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�:	Prevalence of subclinical coronary artery disease in ischemic stroke patients
Kohichiro Iwasaki, MD; Kayo Haraoka, MD; Toshikazu Hamguchi�, MD; Takashi Imamura�, MD; Sanami Kawada�, MD; Manabu Oono�, MD; Kenichi Kashihara�, MD, PhD 
Department of Cardiology, Okayama Kyokuto Hospital 
�Department of Neurology, Okayama Kyokuto Hospital

Running head; coronary artery disease in stroke patients
Address for correspondence
Kohichiro Iwasaki, MD
Department of Cardiology, Okayama Kyokuto Hospital
567-1, Kurata, Naka-ku. Okayama, Japan
TEL +81-86-276-3231,  FAX +81-86-274-1028
E-mail   HYPERLINK "mailto:kiwasaki@kyokuto.or.jp" kiwasaki@kyokuto.or.jp




Abstract 
Background; 
Recently ischemic stroke patients have emerged as a new coronary artery disease (CAD) risk equivalents. Our purpose is to study the prevalence of CAD in ischemic stroke patients compared with non-stroke patients. 
Methods; 
We measured coronary calcium score (CCS) in 151 ischemic stroke patients without known CAD (stroke group) and compared it with 151 age- and sex-matched non-stroke patients (control group). 
Results;
CCS was significantly higher in stroke group than that in control group (median 64, interquartile range 3 to 382 in stroke group vs. 3, 0 to 65 in control group, p<0.0001). No coronary calcium was detected in 23.2% of stroke group compared with 47.7% of control group. High-risk CAD defined as CCSe"400 was detected in 24.5% of stroke group compared with 9.3% of control group (p<0.0001). Agreement between Framingham risk score and CCS was found in only 62 patients (41.1%). In multiple logistic regression analysis, age (HR 1.09, 95%CI 1.03-1.14), diabetes (HR 2.97, 95%CI 1.52-5.78), stroke (HR 3.85, 95%CI 1.89-7.81) and male (HR 4.41, 95%CI 1.82-10.75) were significantly associated with high-risk CAD (p<0.001).
Conclusions; 
Our results showed that the prevalence of subclinical CAD in ischemic stroke patients was very high and a quarter of them had high-risk CAD. The age, diabetes, stroke, and male were independent predictors of high-risk CAD. Our results also suggested that stroke patients deserved to be a CAD risk equivalents. 



Key words; 
ischemic stroke
coronary calcium score
coronary artery disease
cardiac computed tomography




Coronary artery disease (CAD) is a leading cause of mortality and morbidity in the developing and developed countries [1]. Current guideline statements for primary and secondary prevention of cardiovascular disease, such as the American Heart Association guidelines and the National Cholesterol Education Program Adult Treatment Panelb! guideline, defines coronary heart disease (CHD) risk equivalents as patients at the same elevated risk as those with ischemic heart disease [1-3]. CHD risk equivalents include patients with diabetes mellitus, peripheral artery disease, carotid artery disease, and abdominal aortic aneurysm.
 Recently ischemic stroke patients without carotid artery disease have emerged as a new CHD risk equivalents. Dhamoon et al, in a review of evidence from hospital- and population-based studies, proposed the designation of stroke as a CHD risk equivalent and the inclusion of stoke in the outcome cluster for purposes of absolute estimation of risk in primary and secondary prevention [4]. More recently an American Heart Association/ American Stroke Association Scientific Statement is reported [5]. It concludes that patients with atherosclerotic stroke should be included among those deemed to be at high risk (e"20% over 10 years) of further atherosclerotic coronary events. 
 There are several studies which investigated the prevalence of significant CAD in ischemic stroke or transient ischemic attack patients [6-8]. However few studies measured coronary calcium score (CCS), which is the powerful predictor of cardiac events, in stroke patients [9,10]. One study measured CCS and carotid intima-media thickness in community-dwelling men and women with a mean age of 80 years and found that CCS and carotid intima-media had a similar ability to predict total cardiovascular events, myocardial infarction, and stroke [11]. Also no study compared the prevalence of CAD in stroke patients with non-stroke patients. Therefore we measured CCS in ischemic stroke patients without known CAD and compared with age- and sex-matched non-stroke patients.
Methods
Patients
 From September 2011 through September 2012, 184 patients with acute ischemic stroke admitted to our hospital. The diagnosis of ischemic stroke was done according to the National Institute of Neurological Disorders and Stroke criteria [12]. We measured CCS in ischemic stroke patients. The following patients were excluded; 1) patients who died, 2) patients with disabling stroke (modified Rankin scale score g"3), 3) patients aged more than 80 years old, 4) patients with cardioembolic stroke, 5) patients with symptomatic carotid artery disease, defined as stenosis e"50% by Duplex ultrasonography, 5) patients with known CAD, 6) patients with atrial fibrillation, 7) patients who denied CCS measurement. Thus 151 patients underwent CCS measurement (stroke group). Sixty-four patients had lacunar infarcts, 81 patients had atherothrombotic infarcts, and 6 patients had infarcts of unknown type.
In the same period 407 non-stroke patients with coronary risk factors but without known CAD underwent CCS measurement. From these patients we randomly selected 151 patients matched for age and sex to the above 151 ischemic stroke patients (control group). 
Framingham risk score (FRS)
We calculated Framingham risk score (FRS) in each patient in stroke group [13]. The 10-year risk of myocardial infarction and cardiac death was calculated by this score. Risk is defined as follows; low, less than 10%; intermediate, between 10% and 20%, or high, greater than 20%.
64-multidetector computed tomography (MDCT) 
All patients were scanned with a 64-MDCT (SOMATOM Sensation 64 Cardiac, Siemens Medical Solutions, Erlangen, Germany). A native scan without contrast dye was performed to determine the total calcium burden of the coronary tree (sequential scan with 32 x 0.6-mm collimation, tube current 60 mAs at 120 kV). A total of 64 overlapping 3.0-mm slices per rotation were acquired with the use of a focal spot periodically moving in the longitudinal direction (z-flying focal spot). Tube current was modulated according to the ECG, with a maximum current of 200 mAs during a time period of approximately 330 ms centered at 375 ms before the next R-wave, and reduced by 80% during the remaining cardiac cycle (care dose system). 
64-MDCT image interpretation
 CT data sets were transferred to an offline workstation (Aquarius NetStation, Terarecon Inc, San Maeteo, CA, USA) for image analysis. We measured CCS in the right coronary artery, left main trunk, left anterior descending coronary artery, and left circumflex coronary artery, then calculated total CCS with dedicated software. The results were expressed as Agatston score [14]. We used usual definition of risk classification of CCS. Low risk group was defined as CCS from 0 to 99. Intermediate risk group was defined as CCS from 100 to 399. And high risk group was defined as CCS equal or more than 400. 
We studied the difference of CCS between the two groups and the relationship between the FRS and CCS in the stroke group. We also performed univariate and multivariate analysis to find factors associated with high risk CCS (CCSe"400). 
 Informed consent for clinical procedures and research protocol was received from all patients studied. The study was approved by an institutional review board.
Statistical analysis
 Data are expressed as mean�SD. 
 Continuous variables in the laboratory data were compared by two group t-test. Because the data for CCS did not show a normal distribution, the Mann-Whitney test was used to determine the differences between the two groups. Discrete variables were expressed as counts or percentage and compared with chi-square or the Fisher's exact test. The relationship between high risk CCS and patient characteristics was assessed by univariate and multivariate analysis.  We performed multiple logistic regression analysis including the variables with a value of p<0.05 in the univariate analysis. A p value <0.05 was considered to be statistically significant.
Results
Clinical characteristics of studied patients are shown in Table 1. By selection criteria, age and the prevalence of male were the same between the two groups. The prevalence of hypertension was significantly higher in the stroke group. But the prevalence of hyperlipidemia, diabetes, smoking, and obesity was not significantly different between the two groups. Also the laboratory data were not significantly different between the two groups. For medication, usage of angiotensin converting enzyme inhibitor and angiotensin receptor blocker was more prevalent in the stroke group. Other medication use was not significantly different between the two groups.
 Figure 1 shows CCS of the two groups. The CCS was significantly higher in the stroke group than that in the control group (median 64, interquartile range 3 to 382 in stroke group vs. median 3, interquartile range 0 to 65 in control group, p<0.0001). 
 Table 2 shows the distribution of CCS in the two groups. Significantly more patients in the stroke group had higher CCS (p<0.0001). No coronary calcium was detected in 23.2% of the stroke group compared with 47.7% of the control group. High-risk CAD defined as CCSe"400 was detected in 24.5% of the stroke group compared with 9.3% of the control group.
Table 3 shows the relationship between FRS and CCS in stroke group. Among 151 patients in stroke group, 39, 71, and 41 patients were classified as low, intermediate, and high risk, respectively, by FRS. However risk classification by CCS showed different results. The CCS identified low risk in 82.1% of patients with Framingham low risk score. However it identified intermediate and high risk in only 19.7% and 39.0% of patients with Framingham intermediate and high risk score, respectively. Thus agreement between FRS and CCS was found in only 62 patients (41.1%).
 Table 4 shows the results of univariate analysis associated with high risk CCS. The age, prevalence of male, hypertension, diabetes, and stroke was significantly higher in patients with CCSe"400 compared with those with CCS<400. The laboratory data were not significantly different between the two groups. In multiple logistic regression analysis adjusted for variables associated with high risk CCS (CCS e"400), age, diabetes, stroke, and male were significantly associated with high risk CCS (Table 5).
Discussion 
 Our results showed that the prevalence and severity of CAD was higher in stroke patients without known CAD compared with age- and sex-matched non-stroke patients. Almost 80% of stroke patients had CAD detected by CCS compared with 50% of non-stroke patients. About a quarter of stroke patients had high-risk CAD (CCS e"400) compared with less than 10% of non-stroke patients. Thus the prevalence of high-risk CAD was more than two-fold in stroke patients compared with non-stroke patients. To our knowledge this is the first study that measured CCS in stroke patients without known CAD and compared it with non-stroke patients. 
 There are some studies which investigated the prevalence of CAD in stroke patients.  Yoo et al performed coronary computed tomography angiography (CCTA) in 1,304 stroke patients [6]. They found that frequency of significant (e"50%) CAD and any degree of CAD was 32.3% and 70.1%, respectively. Hoshino et al studied 104 patients with cerebral infarction [7]. CCTA showed the prevalence of significant CAD of 37.5%. Calvet et al performed CCTA in 274 patients with non-disabling, non-cardioembolic ischemic stroke or transient ischemic attack and no known CAD [8]. They found significant CAD in 18% of patients. Thus previous studies demonstrate that 20% to 40% of stroke patients have asymptomatic significant CAD. 
 However many studies demonstrate that most myocardial infarction and sudden cardiac death do not occur at the sites of significant coronary narrowing and coronary revascularization therapy of coronary obstruction in patients with stable CAD do not reduce the risk of myocardial infarction or cardiac death [15-18]. These observations are explained by the concept of vulnerable plaque and 70% to 80% of acute coronary events result from coronary lesions that are not hemodynamically significant or flow-limiting before the event [19].
 Therefore we measured CCS in stroke patients. Coronary artery calcification signifies the presence of coronary atherosclerosis and a strong linear correlation exists between total coronary artery atherosclerotic plaque burden and the extent of coronary artery calcification [20-22]. The coronary artery calcification has been found to be the most powerful predictor of cardiac events, providing independent and incremental information over risk factor-based assessment of the asymptomatic patients [9,10]. Patients without detectable calcium have a very low rate of coronary death or myocardial infarction over 3 to 5 years of observation [10,23]. Thus the measurement of CCS rather than detection of significant CAD would be more rational choice for the risk stratification of asymptomatic CAD in stroke patients. Our results showed that a quarter of stroke patients had high-risk CAD (CCS e"400), which was more than two-fold higher prevalence than non-stroke patients. Also multivariate analysis showed that the age, diabetes, stroke, and male gender were independently associated with high-risk CAD. 
 Our study also showed that coronary risk score had limited ability for risk stratification. The CCS identified low risk patients in most low Framingham risk score patients. However it identified intermediate and high risk patients in only 20% and 40% of Framingham intermediate and high risk score patients, respectively. Agreement was achieved in only 41.1% of them. 
Recent research has revealed the limitation of coronary risk scores. Karim et al [24] measured subclinical atherosclerosis in 498 healthy subjects and 69% of them had evidence of subclinical atherosclerosis in more than one of the three vascular beds. Of the 68 subjects with subclinical atherosclerosis in all three vascular beds, only 23% had the high risk FRS. Ahmadi et al investigated mortality risk associated with CCS and FRS in 730 subjects classified as low risk versus high risk based on FRS [25]. Mortality rate was 18.5% in discordant low risk group (FRS <10% and CCS >100) compared with 7.7% in discordant high risk group (FRS >20% and CCS=0). Therefore, a growing body of evidence supports the fact that global risk scores may be useful guides in predicting long term cardiovascular disease risk in healthy populations but often are suboptimal for individual risk estimation [26].
There are several limitations in our study. First, the number of study patients is relatively small. To compensate this limitation we selected age- and sex-matched non-stroke patients in the same period and compared these patients with stroke patients. Second, we excluded patients who died, patients with disabling stroke, and patients aged more than 80 years old. Thus it is likely that due to these exclusions, CCS was underestimated in stroke patients. Third, our study does not include patients with cardioembolic stroke. Cardioembolic stroke may be expected to have a higher likelihood of CAD, probably related to the underlying presence of cardiac disease. One study found the prevalence of significant CAD in 21% of patients with suspected embolic stroke by CCTA, which is similar to those with non-cardioembolic stroke [27]. We excluded cardioembolic patients because the number of patients was small and many patients had disabling stroke. Fourth, we excluded patients with carotid artery disease because carotid artery disease is already designated as a CHD equivalent. Symptomatic carotid artery disease probably accounts for no more than 10% of patients with ischemic stroke [28]. 
 In conclusion, our study showed that the prevalence of asymptomatic CAD in ischemic stroke patients without known CAD was very high and a quarter of them had high-risk CAD defined as CCS e"400. The age, diabetes, stroke, and male were independent predictors of high-risk CAD. 



Disclosure 
None.






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