.7–1.6) (1.0–1.0) (1.1–8.5) (1.7–14.8)
very different compared to our results perhaps due to different scanners (single vs. dual source), patients (cardio-embolic vs. no overt ischemic heart disease) and the fact that plaque subtypes only were evaluated in significant lesions (≥50% stenosis). Furthermore, despite the fact that IS significantly adds over traditional risk factors when predicting cardiovascular events [21], current consensus guidelines do not list IS as a “CAD equivalent”. Our data extend the findings of previous studies by demonstrating that patients with IS had an increased risk of having any plaque and mixed plaques as compared to a cohort of patients with acute chest pain and thus further support the argument that IS may be considered as a CAD equivalent similar to peripheral artery disease or diabetes mellitus [22]. Recently, several papers have suggested that mixed plaques by CTA are associated with outcomes. Interestingly in our study, mixed plaques were independently associated with IS and may be associated with outcome. Thus, both the assessment of stenosis and the presence and composition of non-obstructive plaque may be important for risk stratification of patients with IS and no known CAD [23–26]. Prolonged follow-up of patients surviving cerebrovascular disease indicates that coronary artery disease is the main course of long-term mortality [27]. Thus, primary or secondary prevention of CAD may be equally or more important than prevention of recurrent stroke in these patients. The American Heart Association/American Stroke Association statement recommends risk assessment notably on Framingham Risk Score to identify stroke patients for non-invasive testing of CAD [2]. Thus, only a part of patients with IS are routinely screened for CAD. In addition, the sensitivity and specificity for classic non-invasive tests in detecting CAD are low [28,29].The newest CT technology permits the assessment of CAD with a low radiation scan (b5 mSv) in most patients. Several limitations of this study should be noted. First, the study is a cross-sectional analysis with a small subgroup of patients with IS and does not allow assessment of causality or whether assessment of CAD indeed will improve prognosis of patients with IS. In addition, due to the small number of patients with acute IS the results need to be confirmed in larger patient cohorts. While two different CT scanners were used, both 64-slice MDCT and dual-source CT have comparable spatial resolution. The lack of using beta-blockers in the stroke population may have influenced the image quality, but CT interpretations were performed at a single core laboratory by highly experienced readers. In conclusion, acute IS is independently associated with higher risk and greater extent of subclinical CAD compared to symptomatic patients with acute chest pain at low-to-intermediate risk for ACS. Larger prospective studies are needed to establish ischemic stroke as a CAD equivalent and to establish whether these patients may benefit from medical therapy for CAD; nonetheless in the absence of clear contraindication, logic would dictate a benefit would be expected from aggressive secondary prevention measures.
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