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Silent myocardial ischemia in diabetics with normal autonomic function
International Journal of Cardiology 48 (1995) 147- 153
ELSEVIER
Silent myocardial ischemia in diabetics with normal autonomic function G. Ahluwalia, P. Jain, S.K. Chugh, H.S. Wasir, U. Kaul* Department of Cardiology, All India Institute of Medical Sciences, New Delhi-110029, India
Received 10 August 1994;accepted 31 October 1994
Abstract Twenty male diabetic patients (age range, 40-60 years) with normal autonomic function were studied to determine the prevalence of silent myocardial ischemia on exercise as well as ambulatory electrocardiography. The presenceand extent of silent myocardial &hernia was also correlated with the severity of atherosclerotic coronary artery disease as determined by coronary angiography. A cohort of 20 matched non-diabetic patients were also included in the study. Silent myocardial ischemia was detected in 50% of the diabetic patients on exercise electrocardiography and in 35% on ambulatory electrocardiography compared with 10%and 5% in non-diabetics by the two methods, respectively (P < 0.01 and P < 0.05, respectively). On exercise testing in diabetic patients, silent myocardial ischemia was detected in 64% of the patients with three-vesseldisease,50% of the patients with two-vessel diseaseand 20% of the patients with one-vesseldiseasewhereas in non-diabetic patients silent myocardial ischemia was detected in only 18% of the patients with three-vesseldisease(P < 0.05) and in none of the patients with two- or one-vesseldisease.On ambulatory electrocardiography, only patients (both diabetic and non-diabetic) with three-vesseldiseasemanifested silent myocardial &hernia. Total ischemic burden was similar in both the diabetic and non-diabetic patients. We conclude that silent myocardial ischemia occurs in diabetic patients with coronary artery diseasemore frequently even in the absenceof autonomic dysfunction and the prevalence of silent myocardial ischemia is higher in patients with severedegreeof coronary artery disease. Keywords:
Silent &hernia; Diabetes mellitus
1. Introduction Silent myocardial ischemia is a known predictor
of cardiac events [ 1,2]. Although silent myocardial ischernia has been demonstrated in all categories
of patients with coronary artery disease,patients * Corresponding author.
with diabetesmellitus are known to be more prone to silent myocardial &hernia [3,4]. Diabetic autonomic neuropathy involving the cardiac afferent sympathetic system has been postulated as the causeof silent myocardial ischemia in diabetics by some workers [5,6], whereas other workers have disagreed with this observation [7,8]. Although exercise electrocardiography is a well-
0167-5273/95/%09.500 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(94)02233-Z
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acceptedmethod of evaluation of silent myocardial ischemia [9,10], it does not quantify the extent of silent myocardial ischemia during daily activities. In the present prospective study, we studied patients with diabetes mellitus without any clinical evidence of autonomic neuropathy to determine the prevalence of silent myocardial ischemia on exercise as well as on ambulatory electrocardiography. All diabetic patients and the matched nondiabetic patient population had atherosclerotic coronary artery diseasedocumented by coronary angiography. We have also correlated the presence and extent of silent myocardial ischemia with the severity of atherosclerotic coronary artery disease as determined by coronary angiography. 2. Patients and methods 2.1. Patients
During the period October 1991 to January 1993, 20 consecutive male diabetic [ 1l] patients (agerange, 40-60 years) who had undergone coronary angiography were included for this study. A cohort of 20 matched non-diabetic patients who had symptomatic coronary artery diseaseand had undergone coronary angiography were included in the study. All patients were subjected to a detailed history and physical examination. Hypertension was diagnosed according to the WHO definition of blood pressure (121. Routine laboratory evaluation included hemoglobin, blood sugar (fasting and postprandial), renal function tests, lipid profile, chest X-ray and standard 12-lead electrocardiogram. The diabetic and non-diabetic patients were matched for age,lipid profile, hypertension, smoking, family history and angiographic profile of coronary artery disease. Patients who were females, or who had abnormal autonomic function tests, ECG abnormalities (bundle branch block, atria1 fibrillation or ST segment abnormalities), previous myocardial infarction, unstable angina, inability to do exercisetest or digitalis intake were excluded from the study.
Journal of Cardiology 4R 1199.5) 147-153
2.2. Methods Autonomic function tests
Five bedside manoeuvres reported previously [5,13,14] were performed. (1) Bloodpressure response to standing. The difference in systolic blood pressure was measured with the patient supine and then immediately after the assumption of upright posture. (2) Blood pressure response to sustained handgrip. The difference in diastolic blood pressure
was measuredafter the patient was asked to maintain a handgrip of sphygmomanometer cuff at 50 mm inflation for 3 min. (3) Heart rate response to standing. The ratio of the longest RR interval (usually around the 30th beat) to the shortest RR interval (usually around the 15th beat) was calculated after the patient moved quickly from a supine to upright posture. (4) Heart rate response to Valsalva manoeuvre.
The patient was asked to blow into a mouthpiece connected to a blood pressure sphygmomanometer at a pressureof 40 mmHg for 15 s. The ratio of the longest RR interval after the manoeuvre to the shortest RR interval during the manoeuvre was measured. (5) Heart rate variation during deep breathing.
The patient was asked to breathe deeply at six breaths/min. The mean difference during 3 successive breathing cycles between maximal and minimal heart rates was measured. Medications which could interfere with the assessmentof autonomic function such as beta blockers or diuretics were withheld 48 h before these tests. Normal values of cardiovascular autonomic function testswere defined as [5,13,14]: decreasein systolic blood pressure on standing, 5 10 mmHg; increase in diastolic blood pressure response on sustained hand grip, 2 16 mmHg; heart rate response ratio on standing (30:15 ratio), 2 1.04; Valsalva ratio, L 1.21; and heart rate variation during deep breathing, L 15 beats/min. Based on previous studies [5,13,14] only patients with all five normal autonomic function tests were included in the study.
G. Ahluwalia et al. /International
Journal of Cardiology
Exercise electrocardiography
A symptom limited exercise test using the Bruce protocol [ 151was performed in all patients using a Marquette case 15 system. All cardioactive medications (calcium channel blockers, beta blockers and long acting nitrates) were stopped 24 h before the test. Heart rate and electrocardiogram were monitored continuously. Significant ST segment depression on exercise testing was defined as 11 mm of horizontal or downsloping ST segment depression measured80 ms after the J point and present on > 1 lead. Silent ischemia was defined as significant ST segmentchangeswithout any symptoms irrespective of the heart rate achieved.
48 (1995)
147-153
149
Table 1 Baseline characteristics of diabetic and non-diabetic patientsa
No. of patients Age (years) Cholesterol (mg/dl) LDL (mgdl) Smoking (%) Family history of CAD (%) Hypertension (%) Angina NYHA Class II NYHA Class III
Diabetics
Non-diabetics
20 47.5 f 11.9b 226 f 16b 145 l lib 10 (50%) 2 (10%)
20 50.80 f 5.gb 221 f 13h 144 f 12b 11 (55%) 2 (10%)
10 (50%)
11 (55%)
12 (60%) 8 (40%)
11 (55%) 9 (45%)
aP value not significant.
bMean f SD.
Ambulatory electrocardiography
(Holter)
All patients underwent at least one 24-h electrocardiographic monitoring on a 2-channel (leads V, and Vs) AM monitor (Marquette series 8000 laser Holter system). All the cardioactive drugs were stopped 24 h before the test. The cassettes were analysed for silent myocardial ischemia and total ischemic burden. A significant episode of ST segmentdepression was defined as 11 mm of horizontal or downsloping ST segment depression occurring 80 ms after the J point, lasting 2 1 min and separated from other episodes by 2 1 min.
Statistical analysis
All values are presented as mean f S.D. Differencesbetweenmeanswere assessedfor significance by the t-test, w.r.s. test and x2-test or in case of low observedfrequencies, Fisher’s exact test where appropriate. Statistical significance was set at a P value c 0.05.
3.Redts The baseline characteristics of the diabetic and non-diabetic patients are summarised in Table 1.
Coronary angiography
Coronary angiography was performed with the Judkins technique with selective engagement of right and left coronary arteries and angulated views to completely display the coronary tree. Significant coronary stenosis was defined as at least 70% reduction in diameter of one or more major coronary arteries in at least 2 opposite views. Lesions in the following vesselswere considered onevessel lesions: left anterior descending artery and its diagonal branches, circumflex artery and its marginal branches, right coronary artery and its branches especially posterior descending artery. Depending on the involvement of the coronary arteries, the patients were divided into three groups: one-vesseldisease,two-vessel disease,and three-vesseldisease.Left ventricular ejection fraction was calculated using the area-length method.
Table 2 Autonomic function test values= Diabetics Decreasein systolic blood pressure on standing (mmHg) Increase in diastolic blood pressure on sustained hand grip (nmW9 Heart rate response ratio on standing (30:15 Ratio) Valsalva ratio Heart rate variation during deep breathing (beats/mm)
Non-diabetics
6-8
6-8
18-20
18-22
aValues expressedin range.
1.06- 1.08
1.06- 1.07
1.23-1.26 17-19
1.23-1.25 17-19
150
G. Ahluwalia et al. /International
Table 3 Exercise electrocardiography and silent myocardial &hernia Severity of disease Three-vessel Two-vessel One-vessel Total
Silent myocardial ischemia Diabetics
P value
Non-diabetics
7111(64%) 214(50%) l/5 (20%)
2/11 (18%) o/5 (0%) 014(0%)
< 0.05 >0.05 >0.05
10120(50%)
2/20 ( 10%)
All patients were symptomatic with angina. All the patients had normal autonomic function tests (Table 2). The mean duration of diabetes was 5.4 f 2.3 years and all diabetics were on oral hypoglycemic agents. Out of the 20 diabetic patients, 11 (55%), 4 (20%) and 5 (25%) patients had three-, two- and one-vessel coronary artery disease, respectively and amongst the 20 nondiabetic patients, 11 (550/o),5 (25%) and 4 (20%) patients had three-, two- and one-vesselcoronary artery disease, respectively. The left ventricular ejection fraction was comparable for both groups (62 f 8% for diabetics and 64 f 7% for nondiabetics).
Table 4 Exercise electrocardiography parameters in diabetics and nondiabetic@
Duration of exercise (mm and s) Peak double product (x 1OOOmmHg beats/mm) Recovery time of ischemic ST segment depression (tin) Maximum ST segment depression (mm) Maximum heart rate (beats/min) ‘P value NS.
Diabetics (n = 20)
Non-diabetics (n = 20)
4’56” + 1’24”
4’28” f 1’20”
25.4 * 4.4
21.2 f 2.4
6.4 zt 2.5
6.6 f 2.0
Journal of Cardiology 48 (1995) 147-153
3.1. Exercise electrocardiography
Exercise electrocardiography exhibited silent myocardial ischemia in 10 (50%) of the 20 diabetic patients as compared with 2 (10%) of the 20 nondiabetic patients (P < 0.01) (Table 3). On exercise testing, 64% of the diabetic patients with threevessel disease had silent myocardial ischemia as compared with only 18% in the non-diabetic pa-, tients with similar disease(P <0.05) (Table 3). Silent myocardial ischemia exhibited in diabetic patients with two-vessel disease was 50% and in patients with one-vesseldiseasewas 20%. None of the non-diabetic patients with two- or one-vessel diseasehad silent myocardial ischemia. There was no significant difference observed in the duration of exercise performed, peak double product achieved,magnitude of ST segmentdepression, recovery time of ischemic ST segment depression and the peak heart rate achieved between the two groups (Table 4). 3.2. Ambulatory monitoring
152 zt 10
Table 5 Ambulatory ischemia
electrocardiography
and silent myocardial
Silent myocardial ischemia
P value
Diabetics
Non-diabetics
Three-vessel Two-vessel One-vessel
7/11 (64%) o/4 (0%) 015(0%)
1111(9%) o/5 (0%) o/4 (0%)
<0.015
Total
7120(35%)
l/20 (5%)
< 0.025
2.5 f 0.5 156 f 11
electrocardiographic
Holter monitoring revealed silent myocardial ischemia in 7 (35%) of the 20 diabetic patients as compared with 1 (5%) of the 20 non-diabetic patients (P < 0.025) (Table 5). In both diabetic and non-diabetic patients, only patients with threevessel disease manifested silent myocardial ischemiawhereasnone of the patients with two- or one-vessel disease exhibited silent myocardial ischemia (Table 5). There was no significant difference between the maximum ischemic ST segment
Severity of disease 2.5 A 0.5
(Holter)
G. Ahluwalia et al. /International
Journal of Cardiology 48 (1995) 147-153
Table 6 Ambulatory electrocardiographic parameters in diabetics and non-diabeticsa Diabetics (n = 20) No. of episodes of silent myocardial &hernia/patient (range) Maximum ischemic ST segment depression (mm) Duration of maximum ST segment depression (mm) Minimum heart rate associatedwith ischemia (beats/mm) Maximum heart rate associated with ischemia (beats/mitt) Total ischemic burden (mitt/24 h)
l-7
Non-diabetics (n = 20) 4
2.6 zt 1.11
2.8
7.8 * 4.5
6
79 f 9
87 f 2
115 f 15
105 * 12
42.2 f 38.4
27.1 f 23.2
aP value not significant.
depression, duration of ST segment depression, maximum or minimum heart rates and the total ischemic burden between the two groups (Table 6). 4. Discussion The principal findings of this study are: (1) (2) (3)
significant silent myocardial ischemia was detected in diabetic patients with normal autonomic function, patients with severe coronary artery disease had a greater incidence of silent myocardial ischemia, and total ischemic burden was similar in both diabetic and non-diabetic patients.
To the best of our knowledge, there are no studies comparing diabetic patients with normal autonomic function with non-diabetic matched
1.51
patients to assessthe magnitude of silent myocardial ischemia and total ischemic burden. We have used ambulatory electrocardiography in addition to exercise electrocardiography since the latter does not quantify the extent of silent myocardial ischemia during daily activities. We have also done coronary angiography in all the patients to document the presenceand severity of coronary artery disease. Previous studies [5-81 have revealed conflicting results regarding the presence of autonomic neuropathy and its influence on silent myocardial &hernia in diabetics, hence we selected diabetic patients with normal autonomic function. In our study the prevalence of silent myocardial &hernia in diabetics on ambulatory electrocardiography was 35%, which is in agreementwith other studies [5,6]. However, these studies correlated the presenceof silent myocardial &hernia with autonomic neuropathy and the severity and extent of coronary artery diseasewas not assessedby coronary angiography. In our study, in spite of the similar coronary angiographic profile, the diabetic patients had 7 times higher prevalence of silent myocardial &hernia than non-diabetic patients on ambulatory electrocardiography (P < 0.025). This finding was independent of the presence of autonomic dysfunction in our diabetic patients. It is interesting to note that in both diabetics and non-diabetics, silent myocardial ischemia was present only in patients with three-vessel disease on ambulatory electrocardiography. This observation has not been highlighted in any of the previous studies on this subject. The study also shows that the total ischemic burden is similar in both diabetics and non-diabetics. Only the proportion of silent and symptomatic ischemia is different in diabetic and non-diabetic patients. The reasons are quite obvious as the pathophysiologic mechanisms are the same in both symptomatic and silent myocardial ischemia. Silent myocardial &hernia on exercise electrocardiography occurs frequently in patients with known coronary artery diseaseranging from 17% to 45% as shown by previous studies [ 16- 181.Our results are in agreement with these studies as we have observed this phenomenon in 50% of the diabetic and 10% of the non-diabetic patients. In
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Journal of Cardiology
our study, diabetics had a 5 times higher prevalence of exercise induced silent myocardial ischemia than non-diabetics had. This is higher than the data shown by a previous study [19] where silent myocardial ischemia was 2.2 times more frequent in diabetics but the patients in this study were not classified on the basis of severity of angiographically documented coronary artery disease,thereby making further comparison with our data difficult. The present study also shows that both diabetic and non-diabetic patients with three-vesseldisease had a higher prevalence of exercise induced silent myocardial ischemia. Diabetic patients with threevesseldiseasewere 3.5 times more likely to have silent myocardial &hernia than their non-diabetic counterparts. Our results do not concur with the observation of other investigators [20,21] who concluded that there was no difference in the severity of coronary pathology and prevalence of silent myocardial ischemia. However, in all these studies, the authors examined a heterogenous population of patients with and without previous myocardial infarction and it is obvious that the extent and severity of coronary artery disease might be different in these two patient populations. Analysis of our results revealed that whereas on exercise test, diabetics with two- and one-vessel disease exhibited silent myocardial ischemia, on ambulatory electrocardiography only diabetics with three-vessel disease exhibited silent myocardial &hernia. This observation suggests that diabetics with lesser severity of coronary artery diseasehave a higher prevalence of silent myocardial ischemia on exercise than they have during normal activities. This is possibly due to the fact that during routine activities the level of work load is not comparable with that achieved on exercise testing. Also during ambulatory electrocardiography all 12 leads are not monitored, as is done during exercise electrocardiography; the ischemic electrocardiographic changesmay be underassessed, especially those of the inferior wall. The key question of silent myocardial ischemia as to why it is silent remains unclear. Many explanations have been postulated [22-241. These include low intensity of nociceptive impulse afferent rate, opioid modulation, neurocar-
48 (1995)
147-153
diovascular interactions, etc. The presence of autonomic neuropathy has been incriminated by few workers [5,6] whereas others have disagreed with this observation [7,8]. Our study reveals significant silent myocardial ischemia in diabetic patients without autonomic neuropathy, therefore autonomic neuropathy is not the key culprit for silent myocardial ischemia. The results of our study have important clinical relevance. Ambulatory monitoring, which can be extrapolated to an individual’s normal daily activities reveals that both diabetic and nondiabetic patients with severe coronary artery disease manifest silent myocardial ischemia. On exercise testing the diabetic patients are far more prone to silent myocardial ischemia which is not limited by the extent of coronary artery diseaseas compared with their non-diabetic counterparts. This observation has important prognostic and therapeutic implications. 5. Conclusions Silent myocardial &hernia is more prevalent in patients with diabetes mellitus even in the absence of autonomic dysfunction as compared with their non-diabetic counterparts with a similar severity of underlying coronary artery disease.During normal routine activities silent myocardial &hernia as detected by ambulatory monitoring was observed only in patients (both diabetic and non-diabetic) with three-vessel disease. However, exercise electrocardiography detected silent myocardial ischemia even in diabetic patients with two- and one-vesseldisease,in contrast to non-diabetic patients where silent myocardial ischemia was demonstrated only in patients with three-vessel disease. Total ischemic burden in diabetic and non-diabetic patients was similar in the matched patient population. References [I] Cohn PF. Prognosis for patients with different types of silent CAD. Circulation. 1987;5: 33-35. [2] Kaul U, Dev V, Manchanda SC, Wasir HS. Silent myocardial ischemia after percutaneous transluminal coronary angioplasty and its prognostic significance. Clin Cardiol 1991; 14: 563-566.
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[3] Abenavoli T, Rubler S, Fisher V. Exercise testing with myocardial scintigraphy in asymptomatic diabetic males. Circulation 1981; 63: 54-64. [4] Solar N, Bernett M, Malius J. Myocardial infarction in diabetes. Q J Med 1975;44: 125- 132. [S] Sullivan J, Conroy R, MacDonald K. Silent ischemia in diabetic men with autonomic neuropathy. Br Heart J 1991;66: 313-31s. [6] Langer A, Weeman R, Josse R, Stener G; Detection of SMI in diabetes. Am J Cardiol 1991;67: 1073-1078. [7] Hume L, Ward J, Oakley G. Asymtomatic myocardial ischemia in diabetes and its relationship to diabetic neuropathy: an exercise electrocardiography study in middle aged diabetic men. Diabetes Care 1986; 9:
II51 Bruce RA. Exercise testing of patients with coronary
384-388. [8] Nesto R, Phillips R, Kett K, Hill T. Angina and exer-
&hernia in patients with diabetes mellitus as judged by treadmill exercise test and coronary angiography. Am Heart J 1992. 123:46-53. 1201 Weiner DA, Ryan TJ, McCabe C et al. Significance of silent myocardial &hernia during exercise testing in patients with coronary artery disease.Am J Cardiol 1987;
tional myocardial &hernia in diabetic and non-diabetic patients - assessmentby exercise scintigraphy. Ann Intern Med 1988; 108: 170-175. [9] Assey M, Walter G, Carabello B. Incidence of acute myocardial infarction in patients with exercise induced silent myocardial ischemia. Am J Cardiol 1987; 59: 497-500.
[IO] Deligonul V, Chaitman BR. Prognostic significance of silent myocardial ischemia detected by early TMT. Am J Cardiol 1989;64: 1-5. [I I] WHO Expert Committee on diabetes melhtus, Second report, Technical report series, no. 646. Geneva: WHO, 1980. [12] WHO Expert Committe on arterial hypertension, Tech-
nical report series, no. 678. Geneva: WHO, 1978. [13] Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests; 10year experience in diabetes. Diabetes Care 1985;8: 491-498. [14] Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J 1982; 285: 916-919.
heart disease.Ann Clin Res 1971; 3: 323-332. 1161 Lindsey HE, Cohn PF. Silent myocardial &hernia dur-
ing and after exercise testing in patients with coronary artery disease.Am Heart J 1978; 75: 441-447. 1171 Weiner DA, McCabe C, Hueter DC, Ryan TJ, Hood WB. The predictive value of angina1chest pain as an indicator of coronary disease during exercise testing. Am Heart J 1978;96: 458-462. 1181 Falcone C, De Servi S, Puma E et al. Clinical significance of exerciseinduced silent myocardial ischemia in patients with coronary artery disease.J Am Co11Cardiol 1987:9: 295-299. 1191 Naka M, Aizawa T, Momose A et al. Silent myocardial
59: 725-729. 1211 Ouyang P, Shapiro EP, Chibber Chandra N, Gottlieb
SH, Chew PH, Gottlieb SD. An angiographic and functional comparison of patients with silent and symptomatic treadmill ischemia early after myocardial infarction. Am J Cardiol 1987; 59: 730-734. 1221 Malliani A. Significance of experimental models m assessinglink between myocardial ischemia and pain. Adv Cardiol 1990; 1: 126-141. 1231 Droste C, Greenlee M. Effect of physical exerciseon pant thresholds and plasma beta-endorphin levels in patients with SMI. Eur Heart J, 1988;9: 25-33. 1241 ShepsDS, William M. Mechanismsof pain perception in patients with SMI. Am Heart J 1990; 199: 983-987.
ELSEVIER
Silent myocardial ischemia in diabetics with normal autonomic function G. Ahluwalia, P. Jain, S.K. Chugh, H.S. Wasir, U. Kaul* Department of Cardiology, All India Institute of Medical Sciences, New Delhi-110029, India
Received 10 August 1994;accepted 31 October 1994
Abstract Twenty male diabetic patients (age range, 40-60 years) with normal autonomic function were studied to determine the prevalence of silent myocardial ischemia on exercise as well as ambulatory electrocardiography. The presenceand extent of silent myocardial &hernia was also correlated with the severity of atherosclerotic coronary artery disease as determined by coronary angiography. A cohort of 20 matched non-diabetic patients were also included in the study. Silent myocardial ischemia was detected in 50% of the diabetic patients on exercise electrocardiography and in 35% on ambulatory electrocardiography compared with 10%and 5% in non-diabetics by the two methods, respectively (P < 0.01 and P < 0.05, respectively). On exercise testing in diabetic patients, silent myocardial ischemia was detected in 64% of the patients with three-vesseldisease,50% of the patients with two-vessel diseaseand 20% of the patients with one-vesseldiseasewhereas in non-diabetic patients silent myocardial ischemia was detected in only 18% of the patients with three-vesseldisease(P < 0.05) and in none of the patients with two- or one-vesseldisease.On ambulatory electrocardiography, only patients (both diabetic and non-diabetic) with three-vesseldiseasemanifested silent myocardial &hernia. Total ischemic burden was similar in both the diabetic and non-diabetic patients. We conclude that silent myocardial ischemia occurs in diabetic patients with coronary artery diseasemore frequently even in the absenceof autonomic dysfunction and the prevalence of silent myocardial ischemia is higher in patients with severedegreeof coronary artery disease. Keywords:
Silent &hernia; Diabetes mellitus
1. Introduction Silent myocardial ischemia is a known predictor
of cardiac events [ 1,2]. Although silent myocardial ischernia has been demonstrated in all categories
of patients with coronary artery disease,patients * Corresponding author.
with diabetesmellitus are known to be more prone to silent myocardial &hernia [3,4]. Diabetic autonomic neuropathy involving the cardiac afferent sympathetic system has been postulated as the causeof silent myocardial ischemia in diabetics by some workers [5,6], whereas other workers have disagreed with this observation [7,8]. Although exercise electrocardiography is a well-
0167-5273/95/%09.500 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-5273(94)02233-Z
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acceptedmethod of evaluation of silent myocardial ischemia [9,10], it does not quantify the extent of silent myocardial ischemia during daily activities. In the present prospective study, we studied patients with diabetes mellitus without any clinical evidence of autonomic neuropathy to determine the prevalence of silent myocardial ischemia on exercise as well as on ambulatory electrocardiography. All diabetic patients and the matched nondiabetic patient population had atherosclerotic coronary artery diseasedocumented by coronary angiography. We have also correlated the presence and extent of silent myocardial ischemia with the severity of atherosclerotic coronary artery disease as determined by coronary angiography. 2. Patients and methods 2.1. Patients
During the period October 1991 to January 1993, 20 consecutive male diabetic [ 1l] patients (agerange, 40-60 years) who had undergone coronary angiography were included for this study. A cohort of 20 matched non-diabetic patients who had symptomatic coronary artery diseaseand had undergone coronary angiography were included in the study. All patients were subjected to a detailed history and physical examination. Hypertension was diagnosed according to the WHO definition of blood pressure (121. Routine laboratory evaluation included hemoglobin, blood sugar (fasting and postprandial), renal function tests, lipid profile, chest X-ray and standard 12-lead electrocardiogram. The diabetic and non-diabetic patients were matched for age,lipid profile, hypertension, smoking, family history and angiographic profile of coronary artery disease. Patients who were females, or who had abnormal autonomic function tests, ECG abnormalities (bundle branch block, atria1 fibrillation or ST segment abnormalities), previous myocardial infarction, unstable angina, inability to do exercisetest or digitalis intake were excluded from the study.
Journal of Cardiology 4R 1199.5) 147-153
2.2. Methods Autonomic function tests
Five bedside manoeuvres reported previously [5,13,14] were performed. (1) Bloodpressure response to standing. The difference in systolic blood pressure was measured with the patient supine and then immediately after the assumption of upright posture. (2) Blood pressure response to sustained handgrip. The difference in diastolic blood pressure
was measuredafter the patient was asked to maintain a handgrip of sphygmomanometer cuff at 50 mm inflation for 3 min. (3) Heart rate response to standing. The ratio of the longest RR interval (usually around the 30th beat) to the shortest RR interval (usually around the 15th beat) was calculated after the patient moved quickly from a supine to upright posture. (4) Heart rate response to Valsalva manoeuvre.
The patient was asked to blow into a mouthpiece connected to a blood pressure sphygmomanometer at a pressureof 40 mmHg for 15 s. The ratio of the longest RR interval after the manoeuvre to the shortest RR interval during the manoeuvre was measured. (5) Heart rate variation during deep breathing.
The patient was asked to breathe deeply at six breaths/min. The mean difference during 3 successive breathing cycles between maximal and minimal heart rates was measured. Medications which could interfere with the assessmentof autonomic function such as beta blockers or diuretics were withheld 48 h before these tests. Normal values of cardiovascular autonomic function testswere defined as [5,13,14]: decreasein systolic blood pressure on standing, 5 10 mmHg; increase in diastolic blood pressure response on sustained hand grip, 2 16 mmHg; heart rate response ratio on standing (30:15 ratio), 2 1.04; Valsalva ratio, L 1.21; and heart rate variation during deep breathing, L 15 beats/min. Based on previous studies [5,13,14] only patients with all five normal autonomic function tests were included in the study.
G. Ahluwalia et al. /International
Journal of Cardiology
Exercise electrocardiography
A symptom limited exercise test using the Bruce protocol [ 151was performed in all patients using a Marquette case 15 system. All cardioactive medications (calcium channel blockers, beta blockers and long acting nitrates) were stopped 24 h before the test. Heart rate and electrocardiogram were monitored continuously. Significant ST segment depression on exercise testing was defined as 11 mm of horizontal or downsloping ST segment depression measured80 ms after the J point and present on > 1 lead. Silent ischemia was defined as significant ST segmentchangeswithout any symptoms irrespective of the heart rate achieved.
48 (1995)
147-153
149
Table 1 Baseline characteristics of diabetic and non-diabetic patientsa
No. of patients Age (years) Cholesterol (mg/dl) LDL (mgdl) Smoking (%) Family history of CAD (%) Hypertension (%) Angina NYHA Class II NYHA Class III
Diabetics
Non-diabetics
20 47.5 f 11.9b 226 f 16b 145 l lib 10 (50%) 2 (10%)
20 50.80 f 5.gb 221 f 13h 144 f 12b 11 (55%) 2 (10%)
10 (50%)
11 (55%)
12 (60%) 8 (40%)
11 (55%) 9 (45%)
aP value not significant.
bMean f SD.
Ambulatory electrocardiography
(Holter)
All patients underwent at least one 24-h electrocardiographic monitoring on a 2-channel (leads V, and Vs) AM monitor (Marquette series 8000 laser Holter system). All the cardioactive drugs were stopped 24 h before the test. The cassettes were analysed for silent myocardial ischemia and total ischemic burden. A significant episode of ST segmentdepression was defined as 11 mm of horizontal or downsloping ST segment depression occurring 80 ms after the J point, lasting 2 1 min and separated from other episodes by 2 1 min.
Statistical analysis
All values are presented as mean f S.D. Differencesbetweenmeanswere assessedfor significance by the t-test, w.r.s. test and x2-test or in case of low observedfrequencies, Fisher’s exact test where appropriate. Statistical significance was set at a P value c 0.05.
3.Redts The baseline characteristics of the diabetic and non-diabetic patients are summarised in Table 1.
Coronary angiography
Coronary angiography was performed with the Judkins technique with selective engagement of right and left coronary arteries and angulated views to completely display the coronary tree. Significant coronary stenosis was defined as at least 70% reduction in diameter of one or more major coronary arteries in at least 2 opposite views. Lesions in the following vesselswere considered onevessel lesions: left anterior descending artery and its diagonal branches, circumflex artery and its marginal branches, right coronary artery and its branches especially posterior descending artery. Depending on the involvement of the coronary arteries, the patients were divided into three groups: one-vesseldisease,two-vessel disease,and three-vesseldisease.Left ventricular ejection fraction was calculated using the area-length method.
Table 2 Autonomic function test values= Diabetics Decreasein systolic blood pressure on standing (mmHg) Increase in diastolic blood pressure on sustained hand grip (nmW9 Heart rate response ratio on standing (30:15 Ratio) Valsalva ratio Heart rate variation during deep breathing (beats/mm)
Non-diabetics
6-8
6-8
18-20
18-22
aValues expressedin range.
1.06- 1.08
1.06- 1.07
1.23-1.26 17-19
1.23-1.25 17-19
150
G. Ahluwalia et al. /International
Table 3 Exercise electrocardiography and silent myocardial &hernia Severity of disease Three-vessel Two-vessel One-vessel Total
Silent myocardial ischemia Diabetics
P value
Non-diabetics
7111(64%) 214(50%) l/5 (20%)
2/11 (18%) o/5 (0%) 014(0%)
< 0.05 >0.05 >0.05
10120(50%)
2/20 ( 10%)
All patients were symptomatic with angina. All the patients had normal autonomic function tests (Table 2). The mean duration of diabetes was 5.4 f 2.3 years and all diabetics were on oral hypoglycemic agents. Out of the 20 diabetic patients, 11 (55%), 4 (20%) and 5 (25%) patients had three-, two- and one-vessel coronary artery disease, respectively and amongst the 20 nondiabetic patients, 11 (550/o),5 (25%) and 4 (20%) patients had three-, two- and one-vesselcoronary artery disease, respectively. The left ventricular ejection fraction was comparable for both groups (62 f 8% for diabetics and 64 f 7% for nondiabetics).
Table 4 Exercise electrocardiography parameters in diabetics and nondiabetic@
Duration of exercise (mm and s) Peak double product (x 1OOOmmHg beats/mm) Recovery time of ischemic ST segment depression (tin) Maximum ST segment depression (mm) Maximum heart rate (beats/min) ‘P value NS.
Diabetics (n = 20)
Non-diabetics (n = 20)
4’56” + 1’24”
4’28” f 1’20”
25.4 * 4.4
21.2 f 2.4
6.4 zt 2.5
6.6 f 2.0
Journal of Cardiology 48 (1995) 147-153
3.1. Exercise electrocardiography
Exercise electrocardiography exhibited silent myocardial ischemia in 10 (50%) of the 20 diabetic patients as compared with 2 (10%) of the 20 nondiabetic patients (P < 0.01) (Table 3). On exercise testing, 64% of the diabetic patients with threevessel disease had silent myocardial ischemia as compared with only 18% in the non-diabetic pa-, tients with similar disease(P <0.05) (Table 3). Silent myocardial ischemia exhibited in diabetic patients with two-vessel disease was 50% and in patients with one-vesseldiseasewas 20%. None of the non-diabetic patients with two- or one-vessel diseasehad silent myocardial ischemia. There was no significant difference observed in the duration of exercise performed, peak double product achieved,magnitude of ST segmentdepression, recovery time of ischemic ST segment depression and the peak heart rate achieved between the two groups (Table 4). 3.2. Ambulatory monitoring
152 zt 10
Table 5 Ambulatory ischemia
electrocardiography
and silent myocardial
Silent myocardial ischemia
P value
Diabetics
Non-diabetics
Three-vessel Two-vessel One-vessel
7/11 (64%) o/4 (0%) 015(0%)
1111(9%) o/5 (0%) o/4 (0%)
<0.015
Total
7120(35%)
l/20 (5%)
< 0.025
2.5 f 0.5 156 f 11
electrocardiographic
Holter monitoring revealed silent myocardial ischemia in 7 (35%) of the 20 diabetic patients as compared with 1 (5%) of the 20 non-diabetic patients (P < 0.025) (Table 5). In both diabetic and non-diabetic patients, only patients with threevessel disease manifested silent myocardial ischemiawhereasnone of the patients with two- or one-vessel disease exhibited silent myocardial ischemia (Table 5). There was no significant difference between the maximum ischemic ST segment
Severity of disease 2.5 A 0.5
(Holter)
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Journal of Cardiology 48 (1995) 147-153
Table 6 Ambulatory electrocardiographic parameters in diabetics and non-diabeticsa Diabetics (n = 20) No. of episodes of silent myocardial &hernia/patient (range) Maximum ischemic ST segment depression (mm) Duration of maximum ST segment depression (mm) Minimum heart rate associatedwith ischemia (beats/mm) Maximum heart rate associated with ischemia (beats/mitt) Total ischemic burden (mitt/24 h)
l-7
Non-diabetics (n = 20) 4
2.6 zt 1.11
2.8
7.8 * 4.5
6
79 f 9
87 f 2
115 f 15
105 * 12
42.2 f 38.4
27.1 f 23.2
aP value not significant.
depression, duration of ST segment depression, maximum or minimum heart rates and the total ischemic burden between the two groups (Table 6). 4. Discussion The principal findings of this study are: (1) (2) (3)
significant silent myocardial ischemia was detected in diabetic patients with normal autonomic function, patients with severe coronary artery disease had a greater incidence of silent myocardial ischemia, and total ischemic burden was similar in both diabetic and non-diabetic patients.
To the best of our knowledge, there are no studies comparing diabetic patients with normal autonomic function with non-diabetic matched
1.51
patients to assessthe magnitude of silent myocardial ischemia and total ischemic burden. We have used ambulatory electrocardiography in addition to exercise electrocardiography since the latter does not quantify the extent of silent myocardial ischemia during daily activities. We have also done coronary angiography in all the patients to document the presenceand severity of coronary artery disease. Previous studies [5-81 have revealed conflicting results regarding the presence of autonomic neuropathy and its influence on silent myocardial &hernia in diabetics, hence we selected diabetic patients with normal autonomic function. In our study the prevalence of silent myocardial &hernia in diabetics on ambulatory electrocardiography was 35%, which is in agreementwith other studies [5,6]. However, these studies correlated the presenceof silent myocardial &hernia with autonomic neuropathy and the severity and extent of coronary artery diseasewas not assessedby coronary angiography. In our study, in spite of the similar coronary angiographic profile, the diabetic patients had 7 times higher prevalence of silent myocardial &hernia than non-diabetic patients on ambulatory electrocardiography (P < 0.025). This finding was independent of the presence of autonomic dysfunction in our diabetic patients. It is interesting to note that in both diabetics and non-diabetics, silent myocardial ischemia was present only in patients with three-vessel disease on ambulatory electrocardiography. This observation has not been highlighted in any of the previous studies on this subject. The study also shows that the total ischemic burden is similar in both diabetics and non-diabetics. Only the proportion of silent and symptomatic ischemia is different in diabetic and non-diabetic patients. The reasons are quite obvious as the pathophysiologic mechanisms are the same in both symptomatic and silent myocardial ischemia. Silent myocardial &hernia on exercise electrocardiography occurs frequently in patients with known coronary artery diseaseranging from 17% to 45% as shown by previous studies [ 16- 181.Our results are in agreement with these studies as we have observed this phenomenon in 50% of the diabetic and 10% of the non-diabetic patients. In
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our study, diabetics had a 5 times higher prevalence of exercise induced silent myocardial ischemia than non-diabetics had. This is higher than the data shown by a previous study [19] where silent myocardial ischemia was 2.2 times more frequent in diabetics but the patients in this study were not classified on the basis of severity of angiographically documented coronary artery disease,thereby making further comparison with our data difficult. The present study also shows that both diabetic and non-diabetic patients with three-vesseldisease had a higher prevalence of exercise induced silent myocardial ischemia. Diabetic patients with threevesseldiseasewere 3.5 times more likely to have silent myocardial &hernia than their non-diabetic counterparts. Our results do not concur with the observation of other investigators [20,21] who concluded that there was no difference in the severity of coronary pathology and prevalence of silent myocardial ischemia. However, in all these studies, the authors examined a heterogenous population of patients with and without previous myocardial infarction and it is obvious that the extent and severity of coronary artery disease might be different in these two patient populations. Analysis of our results revealed that whereas on exercise test, diabetics with two- and one-vessel disease exhibited silent myocardial ischemia, on ambulatory electrocardiography only diabetics with three-vessel disease exhibited silent myocardial &hernia. This observation suggests that diabetics with lesser severity of coronary artery diseasehave a higher prevalence of silent myocardial ischemia on exercise than they have during normal activities. This is possibly due to the fact that during routine activities the level of work load is not comparable with that achieved on exercise testing. Also during ambulatory electrocardiography all 12 leads are not monitored, as is done during exercise electrocardiography; the ischemic electrocardiographic changesmay be underassessed, especially those of the inferior wall. The key question of silent myocardial ischemia as to why it is silent remains unclear. Many explanations have been postulated [22-241. These include low intensity of nociceptive impulse afferent rate, opioid modulation, neurocar-
48 (1995)
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diovascular interactions, etc. The presence of autonomic neuropathy has been incriminated by few workers [5,6] whereas others have disagreed with this observation [7,8]. Our study reveals significant silent myocardial ischemia in diabetic patients without autonomic neuropathy, therefore autonomic neuropathy is not the key culprit for silent myocardial ischemia. The results of our study have important clinical relevance. Ambulatory monitoring, which can be extrapolated to an individual’s normal daily activities reveals that both diabetic and nondiabetic patients with severe coronary artery disease manifest silent myocardial ischemia. On exercise testing the diabetic patients are far more prone to silent myocardial ischemia which is not limited by the extent of coronary artery diseaseas compared with their non-diabetic counterparts. This observation has important prognostic and therapeutic implications. 5. Conclusions Silent myocardial &hernia is more prevalent in patients with diabetes mellitus even in the absence of autonomic dysfunction as compared with their non-diabetic counterparts with a similar severity of underlying coronary artery disease.During normal routine activities silent myocardial &hernia as detected by ambulatory monitoring was observed only in patients (both diabetic and non-diabetic) with three-vessel disease. However, exercise electrocardiography detected silent myocardial ischemia even in diabetic patients with two- and one-vesseldisease,in contrast to non-diabetic patients where silent myocardial ischemia was demonstrated only in patients with three-vessel disease. Total ischemic burden in diabetic and non-diabetic patients was similar in the matched patient population. References [I] Cohn PF. Prognosis for patients with different types of silent CAD. Circulation. 1987;5: 33-35. [2] Kaul U, Dev V, Manchanda SC, Wasir HS. Silent myocardial ischemia after percutaneous transluminal coronary angioplasty and its prognostic significance. Clin Cardiol 1991; 14: 563-566.
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II51 Bruce RA. Exercise testing of patients with coronary
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&hernia in patients with diabetes mellitus as judged by treadmill exercise test and coronary angiography. Am Heart J 1992. 123:46-53. 1201 Weiner DA, Ryan TJ, McCabe C et al. Significance of silent myocardial &hernia during exercise testing in patients with coronary artery disease.Am J Cardiol 1987;
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[IO] Deligonul V, Chaitman BR. Prognostic significance of silent myocardial ischemia detected by early TMT. Am J Cardiol 1989;64: 1-5. [I I] WHO Expert Committee on diabetes melhtus, Second report, Technical report series, no. 646. Geneva: WHO, 1980. [12] WHO Expert Committe on arterial hypertension, Tech-
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SH, Chew PH, Gottlieb SD. An angiographic and functional comparison of patients with silent and symptomatic treadmill ischemia early after myocardial infarction. Am J Cardiol 1987; 59: 730-734. 1221 Malliani A. Significance of experimental models m assessinglink between myocardial ischemia and pain. Adv Cardiol 1990; 1: 126-141. 1231 Droste C, Greenlee M. Effect of physical exerciseon pant thresholds and plasma beta-endorphin levels in patients with SMI. Eur Heart J, 1988;9: 25-33. 1241 ShepsDS, William M. Mechanismsof pain perception in patients with SMI. Am Heart J 1990; 199: 983-987.