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High incidence of silent myocardial ischemia in elderly patients with non insulin-dependent diabetes mellitus
Diabetes Research and Clinical Practice 47 (2000) 37 – 44 www.elsevier.com/locate/diabres
High incidence of silent myocardial ischemia in elderly patients with non insulin-dependent diabetes mellitus T. Inoguchi a,*, T. Yamashita a, F. Umeda a, H. Mihara b, O. Nakagaki b, K. Takada b, T. Kawano b, H. Murao b, T. Doi b, H. Nawata a a
The Third Department of Internal Medicine, Faculty of Medicine, Kyusyu Uni6ersity, Higashi-ku, Maidashi 3 -1 -1 -6, Fukuoka 812 -8582, Japan b Di6ision of Cardiology, Saiseikai Fukuoka General Hospital, Fukuoka, Japan Received 25 January 1999; received in revised form 5 August 1999; accepted 11 August 1999
Abstract The present study was designed to reveal the incidence of silent myocardial ischemia in asymptomatic elderly non-insulin-dependent diabetic (NIDDM) patients (aged over 60 years). As a first step screening, maximal treadmill exercise test was performed. Of 140 patients studied, 54 (38.6%) were unable or not expected to achieve diagnostic levels of exercise during treadmill testing. A positive exercise test was noted in 39 of 86 (45.3%) subjects. As a second step examination, dipyridamole thallium scintigraphy was performed for 93 subjects who exhibited a positive exercise test and could not perform a maximal exercise test. Abnormal perfusion pattern was found in 39 of 93 (41.9%), who were finally considered to have a silent myocardial ischemia. Coronary angiography was performed in 18 subjects with diagnosis of silent myocardial ischemia, who gave their consent. Significant coronary artery stenosis was in fact found in 17 of 18 (94.4%) subjects studied, confirming a very high positive predictive value of this diagnostic procedure. In conclusion, elderly NIDDM patients (aged over 60 years) had an extremely high prevalence (estimated 26.3%) of silent myocardial ischemia. This evidence suggests that early and intensive detection may be needed as a part of routine care for this group. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Silent myocardial ischemia; Elderly NIDDM patients; Treadmill exercise test; Dipyridamole thallium scintigraphy; Coronary angiography
1. Introduction It is well known that diabetic patients are particularly prone to silent myocardial infarction [1 – 3]. Silent myocardial ischemia is also reported to * Corresponding author. Tel.: +81-92-642-5284; fax: +8192-642-5287.
be more prevalent in diabetic patients with known coronary artery disease (CAD) [4,5]. Despite being asymptomatic, silent myocardial ischemia may have a poor prognosis in diabetic population [6] as well as in non-diabetic population [6–14]. Early and intensive detection of silent myocardial ischemia might be needed as a part of routine care for diabetic population. First of all, it is essential
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to reveal the incidence of silent myocardial ischemia among asymptomatic diabetic patients who appear to be without CAD. Several previous studies have addressed this issue [15 – 19]. However, most of these studies used either exercise-induced ECG or thallium scintigraphy to evaluate silent myocardial ischemia. These results may be interpreted with caution, because of the lack of angiographic information. Naka et al. demonstrated the incidence of silent myocardial ischemia in non insulin-dependent diabetic (NIDDM) patients as judged by both treadmill exercise testing and coronary angiography [19]. They showed a high incidence (12.1%) of silent myocardial ischemia in NIDDM patients (mean age of 61 9 4 years). We speculated that elderly NIDDM patients might be an extremely high-risk group for silent myocardial ischemia, because silent myocar-
dial ischemia has been reported to increase progressively with age in nondiabetic asymptomatic population [14]. In the present study, we focused on the incidence of silent myocardial ischemia in elderly NIDDM patients (aged over 60 years). Early and intensive detection of silent myocardial ischemia could be targeted toward this high-risk group. Paillole et al. studied prospectively the efficacy of non-invasive tests used for diagnosis of CAD in diabetic patients, concluding that the exercise ECG test should be used as a first line examination because of its cheapness and availability, although dipyridamole thallium myocardial scintigraphy displayed the best sensitivity and specificity [20]. However, they also showed high incidence of false positive (50%) when judged by exercise test alone, in agreement with that reported for non-diabetic subjects [21–23]. As diagnostic procedure we used here a combination of treadmill exercise test (first step screening) and dipyridamole thallium scintigraphy (second step examination). In addition, we confirmed the efficacy of this diagnostic procedure for silent myocardial ischemia in elderly NIDDM patients by performing coronary angiography (Fig. 1).
2. Methods
2.1. Patients
Fig. 1. Diagnostic procedure of silent myocardial ischemia in elderly NIDDM patients. Treadmill exercise test was performed as a first step screening. For the patients who exhibited a positive exercise test and could not perform maximal exercise test (impaired performance of exercise), dipyridamole thallium scintigraphy was performed as the second step examination. The patients who exhibited an abnormal pattern in dipyridamole thallium scintigraphy were diagnosed to have silent myocardial ischemia. These patients were recommended to undergo coronary angiography.
Consecutive NIDDM patients, aged over 60 years, who received the exercise training program in the Saiseikai Fukuoka General Hospital between April 1993 and January 1994, were recruited for this study on the basis that they had no symptoms of CAD. We excluded patients with abnormal ECG at rest, history of angina pectoris, myocardial infarction, or coronary revascularization procedures. Patients with asthma were also excluded as this condition was a contra-indication for dipyridamole myocardial scintigraphy. One hundred and forty elderly patients aged 60 to 81 years (mean 68.19 0.5 years, male 79, female 61) were finally recruited for this study. Informed consent was obtained from all subjects before study. This study was performed in part of ‘Com-
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
prehensive Research on Aging and Health’ from the Ministry of Health and Welfare, Japan.
2.2. Diagnostic procedure Maximal treadmill exercise testing was carried out according to the Bruce protocol as the first step screening. Throughout the exercise testing the 12-lead ECG and blood pressure were monitored and recorded every minute. Exercise was continued until 90% or more of the predicted maximal heart rate for age was achieved. The exercise test was interrupted if there was an occurrence of dyspnea, fatigue, or multiple ventricular ectopic complexes. The test was terminated immediately when an ischemic ST segment response was detected. To increase the sensitivity of exercise testing and detect as many patients with silent myocardial ischemia as possible, we used less stringent criteria. Namely, the test was considered positive if there was an ST segment depression equal to or greater than 1 mm which was horizontal or downsloping at the J point, or ST segment depression equal to greater than 2 mm which was slowly upsloping 0.08 s after the J point. As the second step examination, dipyridamole thallium scintigraphy was performed for both patients exhibiting a positive treadmill exercise test and patients who could not perform a maximal exercise test. All medications being taken by the patients were continued except for theophylline. Dipyridamole testing was performed in the fasting state. Dipyridamole was infused intravenously at a rate of 0.56 mg/kg body weight for 4 min, followed by active leg swinging for 4 min. Then, thallium201 was injected, again followed by leg swinging for an additional 2 min. Early thallium imaging was initiated 5 min after injection using a small field-of-view gamma camera equipped with a low-energy, high-resolution, parallel-hole collimator. Stress and 4-h delayed images were obtained in the anterior, 45 left anterior oblique, and left lateral views. The images were analyzed on X-ray film and computer display by an experienced nuclear cardiologist who was unaware of the patients’ clinical histories. The myocardial thallium activity was divided into five segments per view. Each segment was graded as being
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normal or having reversible or fixed thallium-201 defects. The subjects who exhibited an abnormal pattern in dipyridamole thallium scintigraphy were told that a strong suspicion of CAD existed, and diagnostic coronary angiography was recommended. Informed consent was again obtained from all those who later underwent coronary angiography. Standard coronary angiography was carried out with the Judkins technique, including selective engagement of the right and left coronary arteries and angulated views sufficient to completely display the coronary tree. Coronary angiograms were analyzed blindly by independent observers. Significant coronary artery stenosis was defined as at least 50% reduction in diameter of one or more major coronary arteries in at least two opposite views. Clinical data were obtained by a standardized clinical examination performed at Saiseikai Fukuoka General Hospital. Fundus examination was performed by an ophthalmologist. Neurological history was taken and a physical examination was performed focusing on the symptoms and signs of distal symmetric sensorimotor polyneuropathy and autonomic neuropathy. As for autonomic neuropathy examination, coefficient of variation for 100 consecutive R–R intervals on the ECG (CVR – R) in the resting supine position was measured as an index of autonomic neuropathy. Proteinuria was tested with strips (lower limit of 2.5–3.0 mg/dl). Hypertension was diagnosed according to the blood pressure level (systolic blood pressure ] 140 mmHg and/or diastolic blood pressure ]90 mmHg), the history of antihypertensive drug treatment, or both.
2.3. Statistical analysis Descriptive results of continuous variables are expressed as means9 SE. The Chi-square test was used for comparisons of proportions and the Mann–Whitney U-test was used for group comparisons because none of valuables were normally distributed. P values B 0.05 were considered significant.
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
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Table 1 Results of treadmill exercise tests in 140 elderly NIDDM patients without clinical symptoms of coronary artery disease Finding Impaired performance of exercise test Negative Positive
54/140 (38.6%) 47/140 (33.6%) 39/140 (27.9%)
Table 2 Results of dipyridamole thallium scintigraphy in 93 subjects who exhibited a positive exercise test and who could not perform maximal exercise test Finding Negative Positive
54/93 39/93 15/93 24/93
Persistent defect Reversible defect
(58.1%) (41.9%) (16.1%) (25.8%)
Table 3 Baseline characteristics of 140 elderly NIDDM subjectsa SMI No. of subjects Male/female Age (years) Duration (years) HbA1C (%) T-Cholesterol (mg/dl) Triglyceride (mg/dl)
(+)
(−)
39
101
P value
25/14 70.3 91.0* 9.0 90.9*
54/47 67.59 0.6* 10.691.0*
N.S. PB0.05** N.S.
8.0 90.3* 213 9 16*
7.99 0.2* 210 9 5*
N.S. N.S.
136 915*
1239 5*
N.S.
Type of treatment Diet only Drug Insulin
12 (30.8%) 21 (53.8%) 6 (15.4%)
45 (44.6%) 42(41.6%) 14 (13.9%)
N.S. N.S. N.S.
Hypertension Retinopathy Proteinuria Neuropathy
17 15 20 22
46 33 30 45
N.S. N.S. PB0.05*** N.S.
(43.6%) (38.5%) (51.3%) (56.0%)
(45.5%) (32.2%) (29.7%) (44.6%)
a SMI, silent myocardial ischemia. *Mean 9 SE; **by Student’s t-test; ***by Chi-square test.
3. Results As the first step screening, maximal treadmill exercise test was carried out for 86 of the 140 patients studied. A positive exercise test was noted in 39 of 86 (45.3%) subjects, which was 27.9% of total subjects (Table 1). The remaining 54 (38.6%) were unable or not expected to achieve diagnostic levels of exercise during treadmill testing as a result of clearly non-cardiac limitations such as lower extremity arthritis, vascular disease, severe retinopathy, or as a result of factors such as easy fatigability or deconditioning which may have been at least partly cardiac in origin (Table 1). As the second step examination, dipyridamole thallium scintigraphy was carried out for 93 of 140 (66.4%) subjects, who exhibited a positive exercise test or could not perform a maximal exercise test. Abnormal perfusion pattern was noted in 39 of 93 (41.9%) subjects, which was 27.9% of total subjects, with fixed defects present in 15 (16.1%) and reversible abnormalities in 24 (25.8%) (Table 2). No serious cardiovascular side effects were observed. As a result of this diagnostic procedure, 39 of 140 (27.9%) were considered to have a silent myocardial ischemia. Their baseline characteristics are shown in Table 3. As defined there were no significant differences in sex, duration of diabetes, type of diabetes treatment, total cholesterol level, triglyceride level, hemoglobin A1C level, or prevalence of retinopathy, neuropathy, or hypertension between subjects with and without silent myocardial ischemia. Significant difference was found in only age and prevalence of proteinuria. The mean age was higher in the subjects with silent myocardial ischemia than in those without it (70.3 9 1.0 vs 67.5 9 0.6, respectively, PB0.05). The prevalence of silent myocardial ischemia is 1.7 times higher in subjects with proteinuria than in those without proteinuria (PB0.05). Diagnostic coronary angiography was offered to all subjects who were considered to have a silent myocardial ischemia. Eighteen subjects gave their consent for angiography. Studies of coronary angiography showed that 17 of 18 (94.4%) had a significant coronary artery narrowing with ten single-vessel disease, five double-vessel disease,
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
and two triple-vessel disease (Table 4). The 123 of 140 (87.9%) subjects were followed clinically for a mean period of 4.1 years. Two of 34 in subjects with silent myocardial ischemia and 7 of 89 in subjects without it died of a documented noncardiac cause (four malignancy, four cerebral infarction, one etiology unknown sudden death). Whereas a randomized and blinded approach to the follow-up management would be optimal, this investigative approach would be logistically difficult and ethically tenuous. In this study, the subjects with diagnosis of silent myocardial ischemia had intensive adjustments in antianginal medication (b blocker, nitrates, or calcium antagonists and anti-platelet agents) during follow-up. Whereas these risk modification might reduce cardiac events, the prevalence of cardiac events were still 5.2 times higher in the subjects with silent myocardial ischemia than those without it (17.6 vs 3.4%, respectively, P B 0.01) (Table 5). Cardiac events consisted of three angina pectoris and three pulmonary edema as a result of left ventricular failure in subjects with silent myocardial ischemia, and one angina pectoris, one pulmonary edema as a result of left Table 4 Results of coronary angiography in 18 subjects with diagnosis of silent myocardial ischemia Finding Negative Positive
1/18 (5.6%) 17/18 (94.4%)
Table 5 Cardiac events rates of 123 elderly NIDDM patients during 4.1-years follow upa SMI
(+)
(−)
No. of subjects
34
89
AMI Angina pectoris Pulmonary edema
0 3 3
1 1 1
Total cardiac events rate
6 (17.6%)
3 (3.4%)*
a SMI, silent myocardial ischemia; AMI, acute myocardial infarction. *PB0.01 analyzed by Chi-square test.
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ventricular failure, and one myocardial infarction in subjects without silent myocardial ischemia. There was no cardiac death in both groups.
4. Discussion The present study showed that elderly NIDDM patients (aged over 60 years) may have an extremely high prevalence of silent myocardial ischemia. In the present study, we used treadmill exercise test as the first step screening. A large number of elderly patients (38.6%) were unable or not expected to achieve diagnostic levels of exercise as a result of non-cardiac limitations such as lower extremity arthritis, vascular disease, severe retinopathy, or as a result of factors such as easy fatigability or deconditioning which may have been at least partly cardiac in origin. This evidence suggests that such elderly NIDDM patients need an alternative examination to detect silent myocardial ischemia. Positive test results were found in 45.3% of the subjects studied, which was 27.9% of total subjects. Naka et al. have reported that 7.0% of NIDDM patients studied could not perform maximal exercise testing and 31% exhibited positive results of exercise test [19], both of which are lower than those in the present study. It is likely that the discrepancy in results of exercise tests may be as a result of the difference in age composition. In other words, the present results of exercise test may represent the characteristics of elderly NIDDM patients. In the present study, 66.5% of total subjects was recommended to perform dipyridamole thallium scintigraphy as the second step examination. No serious cardiovascular side effects were observed and all the subjects completed the test. As a result, 41.9% of the subjects studied, which was 27.9% of total subjects, exhibited an abnormal pattern in dipyridamole thallium scintigraphy, who are considered to have a myocardial ischemia. Results of coronary angiographic study showed that 94.4% of the subjects with diagnosis of silent myocardial ischemia in fact had a significant coronary artery stenosis. We could not estimate the sensitivity and specificity of the present diagnostic procedure, because we did not perform coronary angiogra
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T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
phy in subjects with negative findings. Paillole etal. tested the efficacy of the non-invasive tests for diagnosis of CAD in diabetic patients [20]. This report showed the high negative predictive value (true negative/true negative+false negative) of 86% in the ECG exercise tests, although positive predictive value (true positive/true positive+ false positive) is low (50%). This evidence supports the use of the ECG exercise test as the first step screening in diabetic patients, because a negative maximal exercise tests is very likely to exclude the diagnosis of CAD in such a population. In addition, this test is cheaper and more widely available. They also showed that dipyridamole thallium scintigraphy display the best sensitivity (80%) and specificity (87%), with high positive predictive value (76%) and negative predictive value (89%). These data are in agreement with those reported for patients with CAD [24,25]. The combination of treadmill exercise test and dipyridamole thallium scintigraphy we used improved the positive predictive value to 94.4%. These evidences suggest the usefulness of this combination procedure we used as a screening for silent myocardial ischemia in elderly NIDDM patients. The estimated prevalence of silent myocardial ischemia is 26.3% (27.9 times 94.4%) in elderly NIDDM patients (aged over 60 years). This prevalence is approximately two times higher than the results of Naka et al.’s report (12.1%) [19]. The difference may be as a result of the difference in age composition, because the mean age of NIDDM patients of their report was 61 9 4 years. In contrast, there have been numerous reports regarding the prevalence of silent myocardial ischemia in non-diabetic population [6 – 14]. Fleg et al. reported the prevalence and prognosis of silent myocardial ischemia in 407 healthy asymptomatic volunteers evaluated by both treadmill exercise test and exercise-induced thallium scintigrapy [14]. Exercise-induced silent myocardial ischemia were present in 6% of all subjects studied (mean age of 60 years). This report also showed that the presence of exercise-induced silent myocardial ischemia increases progressively with age from 2% in the fifth and sixth decades to 15% in the ninth decade. This result is comparable with the present
result because of similar diagnostic procedure. Naka et al.’s report showed that an estimated prevalence of silent myocardial ischemia was 5.3% in Japanese nondiabetic control subjects (mean age of 60 years) [19]. Even considering age, the prevalence of silent myocardial ischemia is much higher in elderly NIDDM patients than that in non-diabetic population. Although the prevalence of silent myocardial ischemia was very high in elderly NIDDM patients, it may be still important to identify a subgroup of elderly patients at higher risk for silent myocardial ischemia. Recent study [26] showed that the presence of ST–T abnormalities at rest could identify a subgroup at higher risk for silent myocardial ischemia in middle-aged NIDDM patients. Another recent report suggested that the presence of microalbuminuria in NIDDM patients was associated with an increased prevalence of silent myocardial ischemia [27]. The present results from the univariate analysis of major risk factors showed that increasing age and proteinuria were significantly related to the presence of silent myocardial ischemia in elderly NIDDM patients. Patients with proteinuria had a higher prevalence (1.7 times) of silent myocardial than those without it. The mechanism of the link between silent myocardial ischemia and proteinuria or microalbuminuria is unknown. Although proteinuria or microalbuminuria is associated with hyperlipidemia and hypertension which are important risk factors for CAD, it is also a strong independent risk factor for CAD [28–30]. In the present study, there were no significant differences in total cholesterol level, triglyceride level or the prevalence of hypertension between patients with and without silent myocardial ischemia. Higher prevalence of silent myocardial ischemia in patients with proteinuria or microalbuminuria might reflect a higher prevalence of CAD in those patients. In contrast, many previous studies have suggested that silent myocardial ischemia in diabetic patients may be attributed to autonomic neuropathy [31,32]. However, the role of autonomic neuropathy is still controversial [5,33]. Ahluwalia et al. reported that the prevalence of silent myocardial ischemia is still higher in diabetic patients without autonomic neuropa
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
thy than in non-diabetic subjects [34]. In the present study, no significant association between autonomic neuropathy evaluated by CVR – R and silent myocardial ischemia was observed. Autonomic neuropathy might be not the key factor responsible for silent myocardial ischemia in elderly NIDDM patients, although it could be one of the reasons. Further studies may be needed to identify more efficiently a subgroup of elderly patients at higher risk for the presence of silent myocardial ischemia. As a result of 4.1-years follow up, the prevalence of cardiac events were 5.2 times higher in the subjects with silent myocardial ischemia than those without it (17.6 vs 3.4%, respectively), although the subjects with silent myocardial ischemia had intensive adjustments in antianginal medication (b blocker, nitrates, or calcium antagonists and antiplatelet agents) during follow up. Fleg et al. reported a strikingly high incidence of subsequent coronary events (48%) in asymptomatic volunteers with silent myocardial ischemia over a mean follow-up period of 4.6 years [14], which is much higher than that in the present study. The possible explanation in the lower prevalence of cardiac events in the present result is as follow; one is that silent myocardial ischemia in NIDDM patients has a better prognosis than in non-diabetic subjects; the other is that risk modification by medical treatments reduced cardiac events. Considering a poor prognosis of CAD in diabetic patients [6,35,36], the latter explanation is more likely. The early detection and intensive medical treatments may have reduced cardiac events. Further study of a randomized and blinded approach may be needed to clarify whether medical treatments could improve the prognosis of silent myocardial ischemia in NIDDM patients. In conclusion, elderly NIDDM patients have an extremely high prevalence (estimated 26.3%) of silent myocardial ischemia. Although noninvasive screening of asymptomatic diabetic patients for CAD is not justified because of the low probability of significant disease and financial implications, CAD is still the main cause of mortality of this group. The present study suggests that early and intensive detection of silent myocardial is-
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chemia may be needed as a part of routine care for elderly NIDDM patients. Acknowledgements This study was in part supported by Funds for Comprehensive Research on Aging and Health from the Ministry of Health and Welfare, Japan.
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High incidence of silent myocardial ischemia in elderly patients with non insulin-dependent diabetes mellitus T. Inoguchi a,*, T. Yamashita a, F. Umeda a, H. Mihara b, O. Nakagaki b, K. Takada b, T. Kawano b, H. Murao b, T. Doi b, H. Nawata a a
The Third Department of Internal Medicine, Faculty of Medicine, Kyusyu Uni6ersity, Higashi-ku, Maidashi 3 -1 -1 -6, Fukuoka 812 -8582, Japan b Di6ision of Cardiology, Saiseikai Fukuoka General Hospital, Fukuoka, Japan Received 25 January 1999; received in revised form 5 August 1999; accepted 11 August 1999
Abstract The present study was designed to reveal the incidence of silent myocardial ischemia in asymptomatic elderly non-insulin-dependent diabetic (NIDDM) patients (aged over 60 years). As a first step screening, maximal treadmill exercise test was performed. Of 140 patients studied, 54 (38.6%) were unable or not expected to achieve diagnostic levels of exercise during treadmill testing. A positive exercise test was noted in 39 of 86 (45.3%) subjects. As a second step examination, dipyridamole thallium scintigraphy was performed for 93 subjects who exhibited a positive exercise test and could not perform a maximal exercise test. Abnormal perfusion pattern was found in 39 of 93 (41.9%), who were finally considered to have a silent myocardial ischemia. Coronary angiography was performed in 18 subjects with diagnosis of silent myocardial ischemia, who gave their consent. Significant coronary artery stenosis was in fact found in 17 of 18 (94.4%) subjects studied, confirming a very high positive predictive value of this diagnostic procedure. In conclusion, elderly NIDDM patients (aged over 60 years) had an extremely high prevalence (estimated 26.3%) of silent myocardial ischemia. This evidence suggests that early and intensive detection may be needed as a part of routine care for this group. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Silent myocardial ischemia; Elderly NIDDM patients; Treadmill exercise test; Dipyridamole thallium scintigraphy; Coronary angiography
1. Introduction It is well known that diabetic patients are particularly prone to silent myocardial infarction [1 – 3]. Silent myocardial ischemia is also reported to * Corresponding author. Tel.: +81-92-642-5284; fax: +8192-642-5287.
be more prevalent in diabetic patients with known coronary artery disease (CAD) [4,5]. Despite being asymptomatic, silent myocardial ischemia may have a poor prognosis in diabetic population [6] as well as in non-diabetic population [6–14]. Early and intensive detection of silent myocardial ischemia might be needed as a part of routine care for diabetic population. First of all, it is essential
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to reveal the incidence of silent myocardial ischemia among asymptomatic diabetic patients who appear to be without CAD. Several previous studies have addressed this issue [15 – 19]. However, most of these studies used either exercise-induced ECG or thallium scintigraphy to evaluate silent myocardial ischemia. These results may be interpreted with caution, because of the lack of angiographic information. Naka et al. demonstrated the incidence of silent myocardial ischemia in non insulin-dependent diabetic (NIDDM) patients as judged by both treadmill exercise testing and coronary angiography [19]. They showed a high incidence (12.1%) of silent myocardial ischemia in NIDDM patients (mean age of 61 9 4 years). We speculated that elderly NIDDM patients might be an extremely high-risk group for silent myocardial ischemia, because silent myocar-
dial ischemia has been reported to increase progressively with age in nondiabetic asymptomatic population [14]. In the present study, we focused on the incidence of silent myocardial ischemia in elderly NIDDM patients (aged over 60 years). Early and intensive detection of silent myocardial ischemia could be targeted toward this high-risk group. Paillole et al. studied prospectively the efficacy of non-invasive tests used for diagnosis of CAD in diabetic patients, concluding that the exercise ECG test should be used as a first line examination because of its cheapness and availability, although dipyridamole thallium myocardial scintigraphy displayed the best sensitivity and specificity [20]. However, they also showed high incidence of false positive (50%) when judged by exercise test alone, in agreement with that reported for non-diabetic subjects [21–23]. As diagnostic procedure we used here a combination of treadmill exercise test (first step screening) and dipyridamole thallium scintigraphy (second step examination). In addition, we confirmed the efficacy of this diagnostic procedure for silent myocardial ischemia in elderly NIDDM patients by performing coronary angiography (Fig. 1).
2. Methods
2.1. Patients
Fig. 1. Diagnostic procedure of silent myocardial ischemia in elderly NIDDM patients. Treadmill exercise test was performed as a first step screening. For the patients who exhibited a positive exercise test and could not perform maximal exercise test (impaired performance of exercise), dipyridamole thallium scintigraphy was performed as the second step examination. The patients who exhibited an abnormal pattern in dipyridamole thallium scintigraphy were diagnosed to have silent myocardial ischemia. These patients were recommended to undergo coronary angiography.
Consecutive NIDDM patients, aged over 60 years, who received the exercise training program in the Saiseikai Fukuoka General Hospital between April 1993 and January 1994, were recruited for this study on the basis that they had no symptoms of CAD. We excluded patients with abnormal ECG at rest, history of angina pectoris, myocardial infarction, or coronary revascularization procedures. Patients with asthma were also excluded as this condition was a contra-indication for dipyridamole myocardial scintigraphy. One hundred and forty elderly patients aged 60 to 81 years (mean 68.19 0.5 years, male 79, female 61) were finally recruited for this study. Informed consent was obtained from all subjects before study. This study was performed in part of ‘Com-
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
prehensive Research on Aging and Health’ from the Ministry of Health and Welfare, Japan.
2.2. Diagnostic procedure Maximal treadmill exercise testing was carried out according to the Bruce protocol as the first step screening. Throughout the exercise testing the 12-lead ECG and blood pressure were monitored and recorded every minute. Exercise was continued until 90% or more of the predicted maximal heart rate for age was achieved. The exercise test was interrupted if there was an occurrence of dyspnea, fatigue, or multiple ventricular ectopic complexes. The test was terminated immediately when an ischemic ST segment response was detected. To increase the sensitivity of exercise testing and detect as many patients with silent myocardial ischemia as possible, we used less stringent criteria. Namely, the test was considered positive if there was an ST segment depression equal to or greater than 1 mm which was horizontal or downsloping at the J point, or ST segment depression equal to greater than 2 mm which was slowly upsloping 0.08 s after the J point. As the second step examination, dipyridamole thallium scintigraphy was performed for both patients exhibiting a positive treadmill exercise test and patients who could not perform a maximal exercise test. All medications being taken by the patients were continued except for theophylline. Dipyridamole testing was performed in the fasting state. Dipyridamole was infused intravenously at a rate of 0.56 mg/kg body weight for 4 min, followed by active leg swinging for 4 min. Then, thallium201 was injected, again followed by leg swinging for an additional 2 min. Early thallium imaging was initiated 5 min after injection using a small field-of-view gamma camera equipped with a low-energy, high-resolution, parallel-hole collimator. Stress and 4-h delayed images were obtained in the anterior, 45 left anterior oblique, and left lateral views. The images were analyzed on X-ray film and computer display by an experienced nuclear cardiologist who was unaware of the patients’ clinical histories. The myocardial thallium activity was divided into five segments per view. Each segment was graded as being
39
normal or having reversible or fixed thallium-201 defects. The subjects who exhibited an abnormal pattern in dipyridamole thallium scintigraphy were told that a strong suspicion of CAD existed, and diagnostic coronary angiography was recommended. Informed consent was again obtained from all those who later underwent coronary angiography. Standard coronary angiography was carried out with the Judkins technique, including selective engagement of the right and left coronary arteries and angulated views sufficient to completely display the coronary tree. Coronary angiograms were analyzed blindly by independent observers. Significant coronary artery stenosis was defined as at least 50% reduction in diameter of one or more major coronary arteries in at least two opposite views. Clinical data were obtained by a standardized clinical examination performed at Saiseikai Fukuoka General Hospital. Fundus examination was performed by an ophthalmologist. Neurological history was taken and a physical examination was performed focusing on the symptoms and signs of distal symmetric sensorimotor polyneuropathy and autonomic neuropathy. As for autonomic neuropathy examination, coefficient of variation for 100 consecutive R–R intervals on the ECG (CVR – R) in the resting supine position was measured as an index of autonomic neuropathy. Proteinuria was tested with strips (lower limit of 2.5–3.0 mg/dl). Hypertension was diagnosed according to the blood pressure level (systolic blood pressure ] 140 mmHg and/or diastolic blood pressure ]90 mmHg), the history of antihypertensive drug treatment, or both.
2.3. Statistical analysis Descriptive results of continuous variables are expressed as means9 SE. The Chi-square test was used for comparisons of proportions and the Mann–Whitney U-test was used for group comparisons because none of valuables were normally distributed. P values B 0.05 were considered significant.
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
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Table 1 Results of treadmill exercise tests in 140 elderly NIDDM patients without clinical symptoms of coronary artery disease Finding Impaired performance of exercise test Negative Positive
54/140 (38.6%) 47/140 (33.6%) 39/140 (27.9%)
Table 2 Results of dipyridamole thallium scintigraphy in 93 subjects who exhibited a positive exercise test and who could not perform maximal exercise test Finding Negative Positive
54/93 39/93 15/93 24/93
Persistent defect Reversible defect
(58.1%) (41.9%) (16.1%) (25.8%)
Table 3 Baseline characteristics of 140 elderly NIDDM subjectsa SMI No. of subjects Male/female Age (years) Duration (years) HbA1C (%) T-Cholesterol (mg/dl) Triglyceride (mg/dl)
(+)
(−)
39
101
P value
25/14 70.3 91.0* 9.0 90.9*
54/47 67.59 0.6* 10.691.0*
N.S. PB0.05** N.S.
8.0 90.3* 213 9 16*
7.99 0.2* 210 9 5*
N.S. N.S.
136 915*
1239 5*
N.S.
Type of treatment Diet only Drug Insulin
12 (30.8%) 21 (53.8%) 6 (15.4%)
45 (44.6%) 42(41.6%) 14 (13.9%)
N.S. N.S. N.S.
Hypertension Retinopathy Proteinuria Neuropathy
17 15 20 22
46 33 30 45
N.S. N.S. PB0.05*** N.S.
(43.6%) (38.5%) (51.3%) (56.0%)
(45.5%) (32.2%) (29.7%) (44.6%)
a SMI, silent myocardial ischemia. *Mean 9 SE; **by Student’s t-test; ***by Chi-square test.
3. Results As the first step screening, maximal treadmill exercise test was carried out for 86 of the 140 patients studied. A positive exercise test was noted in 39 of 86 (45.3%) subjects, which was 27.9% of total subjects (Table 1). The remaining 54 (38.6%) were unable or not expected to achieve diagnostic levels of exercise during treadmill testing as a result of clearly non-cardiac limitations such as lower extremity arthritis, vascular disease, severe retinopathy, or as a result of factors such as easy fatigability or deconditioning which may have been at least partly cardiac in origin (Table 1). As the second step examination, dipyridamole thallium scintigraphy was carried out for 93 of 140 (66.4%) subjects, who exhibited a positive exercise test or could not perform a maximal exercise test. Abnormal perfusion pattern was noted in 39 of 93 (41.9%) subjects, which was 27.9% of total subjects, with fixed defects present in 15 (16.1%) and reversible abnormalities in 24 (25.8%) (Table 2). No serious cardiovascular side effects were observed. As a result of this diagnostic procedure, 39 of 140 (27.9%) were considered to have a silent myocardial ischemia. Their baseline characteristics are shown in Table 3. As defined there were no significant differences in sex, duration of diabetes, type of diabetes treatment, total cholesterol level, triglyceride level, hemoglobin A1C level, or prevalence of retinopathy, neuropathy, or hypertension between subjects with and without silent myocardial ischemia. Significant difference was found in only age and prevalence of proteinuria. The mean age was higher in the subjects with silent myocardial ischemia than in those without it (70.3 9 1.0 vs 67.5 9 0.6, respectively, PB0.05). The prevalence of silent myocardial ischemia is 1.7 times higher in subjects with proteinuria than in those without proteinuria (PB0.05). Diagnostic coronary angiography was offered to all subjects who were considered to have a silent myocardial ischemia. Eighteen subjects gave their consent for angiography. Studies of coronary angiography showed that 17 of 18 (94.4%) had a significant coronary artery narrowing with ten single-vessel disease, five double-vessel disease,
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
and two triple-vessel disease (Table 4). The 123 of 140 (87.9%) subjects were followed clinically for a mean period of 4.1 years. Two of 34 in subjects with silent myocardial ischemia and 7 of 89 in subjects without it died of a documented noncardiac cause (four malignancy, four cerebral infarction, one etiology unknown sudden death). Whereas a randomized and blinded approach to the follow-up management would be optimal, this investigative approach would be logistically difficult and ethically tenuous. In this study, the subjects with diagnosis of silent myocardial ischemia had intensive adjustments in antianginal medication (b blocker, nitrates, or calcium antagonists and anti-platelet agents) during follow-up. Whereas these risk modification might reduce cardiac events, the prevalence of cardiac events were still 5.2 times higher in the subjects with silent myocardial ischemia than those without it (17.6 vs 3.4%, respectively, P B 0.01) (Table 5). Cardiac events consisted of three angina pectoris and three pulmonary edema as a result of left ventricular failure in subjects with silent myocardial ischemia, and one angina pectoris, one pulmonary edema as a result of left Table 4 Results of coronary angiography in 18 subjects with diagnosis of silent myocardial ischemia Finding Negative Positive
1/18 (5.6%) 17/18 (94.4%)
Table 5 Cardiac events rates of 123 elderly NIDDM patients during 4.1-years follow upa SMI
(+)
(−)
No. of subjects
34
89
AMI Angina pectoris Pulmonary edema
0 3 3
1 1 1
Total cardiac events rate
6 (17.6%)
3 (3.4%)*
a SMI, silent myocardial ischemia; AMI, acute myocardial infarction. *PB0.01 analyzed by Chi-square test.
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ventricular failure, and one myocardial infarction in subjects without silent myocardial ischemia. There was no cardiac death in both groups.
4. Discussion The present study showed that elderly NIDDM patients (aged over 60 years) may have an extremely high prevalence of silent myocardial ischemia. In the present study, we used treadmill exercise test as the first step screening. A large number of elderly patients (38.6%) were unable or not expected to achieve diagnostic levels of exercise as a result of non-cardiac limitations such as lower extremity arthritis, vascular disease, severe retinopathy, or as a result of factors such as easy fatigability or deconditioning which may have been at least partly cardiac in origin. This evidence suggests that such elderly NIDDM patients need an alternative examination to detect silent myocardial ischemia. Positive test results were found in 45.3% of the subjects studied, which was 27.9% of total subjects. Naka et al. have reported that 7.0% of NIDDM patients studied could not perform maximal exercise testing and 31% exhibited positive results of exercise test [19], both of which are lower than those in the present study. It is likely that the discrepancy in results of exercise tests may be as a result of the difference in age composition. In other words, the present results of exercise test may represent the characteristics of elderly NIDDM patients. In the present study, 66.5% of total subjects was recommended to perform dipyridamole thallium scintigraphy as the second step examination. No serious cardiovascular side effects were observed and all the subjects completed the test. As a result, 41.9% of the subjects studied, which was 27.9% of total subjects, exhibited an abnormal pattern in dipyridamole thallium scintigraphy, who are considered to have a myocardial ischemia. Results of coronary angiographic study showed that 94.4% of the subjects with diagnosis of silent myocardial ischemia in fact had a significant coronary artery stenosis. We could not estimate the sensitivity and specificity of the present diagnostic procedure, because we did not perform coronary angiogra
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phy in subjects with negative findings. Paillole etal. tested the efficacy of the non-invasive tests for diagnosis of CAD in diabetic patients [20]. This report showed the high negative predictive value (true negative/true negative+false negative) of 86% in the ECG exercise tests, although positive predictive value (true positive/true positive+ false positive) is low (50%). This evidence supports the use of the ECG exercise test as the first step screening in diabetic patients, because a negative maximal exercise tests is very likely to exclude the diagnosis of CAD in such a population. In addition, this test is cheaper and more widely available. They also showed that dipyridamole thallium scintigraphy display the best sensitivity (80%) and specificity (87%), with high positive predictive value (76%) and negative predictive value (89%). These data are in agreement with those reported for patients with CAD [24,25]. The combination of treadmill exercise test and dipyridamole thallium scintigraphy we used improved the positive predictive value to 94.4%. These evidences suggest the usefulness of this combination procedure we used as a screening for silent myocardial ischemia in elderly NIDDM patients. The estimated prevalence of silent myocardial ischemia is 26.3% (27.9 times 94.4%) in elderly NIDDM patients (aged over 60 years). This prevalence is approximately two times higher than the results of Naka et al.’s report (12.1%) [19]. The difference may be as a result of the difference in age composition, because the mean age of NIDDM patients of their report was 61 9 4 years. In contrast, there have been numerous reports regarding the prevalence of silent myocardial ischemia in non-diabetic population [6 – 14]. Fleg et al. reported the prevalence and prognosis of silent myocardial ischemia in 407 healthy asymptomatic volunteers evaluated by both treadmill exercise test and exercise-induced thallium scintigrapy [14]. Exercise-induced silent myocardial ischemia were present in 6% of all subjects studied (mean age of 60 years). This report also showed that the presence of exercise-induced silent myocardial ischemia increases progressively with age from 2% in the fifth and sixth decades to 15% in the ninth decade. This result is comparable with the present
result because of similar diagnostic procedure. Naka et al.’s report showed that an estimated prevalence of silent myocardial ischemia was 5.3% in Japanese nondiabetic control subjects (mean age of 60 years) [19]. Even considering age, the prevalence of silent myocardial ischemia is much higher in elderly NIDDM patients than that in non-diabetic population. Although the prevalence of silent myocardial ischemia was very high in elderly NIDDM patients, it may be still important to identify a subgroup of elderly patients at higher risk for silent myocardial ischemia. Recent study [26] showed that the presence of ST–T abnormalities at rest could identify a subgroup at higher risk for silent myocardial ischemia in middle-aged NIDDM patients. Another recent report suggested that the presence of microalbuminuria in NIDDM patients was associated with an increased prevalence of silent myocardial ischemia [27]. The present results from the univariate analysis of major risk factors showed that increasing age and proteinuria were significantly related to the presence of silent myocardial ischemia in elderly NIDDM patients. Patients with proteinuria had a higher prevalence (1.7 times) of silent myocardial than those without it. The mechanism of the link between silent myocardial ischemia and proteinuria or microalbuminuria is unknown. Although proteinuria or microalbuminuria is associated with hyperlipidemia and hypertension which are important risk factors for CAD, it is also a strong independent risk factor for CAD [28–30]. In the present study, there were no significant differences in total cholesterol level, triglyceride level or the prevalence of hypertension between patients with and without silent myocardial ischemia. Higher prevalence of silent myocardial ischemia in patients with proteinuria or microalbuminuria might reflect a higher prevalence of CAD in those patients. In contrast, many previous studies have suggested that silent myocardial ischemia in diabetic patients may be attributed to autonomic neuropathy [31,32]. However, the role of autonomic neuropathy is still controversial [5,33]. Ahluwalia et al. reported that the prevalence of silent myocardial ischemia is still higher in diabetic patients without autonomic neuropa
T. Inoguchi et al. / Diabetes Research and Clinical Practice 47 (2000) 37–44
thy than in non-diabetic subjects [34]. In the present study, no significant association between autonomic neuropathy evaluated by CVR – R and silent myocardial ischemia was observed. Autonomic neuropathy might be not the key factor responsible for silent myocardial ischemia in elderly NIDDM patients, although it could be one of the reasons. Further studies may be needed to identify more efficiently a subgroup of elderly patients at higher risk for the presence of silent myocardial ischemia. As a result of 4.1-years follow up, the prevalence of cardiac events were 5.2 times higher in the subjects with silent myocardial ischemia than those without it (17.6 vs 3.4%, respectively), although the subjects with silent myocardial ischemia had intensive adjustments in antianginal medication (b blocker, nitrates, or calcium antagonists and antiplatelet agents) during follow up. Fleg et al. reported a strikingly high incidence of subsequent coronary events (48%) in asymptomatic volunteers with silent myocardial ischemia over a mean follow-up period of 4.6 years [14], which is much higher than that in the present study. The possible explanation in the lower prevalence of cardiac events in the present result is as follow; one is that silent myocardial ischemia in NIDDM patients has a better prognosis than in non-diabetic subjects; the other is that risk modification by medical treatments reduced cardiac events. Considering a poor prognosis of CAD in diabetic patients [6,35,36], the latter explanation is more likely. The early detection and intensive medical treatments may have reduced cardiac events. Further study of a randomized and blinded approach may be needed to clarify whether medical treatments could improve the prognosis of silent myocardial ischemia in NIDDM patients. In conclusion, elderly NIDDM patients have an extremely high prevalence (estimated 26.3%) of silent myocardial ischemia. Although noninvasive screening of asymptomatic diabetic patients for CAD is not justified because of the low probability of significant disease and financial implications, CAD is still the main cause of mortality of this group. The present study suggests that early and intensive detection of silent myocardial is-
43
chemia may be needed as a part of routine care for elderly NIDDM patients. Acknowledgements This study was in part supported by Funds for Comprehensive Research on Aging and Health from the Ministry of Health and Welfare, Japan.
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