Progression of Carotid Atherosclerosis in Japanese Patients With Coronary Artery Disease

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1 946 Progression of Carotid Atherosclerosis in Japanese Patients With Coronary Artery Disease Hidekazu Tanaka, MD; Masami Nishino, MD; Mariko Ishida, MD; Ryuzo Fukunaga, MD, PhD; and Kenji Sueyoshi, MD, PhD Background and Purpose: Along with the recent changes in lifestyle in Japan, the incidence of coronary artery disease has increased while the incidence of stroke appears to be decreasing. We investigated the relation between the progression of carotid atherosclerosis and the severity of coronary artery disease in the Japanese population. Methods: The 2-year change in extracranial carotid atherosclerosis in 50 Japanese patients who underwent coronary angiography was evaluated using carotid echotomography. To quantify the extent of carotid atherosclerosis, the maximal thickness measurements of all plaques were summed for an individual plaque score, except for new plaques found on reexamination. Carotid disease progression was evaluated by the sum of plaque score change and the thickness of the new plaque found on reexamination. Results: The plaque score changed by -3.2 to 10.1 mm (mean±sd, 1.06±2.42 mm). The extent of coronary atherosclerosis (p<0.02) and serum total cholesterol level (p<0.01) were different between the progressing (n=17) and the nonprogressing (n=30) groups of carotid atherosclerosis when the progressing group included the patients with a A plaque score of >1.0 mm. Neither age, serum triglyceride level, serum high-density lipoprotein cholesterol level, pack-years of smoking, percentage of smokers, percentage of hypertensive patients, nor percentage of diabetic patients was different between the two groups. Carotid disease progression was significantly higher in patients with three-vessel coronary disease than in patients without significant coronary artery disease (p<0.005). There was a significant positive linear correlation between carotid disease progression and Gensini's coronary artery disease score (R=0.4ll, p<0.005). Conclusions: Our data showed that severe coronary artery disease and a high serum total cholesterol level were strong predictors for carotid disease progression in Japanese patients with high rates of coronary artery disease. (Stroke 1992;23: ) KEY WORDS cardiovascular diseases carotid artery diseases Japan ultrasonics A therosclerosis at the carotid artery bifurcation has / \ been reported to be a source of cerebrovascular J. A. events. 1-2 A significantly higher incidence of cerebrovascular events with the progression of atherosclerotic plaque in the carotid artery has also been reported. 3 Several previous studies have proposed the predicting factors for carotid disease progression. 4-8 A 30-month follow-up study of 38 patients suggested that coronary atherosclerosis and elevated low density lipoprotein (LDL) and fibrinogen may be predicting factors for carotid stenosis progression. 6 In another study, cigarette smoking, diabetes mellitus, and age were proposed as the major factors associated with disease progression. 7 A 2-year follow-up study using intimal-medial thickness measurement suggested that age, serum LDL cholesterol level, pack-years of smoking, blood leukocyte count, and platelet aggregability were strong predictors for atherosclerosis progression. 8 From the Department of Internal Medicine, Osaka Rosai Hospital, Osaka, Japan. Address for correspondence: Hidekazu Tanaka, MD, Department of Pharmacology 1, Osaka University School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565, Japan. Received August 27, 1991; accepted January 28, Carotid and coronary artery diseases are major manifestations of generalized atherosclerosis. A strong association between the extent of carotid atherosclerosis and coronary atherosclerosis has been demonstrated, 9-12 and one follow-up study has reported the relation between coronary artery disease and carotid plaque progression. 6 It has been reported that mortality from ischemic heart disease in Japan is low compared with that in the United States and, conversely, that mortality from stroke is higher in Japan. 13 It has also been reported that in the Japanese, more severe cerebral vascular lesions were located intracranially, whereas those in the Americans occurred extracranially In accordance with the changing lifestyle in Japan, the incidence of all strokes in Japan appears to have decreased and the incidence of coronary artery disease has increased. 16 However, there is no definitive study demonstrating the changes in coronary and intracranial-extracranial carotid atherosclerosis in the Japanese population. Extracranial carotid atherosclerosis may have recently increased in the Japanese population along with the changes in diseases and lifestyle, so it is meaningful to investigate the progression of extracranial carotid atherosclerosis in the modern Japanese patient with coronary artery disease.

2 Tanaka et al Carotid Plaque Progression and Coronary Artery Disease 947 TABLE 1. Variables Risk Factors and Coronary Status in Patients Followed Up and Lost to Follow-up Age (years) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) Pack-years of smoking % Hypertensive patients % Smoking patients % Diabetic patients Gensini's score Coronary angiography score Followed up (n=50) 59.5± ± ± ± ± % 58% 22% 31.2± Not followed up («=42) 61.8± ± ± ± ± % 52% 29% 26.6± Statistical significance Values are mean±sd, % subpopulation of affected patients, n, Number of patients; HDL, high density lipoprotein. To investigate the relation between the progression of carotid atherosclerosis and the severity of coronary atherosclerosis, we studied the 2-year change of carotid lesions in 50 Japanese patients with high prevalence rates of coronary artery disease, using high-resolution echotomography. Subjects and Methods Ninety-two consecutive Japanese patients (63 men and 29 women) with coronary artery disease (angina and/or post-myocardial infarction), aged years, were studied. The diagnosis of coronary artery disease was made by standard clinical examinations before coronary angiography. None had had a stroke or a transient ischemic attack. All patients signed an informed consent approved by the Osaka Rosai Hospital Ethical Committee. From January to March 1989, selective coronary angiography was performed by the percutaneous technique using either Judkins or multipurpose catheters for all 92 patients. Within 1 week of the coronary angiography, an ultrasonographic assessment of the carotid arteries was performed. The baseline examination also included measurements of height; weight; blood pressure; serum cholesterol, serum triglyceride, and serum high density lipoprotein (HDL) cholesterol levels; and assessment of smoking history with a self-administered questionnaire. All 92 patients who underwent carotid ultrasonography from January to March 1989 were invited to a 2-year reexamination between January and March Of these patients, two had died, five had moved, six refused to participate, and 29 could not be contacted. Of the 29 who could not be contacted on the follow-up exam, 23 were contacted later and found to be alive. Thirty-four men and 16 women underwent reexamination. The baseline characteristics of 42 patients lost to follow-up and 50 who were followed up are listed in Table 1. There was no significant difference between them. Of 42 patients lost to follow-up, 19 were without significant coronary stenosis (75% or greater stenosis), seven had single-vessel involvement, seven had two-vessel involvement, and nine had three-vessel involvement. There was no significant difference in the distribution of the number of coronary branches with 75% or greater stenosis between the patients lost to follow-up and those followed up ("Results" and Figure 2 legend). Treatment of the patients admitted to follow-up was left to the discretion of the referring physician. None underwent carotid endarterectomy. All carotid B-mode imaging was performed with a 7.5-MHz transducer with an axial resolution of <0.4 mm (SSD-256, Aloka, Tokyo). Patients were examined in the supine position, and each carotid system was imaged in the anterior oblique, lateral, and posterior oblique planes. For this study, readings were made from just above the clavicle to the internal carotid artery 15 mm above the bifurcation, including the carotid bulb. Atheromatous plaques were defined as echogenic lesions with an intimal-medial thickness 17 " 19 >1.0 mm. When echogenic plaques were identified, the view that displayed the greatest axial thickness of the lesion was recorded on Polaroid film. If more than one plaque was identified in a carotid artery, all plaques were recorded. The greatest axial thickness of each plaque was measured with a ruler on each Polaroid reproduction. To obtain a plaque score for each patient, these measurements for each patient were summed. Follow-up scans were performed in the same manner. Scanners were informed of the location and the plane of the plaque previously identified, but readers were blinded as to the results of the first measurement. Newly appeared plaques were not recorded or measured on the same plane. If careful scanning at the reexamination failed to visualize the plaque previously recorded, its second measurement was recorded as 0 mm. To quantify the progression of carotid atherosclerosis, the A plaque score was obtained by subtracting the baseline plaque score from the follow-up plaque score. If a new plaque was discovered on the follow-up exam, it was recorded in the new plane displaying the greatest axial thickness, which was measured and added to the A plaque score. Patients were divided into three groups according to the A plaque score: progressing group, nonprogressing group, and regressing group. Paired ultrasound examinations were done 24±16 days apart in 12 patients with atheromatous plaques. The mean difference in plaque score between these 12 paired images was 0.19±0.46 mm (mean±sd). Using the margin of 2SDs, the nonprogressing group was defined as patients with a A plaque score between 1.0 mm and 1.0 mm. The progressing group was defined as those with a A plaque score >1.0 mm and the regressing group as those with a score <-1.0 mm.

3 948 Stroke Vol 23, No 7 July 1992 Plaque score ) l Baseline 2-year follow-up FIGURE 1. Plot of plaque scores at baseline and 2-year follow-up of 50 patients. Each line was drawn from baseline plaque score to 2-year follow-up plaque score for each patient. Mean value is shown as open circle. Vertical lines extending from open circles indicate standard deviation. Line from 0 mm plaque score at baseline to 0 mm plaque score at 2-year follow-up represents plaque scores of 17 patients. Two methods were used to estimate the degree of coronary atherosclerosis: Gensini's score and the coronary angiography score. Gensini's score was calculated from the coronary angiography. 20 The coronary angiography score was denned as the number of coronary branches (right, left anterior descending, and left circumflex) with >75% stenosis, with scores ranging from 0to3. The criteria for hypertension were a systolic blood pressure consistently > 160 mm Hg, a diastolic blood pressure consistently >95 mm Hg, and/or a history of arterial hypertension treated with antihypertensive drugs. Diabetes mellitus was denned as the use of oral hypoglycemic agents or insulin, a fasting blood glucose level >110 mg/dl, and/or a glycosylated hemoglobin (HbAlc) level >6.4%. Serum total cholesterol, triglyceride, and HDL cholesterol levels were determined on blood drawn after an overnight fast. Pack-years of TABLE 2. Risk Factors in Progressing and Nonprogressing Patients Patients Variables Age (years) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL-cholesterol (mg/dl) Pack-years of smoking % Hypertensive patients % Smoking patients % Diabetic patients Nonprogressing («=30) 57.9± ± ± ± ± % 57% 17% smoking was calculated from a self-administered questionnaire. The data were analyzed by paired or unpaired t tests and x 2 tests. The extent of carotid plaque progression was related to the Gensini's score of coronary atherosclerosis in univariate analysis by linear regression. Results The baseline plaque scores ranged from 0 to 7.0 mm (mean±sd, 1.60±1.94 mm) and the 2-year follow-up plaque score from 0 to 13.1 mm (2.67±3.16 mm) (Figure 1). The change in plaque score over 2 years (A plaque score) ranged from -3.2 to 10.1 mm (mean±sd, 1.06 ±2.42 mm). The paired t tests showed that the plaque scores at the follow-up examination were significantly higher than the baseline plaque scores (/?<0.01). As denned by the A plaque score, the progressing group included 17 patients, the nonprogressing group 30, and the regressing group three. Table 2 lists the baseline age, serum total cholesterol level, triglyceride level, HDL cholesterol level, packyears of smoking, and the subpopulation of patients with hypertension, diabetes, and those who were current smokers for the progressing and nonprogressing groups. Because of the small number of patients in the regressing group, these variables were not listed for the group. The two groups listed were not distinguishable except for the serum total cholesterol level (/?<0.01). Table 3 lists the patients' coronary status for the progressing and nonprogressing groups. Both Gensini's score (/?<0.002) and coronary angiography score (/?<0.02) were significantly different between the two groups. These variables were also not examined for the regressing group because of the small number of patients. Sixteen patients did not have a coronary artery branch with >75% stenosis as shown by coronary angiography. Fifteen patients had one involved coronary branch (right, left anterior descending, or left circumflex) with 275% stenosis. Ten patients had two involved coronary branches with >75% stenosis. The remaining nine patients had >75% stenotic lesions in all three coronary branches. The mean A plaque scores of the patients with three involved coronary branches were higher than those of the patients with no involved coronary branch (/?<0.005) (Figure 2). Progressing (" = 17) ± ± % 59% 29% Statistical significance /><0.01 Values are mean±sd, % subpopulation of affected patients, n, Number of patients; nonprogressing group, - 1 mm<a plaque score<l mm; progressing group, A plaque score>l mm.

4 Tanaka et al Carotid Plaque Progression and Coronary Artery Disease 949 TABLE 3. Coronary Atherosclerotic Status for Progressing and Nonprogressing Groups Patients Gensini's score Coronary angiography score Nonprogressing (»=30) 16.7± ±1.03 Progressing («= 17) 49.5± ±1.05 Statistical significance p<0.002 p<0.02 n, Number of patients; nonprogressing group, -1 mm<a plaque score<l mm; progressing group, A plaque scores 1 There was a significant positive linear correlation between A plaque score and Gensini's coronary atherosclerotic score (/?=0.411,/?<0.005) (Figure 3). Discussion Previous studies have reported a correlation between the extent of coronary atherosclerosis and extracranial carotid atherosclerosis using noninvasive ultrasonography ' 22 One study revealed a correlation between carotid disease progression and the extent of coronary atherosclerosis by using the mean percent stenosis. 6 This study showed a strong correlation between the extent of coronary atherosclerosis and the progression of carotid atherosclerosis. The rapid progression of carotid atherosclerosis in patients with severe coronary artery disease demonstrated in this study was compatible with the idea that the rapid progression of systemic atherosclerosis resulted in both severe coronary disease and the 2-year progression of carotid atherosclerosis. Previous follow-up studies have suggested predictive risk factors for carotid disease progression. A prospective follow-up study using intravenous digital subtraction angiography linked the progression of carotid disease to increasing age, hypertension, and more severe disease at entry. 23 In a prospective follow-up study of 167 asymptomatic patients with cervical bruits that were evaluated by the percent stenosis, cigarette smoking, diabetes mellitus, and age were suggested to be the Delta plaque score 41 (mm) 3- ^ major risk factors associated with disease progression. 7 Another study of the progression of carotid stenosis using ultrasonography showed that a combination of coronary artery disease and elevated LDL and fibrinogen predict with an 88% accuracy whether the patient will have progressing carotid stenosis. 6 A 2-year follow-up study of carotid intimal-medial thickness showed that age, serum LDL cholesterol level, pack-years of smoking, blood leukocyte count, and platelet aggregability, measured at baseline, were strong predictors of atherosclerosis progression. 18 In our study, the severity of coronary atherosclerosis and severity of serum total cholesterol were the strongest predictors of carotid disease progression. However, for other risk factors (age, serum triglyceride level, smoking, hypertension, and diabetes mellitus) there was no significant difference between progressing group and nonprogressing group. One possible reason for the different results of our study from previous studies is the population bias. Most of the patients in our study suffered from coronary artery disease accompanied by a high risk for atherosclerosis. Because the possible risk factors such as smoking, hypertension, and diabetes mellitus may have already affected this population, their contribution to the further progression of extracranial carotid atherosclerosis might have been masked. The relatively small number of patients recruited in this follow-up study could also have masked minor risks. But we can at least Number of coronary arteries with 75% or more stenosis FIGURE 2. Bar graph showing average values of 2-year change in carotid plaque score (delta plaque score) according to number of major coronary branches with 75% or more stenosis, i.e., the coronary angiography score. Score of 0 included 16 patients; 1, 15 patients; 2, 10 patients; and 3, nine patients. *p<0.005 different from "no coronary involvement" group Gensini's score FIGURE 3. Scatterplot of Gensini's score versus delta plaque score. Significant positive correlation was shown between these parameters (R=0.411, p<0.005, y= x,

5 950 Stroke Vol 23, No 7 July 1992 believe that in Japanese patients with severe coronary atherosclerosis such as three-vessel disease, carotid disease progression was very rapid, and its strongest predictor was the serum total cholesterol level. Although age has been demonstrated as a strong predicting factor for extracranial carotid atherosclerosj S 8,io,i7,22,24 our data did not show that age was significant to the progression of extracranial carotid atherosclerosis. A follow-up study by Grotta et al 6 also showed no correlation between age and carotid disease progression. Age may not be a risk factor for the progression of carotid atherosclerosis, but it is associated with the extent of carotid atherosclerotic disease. Although it is important to document treatment of high cholesterol or other variables that differed between the progressing and nonprogressing groups, these numbers were too small to tell. For example, there were 13 patients with a total cholesterol level >200 mg/dl in the progressing group (n = 17) compared with 14 patients in the nonprogressing group (n=30). Of the 13 patients with high cholesterol levels in the progressing group, eight received cholesterol-lowering therapy, and the total cholesterol levels of six were lowered to <200 mg/dl on reexamination. Of the 14 patients with high cholesterol in the nonprogressing group, although only five received cholesterol-lowering therapy, six had a total cholesterol level <200 mg/dl on reexamination. Two of 10 smokers in the progressing group had stopped smoking; three of 17 smokers in the nonprogressing group had stopped smoking. Other smokers continued smoking in spite of our proposal to stop smoking. However, we could not know from these data whether smoking cessation contributed to the suppression of carotid disease progression. All hypertensive patients have undergone antihypertensive therapy during the study. Mean arterial blood pressure of the progressing group was 96.9±15.9 mm Hg on the baseline exam and ±11.9 mm Hg on the follow-up exam. Mean arterial blood pressure of the nonprogressing group was 101.6±11.8 mm Hg on the baseline exam and 122.0±24.5 mm Hg on the follow-up exam. All diabetic patients underwent treatment for diabetes mellitus that included diet, exercise, oral hypoglycemic agents, and insulin therapy. Fasting blood glucose level of the progressing group was 108.4±28.7 mg/dl on the baseline exam and 117.6±24.8 mg/dl on the follow-up exam. That of the nonprogressing group was 97.5 ±28.1 mg/dl on the baseline exam and 108.1±11.8 mg/dl on the follow-up exam. These data did not suggest differences in the levels of blood pressure and blood glucose during the study between progressing and nonprogressing groups. Several methods using carotid ultrasonography have been proposed in the place of angiography for the evaluation of carotid atherosclerosis Echostructural profiles such as soft, mixed, and hard plaques have been discussed in relation to the clinical events or progression and regression of plaques. 3 " 5 ' 19 ' 25 ' 26 Some studies have used the percent stenosis for quantification of carotid atherosclerosis, 6-7 others the thickness of the intimal-medial complex The atherosclerotic plaque summed score has shown its usefulness in the study of risk factor contribution to carotid atherosclerosis ' 22 We used a modified scoring system to quantify the extent of carotid atherosclerosis for quantification of the atherosclerosis progression. Because the original method of Crouse et al 9 -" could ignore plaques other than the largest one in each reading site, we did not divide the reading site into four sites but measured the greatest axial thickness of each plaque as visualized through the entire scanned area. This study provides estimates of the increase of carotid atherosclerosis as evaluated by plaque score over time in Japanese patients with high prevalence rates of coronary artery disease. Our findings confirmed the close relation between three-vessel coronary disease and carotid disease progression. The linear correlation between Gensini's score and carotid A plaque score was also suggested. Our data revealed that serum total cholesterol level was the strongest predicting factor for carotid disease progression in Japanese patients with high prevalence rates of coronary artery disease. Acknowledgments We thank Mr. M. Yamaguchi and Mrs. Y. Yamauchi for technical support in carotid ultrasonography. References 1. 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