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Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease
Atherosclerosis 223 (2012) 473e477
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Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease Yoshihiro Araki a, Hisao Kumakura a, *, Hiroyoshi Kanai a, Shu Kasama a, Hiroyuki Sumino a, Akiko Ichikawa a, Toshio Ito a, Toshiya Iwasaki a, Yoshiaki Takayama a, Shuichi Ichikawa a, Kishu Fujita b, Kuniki Nakashima b, Kazutomo Minami b, Masahiko Kurabayashi c a
Department of Internal Medicine, Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital), Shimohakoda 740 Hokkitu-machi, Shibukawa, Gunma, Japan Department of Cardiovascular Surgery, Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital), Shibukawa, Gunma Prefecture 377-0061, Japan c Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 April 2012 Received in revised form 9 May 2012 Accepted 15 May 2012 Available online 4 June 2012
Objective: The purpose of the study was to examine the prevalence and risk factors for cerebral infarction (CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with normal controls. Method: A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT) and CAS were measured with ultrasound. Results: The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%, 41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes mellitus, low HDL cholesterol and CAS 70% (p < 0.05). LI was associated with age, PAD, diabetes mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS 70% and CAS 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively, p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 0.45 vs. 0.90 0.28, 2.67 2.00 vs. 1.73 1.05 mm, respectively, p < 0.001). CAS 70% correlated with high LDL cholesterol, and CAS 50% with age and PAD. IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (p < 0.05). Conclusions: Prevalences of CI and CAS were markedly higher in patients with PAD than in controls, indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and CAS is important for managements in PAD, as with screening for PAD in patients with stroke. Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cerebral infarction Carotid artery stenosis Intima-media thickening Peripheral arterial disease Stroke
1. Introduction Cerebral infarction (CI) and coronary heart disease (CHD) are closely associated with peripheral arterial disease (PAD), and are major causes of death in patients with PAD [1e4]. Patients with PAD also complicate with diabetes mellitus or hyperlipidemia and may have extensive and severe systemic atherosclerosis that is responsible for the mortality due to CI and CHD [1,3]. In patients
* Corresponding author. Tel.: þ81 27 232 7111; fax: þ81 27 233 9092. E-mail address: [email protected] (H. Kumakura). 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.05.019
with stroke or transient ischemic attack (TIA), symptomatic or asymptomatic PAD is independently associated with recurrent vascular events and stroke [5,6], and atherosclerotic carotid artery stenosis (CAS) is an important cause of ischemic stroke [7]. We have reported that stroke is an independent risk factor for progress of Fontaine stages in PAD [8]. Asymptomatic CI is also a precursor of symptomatic stroke or insidious brain damage [9], which indicates the importance of screening for the presence of CI or CAS in patients with PAD. Furthermore, CI or CAS is considerable for treatment and rehabilitation of patients with PAD [1,2]. However, the prevalence and risk factors for CI and CAS are not fully understood in patients with PAD, and the prevalences of these diseases compared with age-matched normal controls are unclear.
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Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
The purpose of the present study was to examine these issues in a population of patients with PAD and in healthy controls. 2. Patients and methods 2.1. Patients and control subjects The study included patients with PAD and healthy controls who were referred to the Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital) between January 1st, 2005 and December 31st, 2010. The subjects with PAD were 543 consecutive patients with ABI < 0.90 at their first visit. The final diagnosis of PAD was based on clinical symptoms and iliac or femoropopliteal artery stenosis 70% on angiography or ultrasound. Clinical stages of PAD were classified using the criteria of the Inter-Society Consensus for the Management of Peripheral Arterial Disease [1]. ABI was determined in all subjects using ABI-form (Colin, Tokyo, Japan), which simultaneously measures bilateral arm and ankle blood pressure by an oscillometric method. In the patients with PAD, blood was collected during fasting in the morning for determination of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride, glucose, glycosylated hemoglobin A1c, and uric acid. Diabetes mellitus, hypertension, stroke, and CHD were studied as risk factors for arteriosclerosis. Diabetes was defined as a fasting plasma glucose level >126 mg/dL for at least two measurements or a requirement for antidiabetic therapy [10]. Hypertension was defined as blood pressure 140/90 mmHg recorded at least twice or intake of antihypertensive agents. The estimated glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease (MDRD) equation for creatinine, as modified by the Japanese Society of Nephrology: eGFR (mL/min/ 1.73 m2) ¼ 194 (Scr)1.094 (Age)0.287 (0.739 if female) [11]. An electrocardiogram was recorded and echocardiography was performed for each patient. CHD was considered to be present when the patient had a history of this disease or showed a positive sign in stress/ rest myocardial perfusion scintigraphy or coronary angiography. The 560 age-matched control subjects were recruited at the time of their annual medical check-up at our hospital. This check-up included a physical examination, measurement of ABI, chest X-ray, stress electrocardiogram, and echocardiography. Blood was collected during fasting in the morning for determination of total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, glucose, glycosylated hemoglobin A1c, and uric acid. Subjects with physician-diagnosed PAD based on ABI < 1.00, physical symptoms, or ABI 1.40 were excluded. Subjects were also excluded if they had physiciandiagnosed diabetes mellitus, hypertension, hyperlipidemia, CHD, or a history of stroke or TIA. Diabetes mellitus and hypertension were diagnosed as noted above. Lipid abnormalities were diagnosed based on intake of lipid-lowering agents or LDL cholesterol 140 mg/dL [12], HDL cholesterol < 40 mg/dL [1,12], or triglyceride 150 mg/dL [12,13]. Recruitment was tailored to yield approximately an age- and gender-matched control group, and 314 healthy subjects were finally recruited as controls. A brain computed tomography (CT) scan and carotid ultrasound were performed in subjects without risk factors for these procedures. Prior to the start of the study, the patients and control subjects received a full explanation of the examination methods, and gave written informed consent. The study protocol was approved by the Cardiovascular Hospital of Central Japan Medical Ethical Committee. 2.2. Assessment of CI and CAS A brain CT scan (Aquillion 64, Toshiba, Tokyo, Japan) was performed in 5- or 10-mm thick sections without use of
a contrast agent. The scans were evaluated by two radiologists who were blinded to the characteristics of the subjects. Infarcts > 1.5 cm in diameter on brain CT are considered to be CI of potential large-artery atherosclerotic origin. A low density lesion with a diameter of 1.5 cm on CT was categorized as a lacunar infarction (LI). The wall thickness of the bilateral carotid arteries was measured by ultrasound (Aplio SSA-770A; Toshiba, Tokyo, Japan) using a 7.5MHz linear type B-mode probe. The measurements were made after the subject had rested for at least 10 min in the supine position with the neck in slight hyperextension for optimal visualization of the common carotid arteries, carotid bulb, and extracranial internal and external carotid arteries on both sides. The imaging protocol involved obtaining 3 longitudinal views (anterior-oblique, lateral, and posterior-oblique) of the distal 10 mm of the right and left common carotid arteries and internal carotid arteries. The internal carotid artery was defined as including the carotid bulb and the extracranial segment of the internal carotid artery distal to the tip of the flow divider that separates the internal and external carotid arteries. The end-diastolic intima-media thickness (IMT) of the far wall of the common carotid artery was measured bilaterally from the 3 scan views 10 mm proximal to the bulb, and averaged to obtain the mean IMT. The max IMT was defined as the single thickest wall in the same way from the 3 scan views on the internal and common carotid arteries. The presence of a plaque was defined as a thickening of the IMT > 1.1 mm. CAS was evaluated using the North American Symptomatic Carotid Endarterectomy Trial Collaborators (NASCET) method [14]. All scans were evaluated by an ultrasonographic physician who was blinded to the clinical characteristics of the subjects.
2.3. Statistical analysis Data are expressed as mean values standard deviation. The two groups were compared using a t-test and proportions were compared by Chi-square analysis. Relationships between atherosclerotic lesions and risk factors were studied using multiple regression analysis and multiple logistic analysis. SPSS v.17.0 (SPSS Inc, Chicago, IL) was used for all calculations. A p-value <0.05 was considered to indicate a significant difference.
Table 1 Baseline clinical characteristics and risk factors in patients with peripheral arterial disease (PAD) and age-matched normal controls. Risk factor
PAD n ¼ 543
Controls n ¼ 314
p-value
Age (year) Gender (male) BMI (kg/m2) ABI Hypertension Diabetes mellitus Stroke or TIA Coronary heart disease Smoker Atrial fibrillation Total-C (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglyceride (mg/dL) Creatinine Uric acid (mg/dL) HbA1c (%)
71.3 9.4 80.8% 22.1 3.4 0.62 0.26 329 (61.2%) 186 (34.5%) 104 (19.3%) 189 (35.3%) 408 (75.7%) 53 (9.8%) 190 40.2 116 35.7 48.7 21.7 150 33.1 1.42 1.66 5.9 1.74 6.0 1.21
71.1 6.7 79.8% 22.5 4.1 1.12 0.21 0 (0%) 0 (0%) 0 (0%) 0 (0%) 246 (58.6%) 0 (0%) 166 26.1 96 21.0 58.3 15.5 103 18.9 0.76 0.20 5.3 1.47 5.3 0.20
0.796 0.823 0.111 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
BMI: body mass index, ABI: ankle brachial pressure index, TIA: transient ischemic attack, Total-C: total cholesterol, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, HbA1c: glycosylated hemoglobin A1c.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
3. Results 3.1. Patient characteristics The subjects were 543 patients with PAD and 314 age-matched healthy controls. The characteristics of the subjects, including complications and risk factors, are shown in Table 1. There were no significant differences in age, gender and body mass index. The prevalences of hypertension, diabetes mellitus, CHD, smoking, and atrial fibrillation were higher in the patients with PAD, and 19.3% of the patients had a history of stroke or TIA. Serum levels of total cholesterol, LDL cholesterol, triglycerides, creatinine, uric acid and glycosylated hemoglobin A1c were higher, and HDL cholesterol was lower, in patients with PAD compared with controls. 3.2. Prevalence of CI and CAS The prevalence of CI on CT was higher in patients with PAD than in controls (p ¼ 0.032, Fig. 1) and the complication rate of LI was also higher in the patients (p < 0.001). The total prevalence of CI or LI was higher in patients with PAD compared to controls (p < 0.001). The prevalences of CAS 70% (p ¼ 0.004) and 50% (p < 0.001) were also higher in patients with PAD. The mean and max IMT were 1.01 0.45 and 2.67 2.00 mm, respectively, in patients with PAD, and 0.90 0.28 and 1.73 1.05 mm, respectively, in controls, with each differing significantly between the groups (both p < 0.001). The prevalence of carotid plaque was also higher in patients with PAD (p ¼ 0.002, Fig. 1). The variability in ultrasonography was assessed by performing 5 measurements over a period of 1 month in 12 volunteers. The intra-observer coefficient of variation for the IMT measurements was 5.5 0.8%. 3.3. Risk factors for CI and CAS Multiple logistic analysis showed that CI was associated with diabetes mellitus, low HDL cholesterol and CAS 70%, and had a tendency to be associated with male gender, PAD, and high LDL cholesterol (Fig. 2a). LI was associated with PAD, age, eGFR, and diabetes mellitus (Fig. 2b). The odds ratio of LI was 2.8 times higher in patients with PAD. LI also showed a tendency to be associated with hypertension and high LDL cholesterol. No carotid ultrasound parameters showed a relationship with LI, and atrial fibrillation was not correlated with CI or LI. CAS 70% was correlated with high LDL cholesterol (Fig. 3a) and CAS 50% showed significant correlations with age and PAD (Fig. 3b). The odds ratio of CAS 50% was 3.2
a
475
Odds ratio (95%CI) p-value
Age (years)
1.031 (0.983-1.043)
0.406
Gender (male)
2.113(0.982-4.549)
0.056
PAD
2.125 (0.962-5.239)
0.079
Hypertension
1.924 0.787-4.703)
0.151
Diabetes mellitus
1.825 (1.019-3.270) 0.043*
Smoking
0.655 (0.334-1.286)
0.219
CHD
1.069 (0.591-1.932)
0.826
eGFR
1.010 (0.999-1.021)
0.088
High LDL-C
1.715 (0.972-3.027)
0.063
Low HDL-C
1.969 (1.147-3.381)
0.014 *
High TG
0.788 (0.450-1.381)
0.406
CAS 70%
3.324(1.025-10.781) 0.045 *
b
Odds ratio (95%CI) p-value
Age (years)
1.028 (1.006-1.051)
0.011 *
Gender (male)
0.998(0.567-1.755)
0.993
PAD
2.763 (1.373-5.561)
0.004 *
Hypertension
1.488 (0.994-2.229)
0.054
Diabetes mellitus
1.582 (1.029-2.439)
0.037 *
Smoking
1.428 (0.842-2.421)
0.186
CHD
1.016 (0.664-1.555)
0.742
eGFR
0.990 (0.981-0.998)
0.015 *
High LDL-C
1.433 (0.967-2.125)
0.075
Low HDL-C
1.050 (0.699-1.577)
0.815
High TG
1.301 (0.876-1.933)
0.192
CAS 70%
0.806(0.295-2.206)
0.675
0.5
1
2
4
10
0.5
1
2
4
10
Fig. 2. Relationships of (a) cerebral infarction and (b) lacunar infarction with risk factors in multiple logistic analysis. *p < 0.05, PAD: peripheral arterial disease, CHD: coronary heart disease, eGFR: estimated glomerular filtration rate, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglyceride, CAS: carotid artery stenosis.
times higher in patients with PAD. Stepwise forward multiple regression analysis indicated that IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (Table 2, p ¼ 0.046). 4. Discussion 4.1. Prevalence for CI and LI
Fig. 1. Prevalence of cerebral infarction (CI), lacunar infarction (LI), CI or LI, carotid artery stenosis (CAS) 70%, CAS 50%, and carotid artery plaque. *p < 0.05, **p < 0.01.
This is the first report of the prevalence and risk factors for CI or LI detected by CT in patients with PAD, compared with agematched controls. In this study, the history of stroke or TIA was 19.3%, but the prevalence of CI or LI by brain CT was 56.0% in patients with PAD, which was significantly higher than the rate of 23.2% in controls. Baseline data in the REduction of Atherothrombosis for Continued Health (REACH) registry indicate that 16.58% and 15.23% of PAD patients have a history of stroke and TIA, respectively, worldwide [15]. In the Japanese population, 20.66% of PAD patients have a history of stroke or TIA [16]. Our data suggest a high prevalence of asymptomatic CI or LI that remained hidden in the patients with PAD, whose mean age was 71 years old. Asymptomatic CI is a precursor of symptomatic stroke or insidious brain damage [9], which indicates the importance of screening for the presence of CI or LI in patients with PAD.
476
a
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
Odds ratio (95%CI) p-value
Age (years)
1.011 (0.958-1.065)
0.684
Gender (male)
1.841(0.331-9.229)
0.485
PAD
1.851 (0.146-23.543) 0.635
Hypertension
0.940 (0.346-2.369)
0.840
Diabetes mellitus
1.603 (0.600-4.278)
0.347
Smoking
3.038 (0.478-19.294) 0.239
CHD
0.482 (0.166-1.407)
0.184
eGFR
0.999 (0.978-1.20)
0.899
High LDL-C
2.729 (1.066-6.989)
0.036 *
Low HDL-C
1.640 (0.638-4.219)
0.305
High TG
1.137 (0.441-2.932)
0.790
b
Odds ratio (95%CI) p-value
Age (years)
1.036 (1.005-1.067)
0.024 *
Gender (male)
1.258(0.551-2.876)
0.586
PAD
3.213 (1.036-9.962)
0.043 *
Hypertension
0.786 (0.458-1.350)
0.383
Diabetes mellitus
1.157 (0.652-2.054)
0.619
Smoking
1.450 (0.656-3.203)
0.359
CHD
1.234 (0.715-2.133)
0.450
eGFR
0.995 (0.983-1.007)
0.431
High LDL-C
1.502 (0.888-2.541)
0.125
Low HDL-C
1.344 (0.781-2.311)
0.287
High TG
1.077 (0.627-1.849)
0.788
0.5
0.5
1
1
2
2
4
4
10
10
4.3. Correlation between PAD and CI Despite the high risks of stroke in patients with PAD [21] and of PAD in patients with stroke [5], consideration of PAD is omitted from guidelines for treatment, rehabilitation, and prevention of stroke [2,17,22]. We have reported that stroke is an independent risk factor for progress of Fontaine stages in PAD, along with age, diabetes, and female gender [8]. Decreased physical capability, sensory disturbance for wounds, and systemic atherosclerosis may be contributors to these findings [1,8]. Based on a large epidemiologic study [23], the 2011 ACCF/AHA guidelines modified the age for consideration of ABI diagnostic testing to 65 years old or 50 years old with a history of smoking or diabetes [24]. It was also suggested that antiplatelet therapy can be useful to reduce the risk of cardiovascular events in asymptomatic individuals with ABI 0.90 [24]. In patients with CI, symptomatic or asymptomatic PAD is independently associated with recurrent stroke or TIA [5,6]. Our results also suggest that screening for PAD in patients with stroke or TIA is as important as screening for CI or CAS in patients with PAD. 4.4. Prevalence for CAS
Fig. 3. Relationships of (a) carotid artery stenosis 70% and (b) carotid artery stenosis 50% with risk factors in multiple logistic analysis. *p < 0.05, PAD: peripheral arterial disease, CHD: coronary heart disease, eGFR: estimated glomerular filtration rate, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglyceride.
Atherosclerotic CAS is an important cause of ischemic stroke [7]. Our study showed that 17.6% of patients with PAD had CAS 50% and 5.2% had CAS 70%. Mostaza et al. found a 14.3% prevalence of CAS 50% in patients with PAD (mean age: 66.7 years old), compared to 4.7% in a control group with normal ABI and matched for age, gender and diabetes [25]. Our results showed a prevalence of CAS 50% that was slightly higher than those in previous studies, which may be due to the higher mean age of our patients. Among the controls in the current study, 3.8% had CAS 50% and 0.6% had CAS 70%. In population-based studies the rates of CAS have varied from 2% to 11% [26,27]. The slightly lower rate of CAS in our controls may have arisen because we excluded subjects with diabetes mellitus. Thus, the results of our study are in accordance with previous studies.
4.2. Risk factors for CI and LI
4.5. Risk factors for CAS
In our study, CI was associated with diabetes mellitus, low HDL cholesterol and CAS 70%, and showed a tendency to be associated with male gender, PAD, and high LDL cholesterol. Diabetes mellitus, low HDL cholesterol, and high LDL cholesterol are important risk factors for development of large-artery atherosclerotic stroke [17]. In contrast, LI results from occlusion of a single perforating artery [18], and in this study LI was associated with age, PAD, and low eGFR. No carotid ultrasound parameters showed a relationship with LI. The odds ratio of LI was 2.8 times higher in patients with PAD compared with controls after adjustment for other risk factors. Age and eGFR are important risk factors for systemic atherosclerosis [19,20], and our study also showed that asymptomatic microvascular cerebral disease progressed silently in patients with PAD.
The presence of intermittent claudication or asymptomatic PAD has been reported to be significantly associated with increased IMT [28]. In our subjects, multiple regression analysis showed that IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension. Analysis of the relationship between CAS 70% and potential risk factors revealed a correlation with high LDL cholesterol. The odds ratio of CAS 50% was 3.2 times higher in patients with PAD. Carotid and femoral IMT have been positively correlated with LDL cholesterol [29] and Rockman et al. found relationships of occult CAS with CHD, smoking, and hypertension in patients with these risk factors, without data for PAD [27]. Our study highlighted PAD and high LDL cholesterol as risk factors for CAS, with CI associated with CAS 70%, along with low HDL cholesterol and diabetes mellitus.
Table 2 Correlation between intima-media thickness (IMT) and other risk factors in stepwise forward multiple regressions analysis. Risk factor
b
95% C.I.
p-value
PAD High LDL-C Age Hypertension
0.124 0.117 0.106 0.101
0.026e0.244 0.029e0.194 0.001e0.010 0.002e0.180
0.015 0.008 0.014 0.046
R2 ¼ 0.057, F for change in R2 ¼ 3.991, p ¼ 0.046. PAD: peripheral arterial disease, LDL-C: low density lipoprotein cholesterol.
4.6. Study limitations The limitations of this study include the relatively small sample size and the performance of the study at a single facility. We did not exclude smokers from the controls because the prevalence of former or current smokers was too high to ignore. We also did not use population-based data. Therefore, further studies are needed to determine the exact prevalence and risk factors for CI, LI, and CAS in patients with PAD.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
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Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease Yoshihiro Araki a, Hisao Kumakura a, *, Hiroyoshi Kanai a, Shu Kasama a, Hiroyuki Sumino a, Akiko Ichikawa a, Toshio Ito a, Toshiya Iwasaki a, Yoshiaki Takayama a, Shuichi Ichikawa a, Kishu Fujita b, Kuniki Nakashima b, Kazutomo Minami b, Masahiko Kurabayashi c a
Department of Internal Medicine, Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital), Shimohakoda 740 Hokkitu-machi, Shibukawa, Gunma, Japan Department of Cardiovascular Surgery, Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital), Shibukawa, Gunma Prefecture 377-0061, Japan c Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 April 2012 Received in revised form 9 May 2012 Accepted 15 May 2012 Available online 4 June 2012
Objective: The purpose of the study was to examine the prevalence and risk factors for cerebral infarction (CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with normal controls. Method: A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT) and CAS were measured with ultrasound. Results: The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%, 41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes mellitus, low HDL cholesterol and CAS 70% (p < 0.05). LI was associated with age, PAD, diabetes mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS 70% and CAS 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively, p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 0.45 vs. 0.90 0.28, 2.67 2.00 vs. 1.73 1.05 mm, respectively, p < 0.001). CAS 70% correlated with high LDL cholesterol, and CAS 50% with age and PAD. IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (p < 0.05). Conclusions: Prevalences of CI and CAS were markedly higher in patients with PAD than in controls, indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and CAS is important for managements in PAD, as with screening for PAD in patients with stroke. Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cerebral infarction Carotid artery stenosis Intima-media thickening Peripheral arterial disease Stroke
1. Introduction Cerebral infarction (CI) and coronary heart disease (CHD) are closely associated with peripheral arterial disease (PAD), and are major causes of death in patients with PAD [1e4]. Patients with PAD also complicate with diabetes mellitus or hyperlipidemia and may have extensive and severe systemic atherosclerosis that is responsible for the mortality due to CI and CHD [1,3]. In patients
* Corresponding author. Tel.: þ81 27 232 7111; fax: þ81 27 233 9092. E-mail address: [email protected] (H. Kumakura). 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.05.019
with stroke or transient ischemic attack (TIA), symptomatic or asymptomatic PAD is independently associated with recurrent vascular events and stroke [5,6], and atherosclerotic carotid artery stenosis (CAS) is an important cause of ischemic stroke [7]. We have reported that stroke is an independent risk factor for progress of Fontaine stages in PAD [8]. Asymptomatic CI is also a precursor of symptomatic stroke or insidious brain damage [9], which indicates the importance of screening for the presence of CI or CAS in patients with PAD. Furthermore, CI or CAS is considerable for treatment and rehabilitation of patients with PAD [1,2]. However, the prevalence and risk factors for CI and CAS are not fully understood in patients with PAD, and the prevalences of these diseases compared with age-matched normal controls are unclear.
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The purpose of the present study was to examine these issues in a population of patients with PAD and in healthy controls. 2. Patients and methods 2.1. Patients and control subjects The study included patients with PAD and healthy controls who were referred to the Cardiovascular Hospital of Central Japan (Kitakanto Cardiovascular Hospital) between January 1st, 2005 and December 31st, 2010. The subjects with PAD were 543 consecutive patients with ABI < 0.90 at their first visit. The final diagnosis of PAD was based on clinical symptoms and iliac or femoropopliteal artery stenosis 70% on angiography or ultrasound. Clinical stages of PAD were classified using the criteria of the Inter-Society Consensus for the Management of Peripheral Arterial Disease [1]. ABI was determined in all subjects using ABI-form (Colin, Tokyo, Japan), which simultaneously measures bilateral arm and ankle blood pressure by an oscillometric method. In the patients with PAD, blood was collected during fasting in the morning for determination of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride, glucose, glycosylated hemoglobin A1c, and uric acid. Diabetes mellitus, hypertension, stroke, and CHD were studied as risk factors for arteriosclerosis. Diabetes was defined as a fasting plasma glucose level >126 mg/dL for at least two measurements or a requirement for antidiabetic therapy [10]. Hypertension was defined as blood pressure 140/90 mmHg recorded at least twice or intake of antihypertensive agents. The estimated glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease (MDRD) equation for creatinine, as modified by the Japanese Society of Nephrology: eGFR (mL/min/ 1.73 m2) ¼ 194 (Scr)1.094 (Age)0.287 (0.739 if female) [11]. An electrocardiogram was recorded and echocardiography was performed for each patient. CHD was considered to be present when the patient had a history of this disease or showed a positive sign in stress/ rest myocardial perfusion scintigraphy or coronary angiography. The 560 age-matched control subjects were recruited at the time of their annual medical check-up at our hospital. This check-up included a physical examination, measurement of ABI, chest X-ray, stress electrocardiogram, and echocardiography. Blood was collected during fasting in the morning for determination of total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, glucose, glycosylated hemoglobin A1c, and uric acid. Subjects with physician-diagnosed PAD based on ABI < 1.00, physical symptoms, or ABI 1.40 were excluded. Subjects were also excluded if they had physiciandiagnosed diabetes mellitus, hypertension, hyperlipidemia, CHD, or a history of stroke or TIA. Diabetes mellitus and hypertension were diagnosed as noted above. Lipid abnormalities were diagnosed based on intake of lipid-lowering agents or LDL cholesterol 140 mg/dL [12], HDL cholesterol < 40 mg/dL [1,12], or triglyceride 150 mg/dL [12,13]. Recruitment was tailored to yield approximately an age- and gender-matched control group, and 314 healthy subjects were finally recruited as controls. A brain computed tomography (CT) scan and carotid ultrasound were performed in subjects without risk factors for these procedures. Prior to the start of the study, the patients and control subjects received a full explanation of the examination methods, and gave written informed consent. The study protocol was approved by the Cardiovascular Hospital of Central Japan Medical Ethical Committee. 2.2. Assessment of CI and CAS A brain CT scan (Aquillion 64, Toshiba, Tokyo, Japan) was performed in 5- or 10-mm thick sections without use of
a contrast agent. The scans were evaluated by two radiologists who were blinded to the characteristics of the subjects. Infarcts > 1.5 cm in diameter on brain CT are considered to be CI of potential large-artery atherosclerotic origin. A low density lesion with a diameter of 1.5 cm on CT was categorized as a lacunar infarction (LI). The wall thickness of the bilateral carotid arteries was measured by ultrasound (Aplio SSA-770A; Toshiba, Tokyo, Japan) using a 7.5MHz linear type B-mode probe. The measurements were made after the subject had rested for at least 10 min in the supine position with the neck in slight hyperextension for optimal visualization of the common carotid arteries, carotid bulb, and extracranial internal and external carotid arteries on both sides. The imaging protocol involved obtaining 3 longitudinal views (anterior-oblique, lateral, and posterior-oblique) of the distal 10 mm of the right and left common carotid arteries and internal carotid arteries. The internal carotid artery was defined as including the carotid bulb and the extracranial segment of the internal carotid artery distal to the tip of the flow divider that separates the internal and external carotid arteries. The end-diastolic intima-media thickness (IMT) of the far wall of the common carotid artery was measured bilaterally from the 3 scan views 10 mm proximal to the bulb, and averaged to obtain the mean IMT. The max IMT was defined as the single thickest wall in the same way from the 3 scan views on the internal and common carotid arteries. The presence of a plaque was defined as a thickening of the IMT > 1.1 mm. CAS was evaluated using the North American Symptomatic Carotid Endarterectomy Trial Collaborators (NASCET) method [14]. All scans were evaluated by an ultrasonographic physician who was blinded to the clinical characteristics of the subjects.
2.3. Statistical analysis Data are expressed as mean values standard deviation. The two groups were compared using a t-test and proportions were compared by Chi-square analysis. Relationships between atherosclerotic lesions and risk factors were studied using multiple regression analysis and multiple logistic analysis. SPSS v.17.0 (SPSS Inc, Chicago, IL) was used for all calculations. A p-value <0.05 was considered to indicate a significant difference.
Table 1 Baseline clinical characteristics and risk factors in patients with peripheral arterial disease (PAD) and age-matched normal controls. Risk factor
PAD n ¼ 543
Controls n ¼ 314
p-value
Age (year) Gender (male) BMI (kg/m2) ABI Hypertension Diabetes mellitus Stroke or TIA Coronary heart disease Smoker Atrial fibrillation Total-C (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglyceride (mg/dL) Creatinine Uric acid (mg/dL) HbA1c (%)
71.3 9.4 80.8% 22.1 3.4 0.62 0.26 329 (61.2%) 186 (34.5%) 104 (19.3%) 189 (35.3%) 408 (75.7%) 53 (9.8%) 190 40.2 116 35.7 48.7 21.7 150 33.1 1.42 1.66 5.9 1.74 6.0 1.21
71.1 6.7 79.8% 22.5 4.1 1.12 0.21 0 (0%) 0 (0%) 0 (0%) 0 (0%) 246 (58.6%) 0 (0%) 166 26.1 96 21.0 58.3 15.5 103 18.9 0.76 0.20 5.3 1.47 5.3 0.20
0.796 0.823 0.111 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
BMI: body mass index, ABI: ankle brachial pressure index, TIA: transient ischemic attack, Total-C: total cholesterol, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, HbA1c: glycosylated hemoglobin A1c.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
3. Results 3.1. Patient characteristics The subjects were 543 patients with PAD and 314 age-matched healthy controls. The characteristics of the subjects, including complications and risk factors, are shown in Table 1. There were no significant differences in age, gender and body mass index. The prevalences of hypertension, diabetes mellitus, CHD, smoking, and atrial fibrillation were higher in the patients with PAD, and 19.3% of the patients had a history of stroke or TIA. Serum levels of total cholesterol, LDL cholesterol, triglycerides, creatinine, uric acid and glycosylated hemoglobin A1c were higher, and HDL cholesterol was lower, in patients with PAD compared with controls. 3.2. Prevalence of CI and CAS The prevalence of CI on CT was higher in patients with PAD than in controls (p ¼ 0.032, Fig. 1) and the complication rate of LI was also higher in the patients (p < 0.001). The total prevalence of CI or LI was higher in patients with PAD compared to controls (p < 0.001). The prevalences of CAS 70% (p ¼ 0.004) and 50% (p < 0.001) were also higher in patients with PAD. The mean and max IMT were 1.01 0.45 and 2.67 2.00 mm, respectively, in patients with PAD, and 0.90 0.28 and 1.73 1.05 mm, respectively, in controls, with each differing significantly between the groups (both p < 0.001). The prevalence of carotid plaque was also higher in patients with PAD (p ¼ 0.002, Fig. 1). The variability in ultrasonography was assessed by performing 5 measurements over a period of 1 month in 12 volunteers. The intra-observer coefficient of variation for the IMT measurements was 5.5 0.8%. 3.3. Risk factors for CI and CAS Multiple logistic analysis showed that CI was associated with diabetes mellitus, low HDL cholesterol and CAS 70%, and had a tendency to be associated with male gender, PAD, and high LDL cholesterol (Fig. 2a). LI was associated with PAD, age, eGFR, and diabetes mellitus (Fig. 2b). The odds ratio of LI was 2.8 times higher in patients with PAD. LI also showed a tendency to be associated with hypertension and high LDL cholesterol. No carotid ultrasound parameters showed a relationship with LI, and atrial fibrillation was not correlated with CI or LI. CAS 70% was correlated with high LDL cholesterol (Fig. 3a) and CAS 50% showed significant correlations with age and PAD (Fig. 3b). The odds ratio of CAS 50% was 3.2
a
475
Odds ratio (95%CI) p-value
Age (years)
1.031 (0.983-1.043)
0.406
Gender (male)
2.113(0.982-4.549)
0.056
PAD
2.125 (0.962-5.239)
0.079
Hypertension
1.924 0.787-4.703)
0.151
Diabetes mellitus
1.825 (1.019-3.270) 0.043*
Smoking
0.655 (0.334-1.286)
0.219
CHD
1.069 (0.591-1.932)
0.826
eGFR
1.010 (0.999-1.021)
0.088
High LDL-C
1.715 (0.972-3.027)
0.063
Low HDL-C
1.969 (1.147-3.381)
0.014 *
High TG
0.788 (0.450-1.381)
0.406
CAS 70%
3.324(1.025-10.781) 0.045 *
b
Odds ratio (95%CI) p-value
Age (years)
1.028 (1.006-1.051)
0.011 *
Gender (male)
0.998(0.567-1.755)
0.993
PAD
2.763 (1.373-5.561)
0.004 *
Hypertension
1.488 (0.994-2.229)
0.054
Diabetes mellitus
1.582 (1.029-2.439)
0.037 *
Smoking
1.428 (0.842-2.421)
0.186
CHD
1.016 (0.664-1.555)
0.742
eGFR
0.990 (0.981-0.998)
0.015 *
High LDL-C
1.433 (0.967-2.125)
0.075
Low HDL-C
1.050 (0.699-1.577)
0.815
High TG
1.301 (0.876-1.933)
0.192
CAS 70%
0.806(0.295-2.206)
0.675
0.5
1
2
4
10
0.5
1
2
4
10
Fig. 2. Relationships of (a) cerebral infarction and (b) lacunar infarction with risk factors in multiple logistic analysis. *p < 0.05, PAD: peripheral arterial disease, CHD: coronary heart disease, eGFR: estimated glomerular filtration rate, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglyceride, CAS: carotid artery stenosis.
times higher in patients with PAD. Stepwise forward multiple regression analysis indicated that IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (Table 2, p ¼ 0.046). 4. Discussion 4.1. Prevalence for CI and LI
Fig. 1. Prevalence of cerebral infarction (CI), lacunar infarction (LI), CI or LI, carotid artery stenosis (CAS) 70%, CAS 50%, and carotid artery plaque. *p < 0.05, **p < 0.01.
This is the first report of the prevalence and risk factors for CI or LI detected by CT in patients with PAD, compared with agematched controls. In this study, the history of stroke or TIA was 19.3%, but the prevalence of CI or LI by brain CT was 56.0% in patients with PAD, which was significantly higher than the rate of 23.2% in controls. Baseline data in the REduction of Atherothrombosis for Continued Health (REACH) registry indicate that 16.58% and 15.23% of PAD patients have a history of stroke and TIA, respectively, worldwide [15]. In the Japanese population, 20.66% of PAD patients have a history of stroke or TIA [16]. Our data suggest a high prevalence of asymptomatic CI or LI that remained hidden in the patients with PAD, whose mean age was 71 years old. Asymptomatic CI is a precursor of symptomatic stroke or insidious brain damage [9], which indicates the importance of screening for the presence of CI or LI in patients with PAD.
476
a
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
Odds ratio (95%CI) p-value
Age (years)
1.011 (0.958-1.065)
0.684
Gender (male)
1.841(0.331-9.229)
0.485
PAD
1.851 (0.146-23.543) 0.635
Hypertension
0.940 (0.346-2.369)
0.840
Diabetes mellitus
1.603 (0.600-4.278)
0.347
Smoking
3.038 (0.478-19.294) 0.239
CHD
0.482 (0.166-1.407)
0.184
eGFR
0.999 (0.978-1.20)
0.899
High LDL-C
2.729 (1.066-6.989)
0.036 *
Low HDL-C
1.640 (0.638-4.219)
0.305
High TG
1.137 (0.441-2.932)
0.790
b
Odds ratio (95%CI) p-value
Age (years)
1.036 (1.005-1.067)
0.024 *
Gender (male)
1.258(0.551-2.876)
0.586
PAD
3.213 (1.036-9.962)
0.043 *
Hypertension
0.786 (0.458-1.350)
0.383
Diabetes mellitus
1.157 (0.652-2.054)
0.619
Smoking
1.450 (0.656-3.203)
0.359
CHD
1.234 (0.715-2.133)
0.450
eGFR
0.995 (0.983-1.007)
0.431
High LDL-C
1.502 (0.888-2.541)
0.125
Low HDL-C
1.344 (0.781-2.311)
0.287
High TG
1.077 (0.627-1.849)
0.788
0.5
0.5
1
1
2
2
4
4
10
10
4.3. Correlation between PAD and CI Despite the high risks of stroke in patients with PAD [21] and of PAD in patients with stroke [5], consideration of PAD is omitted from guidelines for treatment, rehabilitation, and prevention of stroke [2,17,22]. We have reported that stroke is an independent risk factor for progress of Fontaine stages in PAD, along with age, diabetes, and female gender [8]. Decreased physical capability, sensory disturbance for wounds, and systemic atherosclerosis may be contributors to these findings [1,8]. Based on a large epidemiologic study [23], the 2011 ACCF/AHA guidelines modified the age for consideration of ABI diagnostic testing to 65 years old or 50 years old with a history of smoking or diabetes [24]. It was also suggested that antiplatelet therapy can be useful to reduce the risk of cardiovascular events in asymptomatic individuals with ABI 0.90 [24]. In patients with CI, symptomatic or asymptomatic PAD is independently associated with recurrent stroke or TIA [5,6]. Our results also suggest that screening for PAD in patients with stroke or TIA is as important as screening for CI or CAS in patients with PAD. 4.4. Prevalence for CAS
Fig. 3. Relationships of (a) carotid artery stenosis 70% and (b) carotid artery stenosis 50% with risk factors in multiple logistic analysis. *p < 0.05, PAD: peripheral arterial disease, CHD: coronary heart disease, eGFR: estimated glomerular filtration rate, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, TG: triglyceride.
Atherosclerotic CAS is an important cause of ischemic stroke [7]. Our study showed that 17.6% of patients with PAD had CAS 50% and 5.2% had CAS 70%. Mostaza et al. found a 14.3% prevalence of CAS 50% in patients with PAD (mean age: 66.7 years old), compared to 4.7% in a control group with normal ABI and matched for age, gender and diabetes [25]. Our results showed a prevalence of CAS 50% that was slightly higher than those in previous studies, which may be due to the higher mean age of our patients. Among the controls in the current study, 3.8% had CAS 50% and 0.6% had CAS 70%. In population-based studies the rates of CAS have varied from 2% to 11% [26,27]. The slightly lower rate of CAS in our controls may have arisen because we excluded subjects with diabetes mellitus. Thus, the results of our study are in accordance with previous studies.
4.2. Risk factors for CI and LI
4.5. Risk factors for CAS
In our study, CI was associated with diabetes mellitus, low HDL cholesterol and CAS 70%, and showed a tendency to be associated with male gender, PAD, and high LDL cholesterol. Diabetes mellitus, low HDL cholesterol, and high LDL cholesterol are important risk factors for development of large-artery atherosclerotic stroke [17]. In contrast, LI results from occlusion of a single perforating artery [18], and in this study LI was associated with age, PAD, and low eGFR. No carotid ultrasound parameters showed a relationship with LI. The odds ratio of LI was 2.8 times higher in patients with PAD compared with controls after adjustment for other risk factors. Age and eGFR are important risk factors for systemic atherosclerosis [19,20], and our study also showed that asymptomatic microvascular cerebral disease progressed silently in patients with PAD.
The presence of intermittent claudication or asymptomatic PAD has been reported to be significantly associated with increased IMT [28]. In our subjects, multiple regression analysis showed that IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension. Analysis of the relationship between CAS 70% and potential risk factors revealed a correlation with high LDL cholesterol. The odds ratio of CAS 50% was 3.2 times higher in patients with PAD. Carotid and femoral IMT have been positively correlated with LDL cholesterol [29] and Rockman et al. found relationships of occult CAS with CHD, smoking, and hypertension in patients with these risk factors, without data for PAD [27]. Our study highlighted PAD and high LDL cholesterol as risk factors for CAS, with CI associated with CAS 70%, along with low HDL cholesterol and diabetes mellitus.
Table 2 Correlation between intima-media thickness (IMT) and other risk factors in stepwise forward multiple regressions analysis. Risk factor
b
95% C.I.
p-value
PAD High LDL-C Age Hypertension
0.124 0.117 0.106 0.101
0.026e0.244 0.029e0.194 0.001e0.010 0.002e0.180
0.015 0.008 0.014 0.046
R2 ¼ 0.057, F for change in R2 ¼ 3.991, p ¼ 0.046. PAD: peripheral arterial disease, LDL-C: low density lipoprotein cholesterol.
4.6. Study limitations The limitations of this study include the relatively small sample size and the performance of the study at a single facility. We did not exclude smokers from the controls because the prevalence of former or current smokers was too high to ignore. We also did not use population-based data. Therefore, further studies are needed to determine the exact prevalence and risk factors for CI, LI, and CAS in patients with PAD.
Y. Araki et al. / Atherosclerosis 223 (2012) 473e477
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