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Different patterns of silent cerebral infarct in patients with coronary artery disease or hypertension
AJH
2001; 14:509 –515
Different Patterns of Silent Cerebral Infarct in Patients With Coronary Artery Disease or Hypertension Satoshi Hoshide, Kazuomi Kario, Takeshi Mitsuhashi, Yoko Sato, Yuji Umeda, Takaaki Katsuki, and Kazuyuki Shimada The aim of the present study was to clarify the differences in the progression and the characteristics of silent cerebral infarcts (SCI) between patients with coronary artery disease (CAD) and hypertensive patients. Silent cerebral infarcts, a powerful prognostic indicator for stroke, are frequently found in patients with CAD and in hypertensives. However, the differences in the characteristics of SCI and related risk factors between CAD and hypertensive patients have not been thoroughly investigated. We evaluated the number of SCI and their distribution using brain magnetic resonance imaging (T1- and T2-weighted images) in 107 patients with CAD (validated by coronary angiography) and 101 hypertensive patients without history of clinical stroke. The prevalence of multiple SCI (three or more infarcts per person) in patients with CAD and with hypertension was significantly higher than in hypertensives without CAD (46% v 21%; P ⫽ .001), whereas that of patients with CAD without hypertension was intermediate (31%). The patients with multi- (two- or three-vessel) vessel diseases (VD) had a significantly higher prevalence of multiple SCI than the hypertensives and the no-stenosis or 1-VD group (68.1% in the 3-VD group, 52.0% in the 2-VD group, 26.8% in the 1-VD group, and 21.0% in the no-stenosis group). Multiple
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logistic regression analysis revealed that in the CAD group, the number of involved coronary arteries was an independent determinant of SCI (P ⬍ .005), whereas in the hypertensive group, age was an independent determinant of SCI (P ⬍ .005). When we investigated the distribution of SCI, in the CAD group, SCI in the deep perforator territory (the basal ganglia and the thalamus) were independently associated with the number of involved coronary arteries (P ⬍ .005), whereas SCI in the white matter were independently associated with age only (P ⬍ .005). In conclusion, SCI were more advanced in the patients with multivessel CAD than in the hypertensive patients, and were more common in patients with CAD and hypertension than in those without hypertension. Coronary atherosclerosis was independently and specifically associated with SCI located in the deep perferator territory but not of SCI located in the white matter. The CAD– atherosclerosis and hypertension may be independently involved in the pathologic process of SCI. Am J Hypertens 2001;14:509 –515 © 2001 American Journal of Hypertension, Ltd. Key Words: Silent cerebral infarction, coronary artery disease, hypertension, atherosclerosis.
oronary artery disease (CAD) and cerebrovascular disease often coexist and have similar risk factors. A third of patients with ischemic stroke already have clinical manifestations of CAD, such as angina or a past myocardial infarction.1 Patients with a history of CAD events tend to have more cerebrovascular events than those without CAD events.2 In the Framingham Heart Study, CAD increased the possibility of stroke events
independent of other well-known cardiovascular risk factors.3 The association between cerebrovascular disease and CAD is an important prognostic determinant for these patients with cardiovascular disease. The National Institute of Neurological Disorders and Stroke defines silent cerebrovascular disease (infarction and hemorrhage), which is detected by computed tomography or nuclear magnetic resonance imaging (MRI) by
Received July 28, 2000. Accepted September 28, 2000. From the Department of Cardiology, Jichi Medical School, Tochigi, Japan. Dr. Kario was supported in part by grants-in-aid (1992–1999) from the Foundation for the Development of the Community, Tochigi, Japan, and by a Scientific Research Grant-in-Aid 09670746 from the Ministry of Education of the Government of Japan.
This work was presented, in part, at the 71st Scientific Session, American Heart Association, Dallas, 1998.
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
Address correspondence and reprint requests to Kazuomi Kario, MD, PhD, FACC, FACP, Department of Cardiology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi, Kawachi, Tochigi, 329-0498, Japan; e-mail: [email protected] 0895-7061/01/$20.00 PII S0895-7061(00)01293-0
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chance, as a predisposing condition of clinical cerebrovascular disease.4 In a recent prospective study, silent cerebral infarct (SCI), mostly lacunar infarct, was found to be a strong predictor of clinical cerebrovascular disease.5 The mechanisms of lacunar infarcts vary widely.6 – 8 Hypertensive small-vessel vasculopathy is considered to be the most common cause of lacunar infarction.7,8 Actually, in previous studies, hypertension and advanced age were strong determinants of SCI.9 –12 However, the SCI also were more advanced in the patients with CAD13,14 or with carotid artery stenosis,15,16 indicating that systemic atherosclerosis of the large artery also may play a role in the progression of SCI. A recent study found that SCI located in the basal ganglia area were more closely associated with CAD, and that SCI in the white matter (WM) area were associated with hypertension.9 Thus, the distribution of SCI, related risk factors, and characteristics may be different between patients with CAD and hypertensive patients. However, precise comparison of the relationships between these two groups has not been performed. We performed brain MRI (T1- and T2-weighted images) in patients with CAD and hypertensive patients to investigate the differences in the progression and characteristics of SCI and the related risk factors between the two groups.
Methods Subjects The patients in this study were 208 adults who visited and were admitted to the Department of Cardiology at Jichi Medical School or Washiya Hospital between February 1996 and August 1998. The CAD group consisted of 107 patients in whom coronary angiography was performed because of the symptoms of chest pain and significant ST-T change on the electrocardiogram during a treadmill stress test. The hypertensive group consisted of 101 asymptomatic patients with a mean office blood pressure (BP) of ⱖ140 mm Hg or ⱖ90 mm Hg, or who were taking antihypertensive medication. We excluded those patients with a history of or any clinical or laboratory signs of CAD, or those with ischemic electrocardiographic changes (abnormal Q and ischemic ST change) from the hypertensive group. We excluded patients with renal failure (serum creatinine level, ⬎130 mmol/L; urea nitrogen level ⬎10.7 mmol/L), hepatic damage (aspartate aminotransferase or alanine aminotransferase levels, ⬎40 IU/L), and those who had atrial fibrillation, intracardiac thrombus, or valvular heart disease from both the CAD group and the hypertensive group. No patients had a history of stroke or of transient ischemic attack. Diabetes mellitus was defined as a fasting glucose level of ⬎7.7 mmol/L or a history of treatment for diabetes mellitus. Hyperlipidemia was defined as a total cholesterol level of ⬎5.7 mmol/L at the laboratory examination of serum at presentation, a fasting triglyceride level of ⬎1.7 mmol/L, or a history of lipidlowering treatment. Smokers were current smokers and
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ex-smokers were those who had stopped smoking at least 1 year before this study. Cardiac Evaluation Coronary angiography and radionuclide ventriculography were performed in all patients with CAD. In the evaluation of coronary atherosclerosis, significant stenosis was defined as ⱖ75% diameter stenosis by the modified American College of Cardiology/American Heart Association lesion classification in three coronary arteries (the left anterior descending artery, left circumflex, or right coronary artery).17 According to the number of coronary arteries with significant stenosis, patients with CAD were classified as no-stenosis, 1-vessel disease (1-VD), 2-VD, and 3-VD. Brain MRI Brain MRI was carried out in all 208 patients using a superconducting magnet with a main strength of 1.5T (SIGNA Horizon Version 5.8, General Electric Co., Tokyo, Japan, or Vision, Siemens, Tokyo, Japan). T1- and T2-weighted images were obtained in the transverse plane with 7.8-mm thick sections. The images were evaluated for the number and location of SCI. An SCI (lacunar infarct) was defined as a low-signal intensity area (ⱖ3 mm and ⬍15 mm) on T1-weighted images that also was visible as a hyperintense lesion on T2-weighted images.18 A few SCI were defined as one or two SCI per person. Multiple SCI were defined as three SCI or more per person. Statistical Analysis Continuous values are expressed as means. The t test was used to detect differences in the mean values of factors between the CAD group and the hypertensive group. The 2 test was used to detect the differences among groups in the prevalence of SCI or of risk factors. Multiple logistic regression analysis was used to estimate independent effects of the predictive variables on SCI. Differences with a value of P ⬍ .05 were considered significant.
Results Characteristics Table 1 shows the characteristics of the CAD and the hypertensive groups. The prevalence of men and smokers in the CAD group was higher than in the hypertensive group. The office systolic BP (SBP) and diastolic BP (DBP) were higher in the hypertensive group than in the CAD group. Silent Cerebral Infarcts A total of 161 SCI were detected in the hypertensive group, and 297 SCI were detected in the CAD group. All SCI were lacunar infarcts. The prevalence of multiple SCI in the CAD group was significantly higher than that in the
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Table 1. Characteristics of hypertensive and coronary artery disease patients
Number Age, years Male, n (%) Body mass index (kg/m2) Smoker, n (%) Family history of stroke, n (%) Office SBP (mm Hg) Office DBP (mm Hg) Hypertension, n (%) Treated hypertension, n (%) Hyperlipidemia, n (%) Diabetes mellitus, n (%)
Hypertensive Group
CAD Group
101 60 (11) 54 (54)
107 62 (10) 88 (82)*
25 (3.4) 20 (20)
24 (3.2) 41 (38)*
7 154 90 101
(7.0) (20) (15) (100)
60 (59) 44 (44) 20 (20)
15 131 75 59
(14) (20)* (14)* (55)*
55 (51) 50 (47) 16 (15)
CAD ⫽ coronary artery disease; DBP ⫽ diastolic blood pressure; SBP ⫽ systolic blood pressure. Values are shown as the mean (SD) or the number [percentage]. * P ⬍ .01 v hypertensive group.
hypertensive group (Fig. 1), and there was no significant difference in the prevalence of a few SCI between the two groups. When we divided the CAD group by the presence or absence of hypertension, the prevalence of multiple SCI (three or more infarcts per person) in the CAD group with hypertension was significantly higher than the hypertensive group (46% v 21%; P ⫽ .001), whereas that of the CAD group without hypertension was immediate (31%). Neither difference in the multiple SCI between the CAD group with hypertension (46%) and the CAD group without hypertension (31%, 2 ⫽ 2.3, P ⫽ .16) nor the
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difference between the CAD group without hypertension (31%) and the hypertensive group without CAD (21%, 2 ⫽ 1.9, P ⫽ .22) were significant, because of the small number in each group. There were no differences in the mean number of involved coronary arteries (1.5 v 1.4), and the prevalence of 2-VD or 3-VD (45% v 44%) between the CAD group with hypertension and the CAD group without hypertension. Risk Factors In the CAD group, the prevalence of SCI was increased, along with the number of involved coronary arteries (Fig. 2). Table 2 shows the findings of multiple logistic regression analyses of risk factors for SCI in the CAD and hypertensive groups. Age was independently associated with SCI in the hypertensive group and in the CAD group. The number of involved coronary arteries was independently associated with SCI in the CAD group. In the hypertensive group, there were no significant differences in the prevalence of SCI between diabetic and nondiabetic patients (18% v 22%), or between hyperlipidemic and normolipidemic subjects (41% v 47%). In the CAD group, there were no significant differences in the prevalence of SCI between diabetic and nondiabetic patients (17% v 14%), or between hyperlipidemic and normolipidemic subjects (51% v 44%). Cardiac Function There were no significant differences in the prevalence of multiple SCI between patients with myocardial infarction and those without (40% v 38%). There was also no association between the number of SCI with left ventricular function (ejection fraction) or with abnormal wall motion of either ventricular wall and SCIs (data not shown).
FIG. 1. Prevalence of silent cerebral infarcts (SCI) detected by brain magnetic resonance imaging in hypertensive and coronary artery disease (CAD) groups. *P ⫽ .001 v hypertensive group. A few SCI ⫽ one or two SCI per person; Multiple SCI ⫽ three or more SCI per person.
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FIG. 2. Prevalence of SCI in coronary artery disease group. VD ⫽ vessel disease. *P ⬍ .05, **P ⬍ .01 v no stenosis group, †P ⬍ .05, ††P ⬍ .01 v 1-VD group. Other abbreviations as in Fig. 1.
Location of Silent Cerebral Infarcts
SCI. The prevalence of SCI was 36% in Q1 (the lowest SBP group), 30% in Q2, 45% in Q3, 30% in Q4, and 54% in Q5 (the highest SBP group). The prevalences of SCI was 43% in Q1 of DBP, 41% in Q2, 36% in Q3, 47% in Q4, and 33% in Q5. Thus, there was no significant J curve relationship between BP and SCI in the CAD group. We also divided the hypertensive group into quintiles of SBP or DBP, but there were no significant relationships of SBP or DBP with SCI.
The location of subcortical SCI was divided into three categories such as the following: 1) deep perforator territory (DP), corresponding to the basal ganglia and the thalamus, and 2) white matter (WM), corresponding to periventricular or deep WM and superficial subcortical WM, as described previously.9 In the CAD group, the number of involved coronary arteries was independently associated with SCI in the DP, but was not associated with those in the WM (Table 3). Age was independently associated with SCI in the WM and also tended to be similar in the DP (P ⫽ .07). In the hypertensive group, multiple logistic regression analyses revealed that age and body mass index were independently associated with SCI in the DP. Age also tended to be independently associated with SCI in the WM (P ⫽ .08) (Table 4).
Discussion We investigated the difference in the progression and the characteristics of SCI detected by brain MRI between patients with CAD and hypertensive patients. In the present study, the prevalence of multiple SCI in the CAD group was significantly higher than that in the hypertensive group. The prevalence of multiple SCI in the 2-VD or 3-VD patients was significantly higher than that of patients
Blood Pressure We then divided the CAD group into quintiles of SBP or DBP to study the J curve relationships between BP and Table 2. patients
Analysis of risk factors for silent cerebral infarcts in hypertensive and coronary artery disease Hypertensive Group
Age Male gender Body mass index Smoking Family history Hypertension Hyperlipidemia Diabetes mellitus No. of involved CA
CAD Group
OR
95% CI
P Value
OR
95% CI
P Value
1.09 1.15 1.08 1.26 0.23
1.04–1.15 0.42–3.11 0.94–1.25 0.37–4.31 0.04–1.30
⬍.001 NS NS NS NS
1.21 0.83
0.46–3.18 0.27–2.53
NS NS
1.05 0.89 0.93 0.65 0.92 1.31 1.09 0.36 2.28
1.00–1.09 0.20–4.01 0.81–1.08 0.24–1.73 0.31–2.72 0.49–3.28 0.42–2.82 0.10–1.17 1.39–3.76
⬍.05 NS NS NS NS NS NS NS ⬍.005
OR ⫽ odds ratio; CI ⫽ confidence interval; NS ⫽ not significant; Family history ⫽ family history of stroke; CA ⫽ coronary artery; other abbreviation as in Table 1.
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Table 3. Analysis of risk factors between deep perforator infarct and white matter infarct in the coronary artery disease group Deep Perforator Infarct Age Male gender Body mass index Smoking Family history Hypertension Hyperlipidemia Diabetes mellitus No. of involved CA
White Matter Infarct
OR
95% CI
P Value
OR
95% CI
P Value
1.03 0.98 0.94 0.80 0.74 2.44 1.19 0.68 2.11
0.99–1.08 0.23–4.12 0.81–1.09 0.31–2.06 0.25–2.12 0.92–6.51 0.47–3.00 0.39–2.37 1.31–3.41
NS NS NS NS NS NS NS NS ⬍.005
1.08 2.25 1.12 0.64 0.98 2.82 1.27 0.34 1.41
1.02–1.15 0.46–11.08 0.96–1.30 0.24–1.75 0.32–3.04 0.85–9.33 0.46–3.55 0.08–1.40 0.87–2.27
⬍.005 NS NS NS NS NS NS NS NS
Abbreviations as in Table 2.
with no stenosis or the 1-VD patients. This finding was consistent with the findings of previous studies.13,14 Silent cerebral infarct on MRI are a predictor of a subsequent clinical stroke.5 The multi-VD CAD patients may be at risk not only for CAD, but also for stroke. Pathogenic Mechanism of Silent Lacunar Infarct Lacunar infarct is the most frequent type of SCI.19 The mechanisms of lacunar infarcts are varied, but are mainly because of arteriosclerosis of the small artery, although they may be partly because of the progression of atherosclerosis or the microemboli from larger arteries or the heart.20 –22 Silent cerebral infarct (silent lacunar infarct) could advance in CAD through these mechanisms. Stroke is a known early complication of myocardial infarction, because of mural microthrombi formed from greater left ventricular dysfunction and complicated atrial fibrillation, abnormal hemodynamics, and other factors.21 The rate of mural thrombus formation and the early rate of stroke appear to be lower after inferior wall myocardial infarction than after anterior infarction.23,24 Recently, one study reported that circulating cerebral microemboli, estimated by transcranial Doppler sonography, were detected in patients who experienced stroke events during the follow-up pe-
riod after acute myocardial infarction.25 In the present study, there was no difference in the prevalence of SCI between patients with myocardial infarction and those without myocardial infarction. Furthermore, the number of SCI was not related to left ventricular function or abnormal motion of either left ventricular wall in the CAD group. The progression of SCI in CAD might be unrelated to cardiac functional status and to microemboli from the cardiac ventricle. Another candidate for the pathogenesis that might explain the link between the number of diseased coronary arteries and the progression of SCI in the CAD group is advanced atherosclerosis of the large arteries.26 The present study demonstrated that the higher the number of diseased coronary arteries, the higher the increase in frequency of SCI. Coronary atherosclerosis is known to advance along with systemic atherosclerosis of the large arteries, including the carotid artery and major cerebral arteries.27 Thus, multiple SCI might reflect an advanced stage of systemic atherosclerosis, which is manifested in CAD. Microemboli from the large artery system (the carotid artery or the aortic arch) or carotid stenosis or stenosis of a major cerebral artery may contribute to the progression of SCI in CAD patients.
Table 4. Analysis of risk factors between deep perforator infarct and white matter infarct in the hypertensive group Deep Perforator Infarct Age Male gender Body mass index Smoking Family history Hyperlipidemia Diabetes mellitus
White Matter Infarct
OR
95% CI
P Value
OR
95% CI
P Value
1.09 1.64 1.17 0.83 0.37 1.08 0.90
1.03–1.14 0.61–4.47 1.01–1.35 0.24–2.81 0.07–2.12 0.41–2.84 0.29–2.75
⬍.001 NS ⬍.05 NS NS NS NS
1.05 0.85 0.96 1.25 1.09 1.56 1.20
0.99–1.12 0.28–2.64 0.81–1.13 0.31–5.08 0.39–6.12 0.50–4.48 0.35–4.13
NS NS NS NS NS NS NS
Abbreviations as in Tables 2 and 3.
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Distribution of Silent Cerebral Infarct
Hypertension in Coronary Artery Disease
We also investigated the distribution of SCI. The underlying vascular pathology may be different between SCI in the DP and those in the WM.28 Sclerotic changes in the medullary arteries (small cerebral arteries) supplying the WM appear to be different from those in the perforating arteries in the DP.28 In the present study, the prevalence of SCI in the DP was significantly higher in the 2-VD or 3-VD patients than in the patients with hypertension and no stenosis or 1-VD. We found that the progression of SCI in 2-VD or 3-VD patients was more related to the increase in SCI in the DP than to that in the WM. Multiple logistic regression analysis showed that in patients with CAD, CAD was independently associated with SCI in the DP, and age was independently associated with SCI in the WM. These findings support our hypothesis that the determinant for SCI in the DP and those in the WM are different in patients with CAD. The SCI in the DP may be partly determined by atherosclerosis of a relatively larger cerebral artery than the small cerebral arteries, like the medullary artery. Thus, SCI in the DP may be more likely to be paralleled by subclinical systemic atherosclerosis, which also partly determines coronary atherosclerosis, than SCI in the WM. In contrast, SCI in the WM may be mainly associated with fibrohyaline thickening of the wall of the small medullary artery,28 and thus independently associated with age in the patients with CAD.
The prevalence of multiple SCI in CAD patients with hypertension was marginally higher than that of patients with CAD without hypertension (46% v 31%, P ⫽ .16). Thus, also in the patients with CAD, hypertension was associated with multiple SCI. Because some patients could have started taking antihypertensive medication, this might have decreased the risk. However, a recent prospective study reported the J curve relationship between stroke incidence and office BP in treated elderly hypertensive patients.30 In the present study, there was no association between SCI and office BP when patients were taking antihypertensive medication in either the CAD or hypertensive groups. However, in the patients with CAD, the degree of CAD (the mean number of involved coronary arteries and the prevalence of 2-VD or 3-VD) of those with hypertension was comparable to those without hypertension. These findings suggest that in the patients with CAD, the impact of hypertension might be stronger for SCI than for the severity of CAD.
Aging The majority of previous studies demonstrated that age and hypertension were strongly and independently correlated with lacunar infarction and SCI.9 –12,18,29 Age-related or hypertensive small vessel vasculopathy was considered to be the predominant pathogenesis of these silent and symptomatic lacunar infarcts.7,8 In the present study, multiple logistic regression analysis showed that age was independently associated with SCI in both patients with CAD and hypertensive patients. A previous study demonstrated an association for aging and hypertension with SCI in the WM, whereas aging was associated with SCI in the DP.9 In the present hypertensive group, age was more strongly associated with SCI in the DP than for those in the WM. This discrepancy may be from differences in the study design and subjects. Also, the definition of SCI in the WM might be different. In the present study, 21% of the subjects with SCI had a lesion in the WM, whereas 93.2% of the subjects with SCI had a lesion in the WM in a previous study.9 Another study also reported that SCI in the WM were detected in 11.5% of all silent infarcts found in elderly subjects.6 Previously, we reported that SCI in the WM were detected in 25% of all SCI found in elderly hypertensive subjects with older age (mean age, 70 years).29
Diabetes and Hyperlipidemia Diabetes and hyperlipidemia, both major risk factors of CAD, also increase the risk for ischemic stroke, particularly atherothrombotic infarction, which occurs in the larger cerebral artery more often than lacunar infarction. In the present study, there was no relationship between these risk factors and SCI in either the CAD group or the hypertensive group. However, it remains possible that in the absence of diagnosed CAD or hypertension, diabetes or hyperlipidemia might be associated with SCI. In conclusion, the prevalence of SCI was significantly higher in patients with CAD than in hypertensives. The prevalence of SCI was higher in patients with CAD with hypertension than in those without hypertension. In patients with CAD, coronary atherosclerosis was independently associated with SCI located in the DP but was not related to SCI located in the WM. These findings indicated that CAD–atherosclerosis and hypertension may be independently involved in the pathologic process of SCI.
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Different Patterns of Silent Cerebral Infarct in Patients With Coronary Artery Disease or Hypertension Satoshi Hoshide, Kazuomi Kario, Takeshi Mitsuhashi, Yoko Sato, Yuji Umeda, Takaaki Katsuki, and Kazuyuki Shimada The aim of the present study was to clarify the differences in the progression and the characteristics of silent cerebral infarcts (SCI) between patients with coronary artery disease (CAD) and hypertensive patients. Silent cerebral infarcts, a powerful prognostic indicator for stroke, are frequently found in patients with CAD and in hypertensives. However, the differences in the characteristics of SCI and related risk factors between CAD and hypertensive patients have not been thoroughly investigated. We evaluated the number of SCI and their distribution using brain magnetic resonance imaging (T1- and T2-weighted images) in 107 patients with CAD (validated by coronary angiography) and 101 hypertensive patients without history of clinical stroke. The prevalence of multiple SCI (three or more infarcts per person) in patients with CAD and with hypertension was significantly higher than in hypertensives without CAD (46% v 21%; P ⫽ .001), whereas that of patients with CAD without hypertension was intermediate (31%). The patients with multi- (two- or three-vessel) vessel diseases (VD) had a significantly higher prevalence of multiple SCI than the hypertensives and the no-stenosis or 1-VD group (68.1% in the 3-VD group, 52.0% in the 2-VD group, 26.8% in the 1-VD group, and 21.0% in the no-stenosis group). Multiple
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logistic regression analysis revealed that in the CAD group, the number of involved coronary arteries was an independent determinant of SCI (P ⬍ .005), whereas in the hypertensive group, age was an independent determinant of SCI (P ⬍ .005). When we investigated the distribution of SCI, in the CAD group, SCI in the deep perforator territory (the basal ganglia and the thalamus) were independently associated with the number of involved coronary arteries (P ⬍ .005), whereas SCI in the white matter were independently associated with age only (P ⬍ .005). In conclusion, SCI were more advanced in the patients with multivessel CAD than in the hypertensive patients, and were more common in patients with CAD and hypertension than in those without hypertension. Coronary atherosclerosis was independently and specifically associated with SCI located in the deep perferator territory but not of SCI located in the white matter. The CAD– atherosclerosis and hypertension may be independently involved in the pathologic process of SCI. Am J Hypertens 2001;14:509 –515 © 2001 American Journal of Hypertension, Ltd. Key Words: Silent cerebral infarction, coronary artery disease, hypertension, atherosclerosis.
oronary artery disease (CAD) and cerebrovascular disease often coexist and have similar risk factors. A third of patients with ischemic stroke already have clinical manifestations of CAD, such as angina or a past myocardial infarction.1 Patients with a history of CAD events tend to have more cerebrovascular events than those without CAD events.2 In the Framingham Heart Study, CAD increased the possibility of stroke events
independent of other well-known cardiovascular risk factors.3 The association between cerebrovascular disease and CAD is an important prognostic determinant for these patients with cardiovascular disease. The National Institute of Neurological Disorders and Stroke defines silent cerebrovascular disease (infarction and hemorrhage), which is detected by computed tomography or nuclear magnetic resonance imaging (MRI) by
Received July 28, 2000. Accepted September 28, 2000. From the Department of Cardiology, Jichi Medical School, Tochigi, Japan. Dr. Kario was supported in part by grants-in-aid (1992–1999) from the Foundation for the Development of the Community, Tochigi, Japan, and by a Scientific Research Grant-in-Aid 09670746 from the Ministry of Education of the Government of Japan.
This work was presented, in part, at the 71st Scientific Session, American Heart Association, Dallas, 1998.
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
Address correspondence and reprint requests to Kazuomi Kario, MD, PhD, FACC, FACP, Department of Cardiology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi, Kawachi, Tochigi, 329-0498, Japan; e-mail: [email protected] 0895-7061/01/$20.00 PII S0895-7061(00)01293-0
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chance, as a predisposing condition of clinical cerebrovascular disease.4 In a recent prospective study, silent cerebral infarct (SCI), mostly lacunar infarct, was found to be a strong predictor of clinical cerebrovascular disease.5 The mechanisms of lacunar infarcts vary widely.6 – 8 Hypertensive small-vessel vasculopathy is considered to be the most common cause of lacunar infarction.7,8 Actually, in previous studies, hypertension and advanced age were strong determinants of SCI.9 –12 However, the SCI also were more advanced in the patients with CAD13,14 or with carotid artery stenosis,15,16 indicating that systemic atherosclerosis of the large artery also may play a role in the progression of SCI. A recent study found that SCI located in the basal ganglia area were more closely associated with CAD, and that SCI in the white matter (WM) area were associated with hypertension.9 Thus, the distribution of SCI, related risk factors, and characteristics may be different between patients with CAD and hypertensive patients. However, precise comparison of the relationships between these two groups has not been performed. We performed brain MRI (T1- and T2-weighted images) in patients with CAD and hypertensive patients to investigate the differences in the progression and characteristics of SCI and the related risk factors between the two groups.
Methods Subjects The patients in this study were 208 adults who visited and were admitted to the Department of Cardiology at Jichi Medical School or Washiya Hospital between February 1996 and August 1998. The CAD group consisted of 107 patients in whom coronary angiography was performed because of the symptoms of chest pain and significant ST-T change on the electrocardiogram during a treadmill stress test. The hypertensive group consisted of 101 asymptomatic patients with a mean office blood pressure (BP) of ⱖ140 mm Hg or ⱖ90 mm Hg, or who were taking antihypertensive medication. We excluded those patients with a history of or any clinical or laboratory signs of CAD, or those with ischemic electrocardiographic changes (abnormal Q and ischemic ST change) from the hypertensive group. We excluded patients with renal failure (serum creatinine level, ⬎130 mmol/L; urea nitrogen level ⬎10.7 mmol/L), hepatic damage (aspartate aminotransferase or alanine aminotransferase levels, ⬎40 IU/L), and those who had atrial fibrillation, intracardiac thrombus, or valvular heart disease from both the CAD group and the hypertensive group. No patients had a history of stroke or of transient ischemic attack. Diabetes mellitus was defined as a fasting glucose level of ⬎7.7 mmol/L or a history of treatment for diabetes mellitus. Hyperlipidemia was defined as a total cholesterol level of ⬎5.7 mmol/L at the laboratory examination of serum at presentation, a fasting triglyceride level of ⬎1.7 mmol/L, or a history of lipidlowering treatment. Smokers were current smokers and
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ex-smokers were those who had stopped smoking at least 1 year before this study. Cardiac Evaluation Coronary angiography and radionuclide ventriculography were performed in all patients with CAD. In the evaluation of coronary atherosclerosis, significant stenosis was defined as ⱖ75% diameter stenosis by the modified American College of Cardiology/American Heart Association lesion classification in three coronary arteries (the left anterior descending artery, left circumflex, or right coronary artery).17 According to the number of coronary arteries with significant stenosis, patients with CAD were classified as no-stenosis, 1-vessel disease (1-VD), 2-VD, and 3-VD. Brain MRI Brain MRI was carried out in all 208 patients using a superconducting magnet with a main strength of 1.5T (SIGNA Horizon Version 5.8, General Electric Co., Tokyo, Japan, or Vision, Siemens, Tokyo, Japan). T1- and T2-weighted images were obtained in the transverse plane with 7.8-mm thick sections. The images were evaluated for the number and location of SCI. An SCI (lacunar infarct) was defined as a low-signal intensity area (ⱖ3 mm and ⬍15 mm) on T1-weighted images that also was visible as a hyperintense lesion on T2-weighted images.18 A few SCI were defined as one or two SCI per person. Multiple SCI were defined as three SCI or more per person. Statistical Analysis Continuous values are expressed as means. The t test was used to detect differences in the mean values of factors between the CAD group and the hypertensive group. The 2 test was used to detect the differences among groups in the prevalence of SCI or of risk factors. Multiple logistic regression analysis was used to estimate independent effects of the predictive variables on SCI. Differences with a value of P ⬍ .05 were considered significant.
Results Characteristics Table 1 shows the characteristics of the CAD and the hypertensive groups. The prevalence of men and smokers in the CAD group was higher than in the hypertensive group. The office systolic BP (SBP) and diastolic BP (DBP) were higher in the hypertensive group than in the CAD group. Silent Cerebral Infarcts A total of 161 SCI were detected in the hypertensive group, and 297 SCI were detected in the CAD group. All SCI were lacunar infarcts. The prevalence of multiple SCI in the CAD group was significantly higher than that in the
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Table 1. Characteristics of hypertensive and coronary artery disease patients
Number Age, years Male, n (%) Body mass index (kg/m2) Smoker, n (%) Family history of stroke, n (%) Office SBP (mm Hg) Office DBP (mm Hg) Hypertension, n (%) Treated hypertension, n (%) Hyperlipidemia, n (%) Diabetes mellitus, n (%)
Hypertensive Group
CAD Group
101 60 (11) 54 (54)
107 62 (10) 88 (82)*
25 (3.4) 20 (20)
24 (3.2) 41 (38)*
7 154 90 101
(7.0) (20) (15) (100)
60 (59) 44 (44) 20 (20)
15 131 75 59
(14) (20)* (14)* (55)*
55 (51) 50 (47) 16 (15)
CAD ⫽ coronary artery disease; DBP ⫽ diastolic blood pressure; SBP ⫽ systolic blood pressure. Values are shown as the mean (SD) or the number [percentage]. * P ⬍ .01 v hypertensive group.
hypertensive group (Fig. 1), and there was no significant difference in the prevalence of a few SCI between the two groups. When we divided the CAD group by the presence or absence of hypertension, the prevalence of multiple SCI (three or more infarcts per person) in the CAD group with hypertension was significantly higher than the hypertensive group (46% v 21%; P ⫽ .001), whereas that of the CAD group without hypertension was immediate (31%). Neither difference in the multiple SCI between the CAD group with hypertension (46%) and the CAD group without hypertension (31%, 2 ⫽ 2.3, P ⫽ .16) nor the
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difference between the CAD group without hypertension (31%) and the hypertensive group without CAD (21%, 2 ⫽ 1.9, P ⫽ .22) were significant, because of the small number in each group. There were no differences in the mean number of involved coronary arteries (1.5 v 1.4), and the prevalence of 2-VD or 3-VD (45% v 44%) between the CAD group with hypertension and the CAD group without hypertension. Risk Factors In the CAD group, the prevalence of SCI was increased, along with the number of involved coronary arteries (Fig. 2). Table 2 shows the findings of multiple logistic regression analyses of risk factors for SCI in the CAD and hypertensive groups. Age was independently associated with SCI in the hypertensive group and in the CAD group. The number of involved coronary arteries was independently associated with SCI in the CAD group. In the hypertensive group, there were no significant differences in the prevalence of SCI between diabetic and nondiabetic patients (18% v 22%), or between hyperlipidemic and normolipidemic subjects (41% v 47%). In the CAD group, there were no significant differences in the prevalence of SCI between diabetic and nondiabetic patients (17% v 14%), or between hyperlipidemic and normolipidemic subjects (51% v 44%). Cardiac Function There were no significant differences in the prevalence of multiple SCI between patients with myocardial infarction and those without (40% v 38%). There was also no association between the number of SCI with left ventricular function (ejection fraction) or with abnormal wall motion of either ventricular wall and SCIs (data not shown).
FIG. 1. Prevalence of silent cerebral infarcts (SCI) detected by brain magnetic resonance imaging in hypertensive and coronary artery disease (CAD) groups. *P ⫽ .001 v hypertensive group. A few SCI ⫽ one or two SCI per person; Multiple SCI ⫽ three or more SCI per person.
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FIG. 2. Prevalence of SCI in coronary artery disease group. VD ⫽ vessel disease. *P ⬍ .05, **P ⬍ .01 v no stenosis group, †P ⬍ .05, ††P ⬍ .01 v 1-VD group. Other abbreviations as in Fig. 1.
Location of Silent Cerebral Infarcts
SCI. The prevalence of SCI was 36% in Q1 (the lowest SBP group), 30% in Q2, 45% in Q3, 30% in Q4, and 54% in Q5 (the highest SBP group). The prevalences of SCI was 43% in Q1 of DBP, 41% in Q2, 36% in Q3, 47% in Q4, and 33% in Q5. Thus, there was no significant J curve relationship between BP and SCI in the CAD group. We also divided the hypertensive group into quintiles of SBP or DBP, but there were no significant relationships of SBP or DBP with SCI.
The location of subcortical SCI was divided into three categories such as the following: 1) deep perforator territory (DP), corresponding to the basal ganglia and the thalamus, and 2) white matter (WM), corresponding to periventricular or deep WM and superficial subcortical WM, as described previously.9 In the CAD group, the number of involved coronary arteries was independently associated with SCI in the DP, but was not associated with those in the WM (Table 3). Age was independently associated with SCI in the WM and also tended to be similar in the DP (P ⫽ .07). In the hypertensive group, multiple logistic regression analyses revealed that age and body mass index were independently associated with SCI in the DP. Age also tended to be independently associated with SCI in the WM (P ⫽ .08) (Table 4).
Discussion We investigated the difference in the progression and the characteristics of SCI detected by brain MRI between patients with CAD and hypertensive patients. In the present study, the prevalence of multiple SCI in the CAD group was significantly higher than that in the hypertensive group. The prevalence of multiple SCI in the 2-VD or 3-VD patients was significantly higher than that of patients
Blood Pressure We then divided the CAD group into quintiles of SBP or DBP to study the J curve relationships between BP and Table 2. patients
Analysis of risk factors for silent cerebral infarcts in hypertensive and coronary artery disease Hypertensive Group
Age Male gender Body mass index Smoking Family history Hypertension Hyperlipidemia Diabetes mellitus No. of involved CA
CAD Group
OR
95% CI
P Value
OR
95% CI
P Value
1.09 1.15 1.08 1.26 0.23
1.04–1.15 0.42–3.11 0.94–1.25 0.37–4.31 0.04–1.30
⬍.001 NS NS NS NS
1.21 0.83
0.46–3.18 0.27–2.53
NS NS
1.05 0.89 0.93 0.65 0.92 1.31 1.09 0.36 2.28
1.00–1.09 0.20–4.01 0.81–1.08 0.24–1.73 0.31–2.72 0.49–3.28 0.42–2.82 0.10–1.17 1.39–3.76
⬍.05 NS NS NS NS NS NS NS ⬍.005
OR ⫽ odds ratio; CI ⫽ confidence interval; NS ⫽ not significant; Family history ⫽ family history of stroke; CA ⫽ coronary artery; other abbreviation as in Table 1.
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Table 3. Analysis of risk factors between deep perforator infarct and white matter infarct in the coronary artery disease group Deep Perforator Infarct Age Male gender Body mass index Smoking Family history Hypertension Hyperlipidemia Diabetes mellitus No. of involved CA
White Matter Infarct
OR
95% CI
P Value
OR
95% CI
P Value
1.03 0.98 0.94 0.80 0.74 2.44 1.19 0.68 2.11
0.99–1.08 0.23–4.12 0.81–1.09 0.31–2.06 0.25–2.12 0.92–6.51 0.47–3.00 0.39–2.37 1.31–3.41
NS NS NS NS NS NS NS NS ⬍.005
1.08 2.25 1.12 0.64 0.98 2.82 1.27 0.34 1.41
1.02–1.15 0.46–11.08 0.96–1.30 0.24–1.75 0.32–3.04 0.85–9.33 0.46–3.55 0.08–1.40 0.87–2.27
⬍.005 NS NS NS NS NS NS NS NS
Abbreviations as in Table 2.
with no stenosis or the 1-VD patients. This finding was consistent with the findings of previous studies.13,14 Silent cerebral infarct on MRI are a predictor of a subsequent clinical stroke.5 The multi-VD CAD patients may be at risk not only for CAD, but also for stroke. Pathogenic Mechanism of Silent Lacunar Infarct Lacunar infarct is the most frequent type of SCI.19 The mechanisms of lacunar infarcts are varied, but are mainly because of arteriosclerosis of the small artery, although they may be partly because of the progression of atherosclerosis or the microemboli from larger arteries or the heart.20 –22 Silent cerebral infarct (silent lacunar infarct) could advance in CAD through these mechanisms. Stroke is a known early complication of myocardial infarction, because of mural microthrombi formed from greater left ventricular dysfunction and complicated atrial fibrillation, abnormal hemodynamics, and other factors.21 The rate of mural thrombus formation and the early rate of stroke appear to be lower after inferior wall myocardial infarction than after anterior infarction.23,24 Recently, one study reported that circulating cerebral microemboli, estimated by transcranial Doppler sonography, were detected in patients who experienced stroke events during the follow-up pe-
riod after acute myocardial infarction.25 In the present study, there was no difference in the prevalence of SCI between patients with myocardial infarction and those without myocardial infarction. Furthermore, the number of SCI was not related to left ventricular function or abnormal motion of either left ventricular wall in the CAD group. The progression of SCI in CAD might be unrelated to cardiac functional status and to microemboli from the cardiac ventricle. Another candidate for the pathogenesis that might explain the link between the number of diseased coronary arteries and the progression of SCI in the CAD group is advanced atherosclerosis of the large arteries.26 The present study demonstrated that the higher the number of diseased coronary arteries, the higher the increase in frequency of SCI. Coronary atherosclerosis is known to advance along with systemic atherosclerosis of the large arteries, including the carotid artery and major cerebral arteries.27 Thus, multiple SCI might reflect an advanced stage of systemic atherosclerosis, which is manifested in CAD. Microemboli from the large artery system (the carotid artery or the aortic arch) or carotid stenosis or stenosis of a major cerebral artery may contribute to the progression of SCI in CAD patients.
Table 4. Analysis of risk factors between deep perforator infarct and white matter infarct in the hypertensive group Deep Perforator Infarct Age Male gender Body mass index Smoking Family history Hyperlipidemia Diabetes mellitus
White Matter Infarct
OR
95% CI
P Value
OR
95% CI
P Value
1.09 1.64 1.17 0.83 0.37 1.08 0.90
1.03–1.14 0.61–4.47 1.01–1.35 0.24–2.81 0.07–2.12 0.41–2.84 0.29–2.75
⬍.001 NS ⬍.05 NS NS NS NS
1.05 0.85 0.96 1.25 1.09 1.56 1.20
0.99–1.12 0.28–2.64 0.81–1.13 0.31–5.08 0.39–6.12 0.50–4.48 0.35–4.13
NS NS NS NS NS NS NS
Abbreviations as in Tables 2 and 3.
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Distribution of Silent Cerebral Infarct
Hypertension in Coronary Artery Disease
We also investigated the distribution of SCI. The underlying vascular pathology may be different between SCI in the DP and those in the WM.28 Sclerotic changes in the medullary arteries (small cerebral arteries) supplying the WM appear to be different from those in the perforating arteries in the DP.28 In the present study, the prevalence of SCI in the DP was significantly higher in the 2-VD or 3-VD patients than in the patients with hypertension and no stenosis or 1-VD. We found that the progression of SCI in 2-VD or 3-VD patients was more related to the increase in SCI in the DP than to that in the WM. Multiple logistic regression analysis showed that in patients with CAD, CAD was independently associated with SCI in the DP, and age was independently associated with SCI in the WM. These findings support our hypothesis that the determinant for SCI in the DP and those in the WM are different in patients with CAD. The SCI in the DP may be partly determined by atherosclerosis of a relatively larger cerebral artery than the small cerebral arteries, like the medullary artery. Thus, SCI in the DP may be more likely to be paralleled by subclinical systemic atherosclerosis, which also partly determines coronary atherosclerosis, than SCI in the WM. In contrast, SCI in the WM may be mainly associated with fibrohyaline thickening of the wall of the small medullary artery,28 and thus independently associated with age in the patients with CAD.
The prevalence of multiple SCI in CAD patients with hypertension was marginally higher than that of patients with CAD without hypertension (46% v 31%, P ⫽ .16). Thus, also in the patients with CAD, hypertension was associated with multiple SCI. Because some patients could have started taking antihypertensive medication, this might have decreased the risk. However, a recent prospective study reported the J curve relationship between stroke incidence and office BP in treated elderly hypertensive patients.30 In the present study, there was no association between SCI and office BP when patients were taking antihypertensive medication in either the CAD or hypertensive groups. However, in the patients with CAD, the degree of CAD (the mean number of involved coronary arteries and the prevalence of 2-VD or 3-VD) of those with hypertension was comparable to those without hypertension. These findings suggest that in the patients with CAD, the impact of hypertension might be stronger for SCI than for the severity of CAD.
Aging The majority of previous studies demonstrated that age and hypertension were strongly and independently correlated with lacunar infarction and SCI.9 –12,18,29 Age-related or hypertensive small vessel vasculopathy was considered to be the predominant pathogenesis of these silent and symptomatic lacunar infarcts.7,8 In the present study, multiple logistic regression analysis showed that age was independently associated with SCI in both patients with CAD and hypertensive patients. A previous study demonstrated an association for aging and hypertension with SCI in the WM, whereas aging was associated with SCI in the DP.9 In the present hypertensive group, age was more strongly associated with SCI in the DP than for those in the WM. This discrepancy may be from differences in the study design and subjects. Also, the definition of SCI in the WM might be different. In the present study, 21% of the subjects with SCI had a lesion in the WM, whereas 93.2% of the subjects with SCI had a lesion in the WM in a previous study.9 Another study also reported that SCI in the WM were detected in 11.5% of all silent infarcts found in elderly subjects.6 Previously, we reported that SCI in the WM were detected in 25% of all SCI found in elderly hypertensive subjects with older age (mean age, 70 years).29
Diabetes and Hyperlipidemia Diabetes and hyperlipidemia, both major risk factors of CAD, also increase the risk for ischemic stroke, particularly atherothrombotic infarction, which occurs in the larger cerebral artery more often than lacunar infarction. In the present study, there was no relationship between these risk factors and SCI in either the CAD group or the hypertensive group. However, it remains possible that in the absence of diagnosed CAD or hypertension, diabetes or hyperlipidemia might be associated with SCI. In conclusion, the prevalence of SCI was significantly higher in patients with CAD than in hypertensives. The prevalence of SCI was higher in patients with CAD with hypertension than in those without hypertension. In patients with CAD, coronary atherosclerosis was independently associated with SCI located in the DP but was not related to SCI located in the WM. These findings indicated that CAD–atherosclerosis and hypertension may be independently involved in the pathologic process of SCI.
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