Silent myocardial ischemia in diabetic and nondiabetic patients with coronary artery disease

Background: Patients with diabetes mellitus are at increased risk for CAD; silent ischemia is reported to be frequent in diabetic populations. The aim of the present study was to evaluate the prevalence of silent ischemia in diabetic and nondiabetic patients with assessed CAD. Methods and results: We recruited a total of 618 patients with CAD: 309 were consecutive diabetic patients and 309 were age- and gender-matched nondiabetic patients. Myocardial ischemia was evaluated both during daily life and during exercise testing. Angina pectoris during daily life was more frequent in diabetic than in nondiabetic patients (80% vs. 74%, P<0.05). The anginal pain intensity either during daily life or acute myocardial infarction (MI), the prevalence of a previous MI, the extent of CAD and ergometric parameters were similar in diabetics and nondiabetics. Silent ischemia during exercise was documented in 179 (58%) diabetics and in 197 (64%) nondiabetics (nonsignificant, ns). Both diabetics and nondiabetics with silent exertional myocardial ischemia differed from symptomatic subjects in higher heart rate values (P<0.01), systolic blood pressure (P<0.01), rate–pressure product (P<0.001), work load (P<0.01) and maximum ST-segment depression at peak exercise (P<0.05). Conclusions: The incidence of silent myocardial ischemia during exercise was similar in diabetic and nondiabetic CAD patients. Surprisingly, diabetics showed a higher prevalence of angina pectoris during daily activity than nondiabetics. A significant association between the presence of symptoms during daily life and exercise was observed in both groups. Our results may contribute to the planning of the clinical management of diabetic CAD patients and confirm the individual attitude to pain of CAD patients independent of the presence of diabetes.     

Prevalence and clinical significance of silent myocardial ischemia in exercise test

Prevalence of silent myocardial ischemia in exercise test was retrospectively reviewed from 749 tests performed for 513 patients with definite evidence of ischemic heart disease. The clinical significance was studied and absence of transient ischemia, occurrence of transient ischemia with and without pain were observed in 48%, 30% and 22% of the tests, respectively. Anginal pain was frequently observed in exercise tests for patients with severe coronary artery disease and low exercise tolerance. A large number of tests showing ischemic response were discontinued due to symptoms other than anginal pain and hence silent myocardial ischemia could be thought to be a result of ischemic state which does not reach the angina threshold. Silent myocardial ischemia was frequently observed during usual daily life. However, a definite correlation between severity of transient ischemia and presence or absence of chest pain in the same individuals was not obtained from the study. A day to day variation in the angina threshold might be responsible. In general, silent myocardial ischemia was not rare. However, the consistent condition was very unusual. In angina of effort (EA) and old myocardial infarction (OMI), 3.7% and 12.3% were silent, respectively. A higher incidence was obtained in OMI than in EA. This is important for the management of these patients. The mechanism of silent myocardial ischemia and the cause of the different incidence of this state between EA and OMI were not defined and remained to be further studied.     

Clinical correlates and prognostic significance of type A behavior and silent myocardial ischemia on the treadmill

Type A patients with coronary artery disease (CAD) tend to ignore or underreport symptoms, especially during challenging tasks such as the treadmill exercise test. To determine whether type A CAD patients might be more likely than type B patients to have silent ischemia during exercise and consequently a worse prognosis, 403 patients with stable CAD who had significant coronary disease on angiography, a positive Bruce protocol treadmill test and a structured interview to assess type A behavior were studied. Median follow-up time was 6 years. Type A patients were more likely to experience silent ischemia during exercise than were type B patients (35 vs 25%, p = 0.05). Patients with silent ischemia during exercise had a history of fewer anginal episodes/week, and type A patients with silent ischemia were less likely to have had a history of typical angina. However, using the Cox model, there were no significant differences in survival between type A patients and B patients with silent ischemia (4-year survival 86 vs 79%, p = 0.44) and no significant differences in survival between type A patients with silent ischemia and type A patients with symptomatic ischemia (6-year survival 86 vs 80%, p = 0.59). Similar results were obtained for infarction-free survival. Type A patients are more likely than type B patients to have silent ischemia during exercise, but long-term survival is not affected.     

Silent ischemia: a timely aspect in coronary artery disease

The phenomenon of silent myocardial ischemia is defined as a transient alteration in myocardial perfusion, function or electrical activity in the absence of chest pain or the usual anginal equivalents. Patients may be classified as having one of three types of silent ischemia: type 1-asymptomatic with no history of myocardial infarction or angina; type 2-asymptomatic with previous myocardial infarction; type 3-angina is present in addition to asymptomatic ischemic episodes. Based on exercise testing, silent ischemia has been found in 2.5% of asymptomatic middle-aged men; a substantial number of such subjects subsequently incur cardiac events. In patients with type 2 silent ischemia, post-infarction mortality appears markedly higher than in cohorts without silent ischemia. In type 3 patients, 75 to 80% can be found to have silent ischemic episodes in addition to typical anginal attacks, the frequency of which may be up to three or four times that of the latter counterpart. In persons with coronary artery disease who succumb to sudden cardiac death, 25% have never had clinical symptoms suggesting that there may be a great number of persons with silent disease in the population at large.     

Painless myocardial ischemia. Comparison of 2 groups of patients with a positive exercise test after myocardial infarction

Myocardial ischemia usually presents with chest pain, the characteristics of which are well known. However, anginal pain may be absent during true ischemia, an entity known as painless or silent myocardial ischemia. Does this type of ischemia have special clinical, angiographic or ergometric characteristics after posterior myocardial infarction (MI)? In order to answer this question 183 consecutive patients with recent posterior MI who had undergone coronary angiography and who had positive exercise stress tests on bicycle ergometers were separated into two groups depending on whether they had experienced at least one episode of pain after the acute phase of myocardial infarction or during the exercise stress test (Group S: 83 patients, average age 54 +/- 10 years) or not (Group A: 100 patients, average 54 +/- 8 years). The following parameters were commoner in Group A: cigarette smoking, heart rate and load developed during exercise stress testing provoking electrical signs of ischemia, single vessel disease on coronary angiography, long-term medical treatment. On the other hand, the following parameters were statistically more frequent in Group S: hypercholesterolemia, preinfarction angina, degree of ST depression during exercise testing, reperfusion of the distal vessels of the occluded artery responsible for the infarct by a collateral circulation, triple vessel disease and surgical treatment. However long-term follow-up (average 3 years) shows that mortality and recurrence of MI are similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased occurrence of exercise-induced silent ischemia after treatment with aspirin in patients admitted for suspected acute myocardial infarction.

Patients admitted for suspected acute myocardial infarction within 6 hours (mean 3 hours 42 minutes) after onset of symptoms were randomised to double-blind treatment with low-dose oral aspirin or placebo. Early exercise ischemic responses, exercise capacity and resting left ventricular ejection fraction (radionuclide ventriculography) were estimated in 77 survivors 2-4 weeks later. Exercise performance and ejection fraction in patients with confirmed acute myocardial infarction were equal in the two groups. During exercise, patients treated with aspirin had significantly more silent ischemia (ST depression without chest pain) compared to placebo (28% versus 6%; P = 0.015). The occurrence of positive exercise tests (chest pain or ST-segment depression), however, was similar in the two groups. The results indicate that the administration of aspirin early after acute myocardial infarction increases the occurrence of silent ischemia but has no effect on left ventricular function.     

Naloxone and asymptomatic ischemia: failure to induce angina during exercise testing

Endorphins and endorphin receptors are believed to modulate pain perception. To investigate whether naloxone, a specific antagonist, could initiate anginal pain during exercise-induced myocardial ischemia in asymptomatic patients with angiographically defined coronary artery disease, a single-blind trial was conducted in 10 men with prior positive exercise electrocardiograms. Multistage treadmill exercise tests were performed twice within a week. On the second test, patients received naloxone, 2 mg intravenously, by a syringe infusion pump. Exercise was terminated because of fatigue in 6 patients and completion of the protocol in 4. No patient reported chest pain during exercise. Naloxone did not significantly alter exercise duration, heart rate, blood pressure and ST-segment changes compared with control testing. It is concluded that endorphins do not play a significant role in the recognition of anginal pain in patients who have asymptomatic exercise-induced ischemia.     

Electrocardiographically and symptomatically silent myocardial ischemia during exercise testing

Certain patients with coronary artery disease (CAD) may have neither ST depression nor chest pain during exercise despite the presence of myocardial ischemia. The frequency and characteristics of such electrocardiographically and symptomatically silent ischemia were studied in 171 patients with both angiographically documented CAD and scintigraphically documented ischemia. Fifty-six (33%) of 171 patients had neither ST depression nor chest pain (Group N), and 115 (67%) had ST depression and/or chest pain (Group P). The two groups were similar with respect to age, gender, the prevalence of prior infarction, and peak systolic blood pressure. Group N patients, however, had a higher mean peak heart rate and rate-pressure product, less severe scintigraphic ischemia, a lower lung thallium-201 uptake, and a smaller number of diseased vessels. Stepwise discriminant analysis showed a history of effort angina, lung thallium-201 uptake, and scintigraphic severity of ischemia to be significant discriminators between Groups N and P. In conclusion, electrocardiographically and symptomatically silent ischemia may be common during exercise in patients with CAD, and less severe ischemia may be one of important determinants.     

Frequent episodes of silent myocardial ischemia after apparently uncomplicated myocardial infarction

Frequent episodes of silent myocardial ischemia were documented in two patients, one with recognized and one with unrecognized prior myocardial infarction. Neither patient had symptoms after the infarction, but both demonstrated silent myocardial ischemia on exercise testing, which prompted further study with 48 hour ambulatory electrocardiographic (Holter) recordings. In each patient, heart rate recorded with the Holter monitor during the ischemic episodes was usually less than that observed during ischemia precipitated by exercise testing. This suggests that increased vasoconstrictive tone may play a role in silent ischemic episodes occurring during daily activities.     

Plasma beta-endorphin levels in silent myocardial ischemia induced by exercise

Although silent myocardial ischemia is a well recognized phenomenon, the reasons for the lack of symptoms in patients with coronary artery disease (CAD) is unclear. Because the endogenous opioid beta-endorphin has been related to pain modulation, plasma beta-endorphin levels were studied before, during and after exercise-induced ischemia in symptomatic and asymptomatic men. Because beta-endorphin responses have been closely linked to adrenocorticotropic hormone (ACTH) and cortisol responses, these hormones also were measured. Nine symptomatic and 12 asymptomatic patients with a high probability (at least 95%) of CAD and 8 apparently healthy men completed a Bruce protocol treadmill test. Blood samples were drawn before, during and 10 minutes after exercise. During exercise the measured hormones showed no significant increases from basal levels. However, plasma beta-endorphin, ACTH and cortisol levels were significantly elevated (p less than or equal to 0.01) 10 minutes after exercise in all 3 groups. There was no significant difference in plasma beta-endorphin levels during or after exercise between the symptomatic and asymptomatic patients with CAD. Thus, differences in circulating levels of beta-endorphin, ACTH and cortisol are not associated with the presence or absence of pain during exercise-induced myocardial ischemia.     

Risk of developing an acute myocardial infarction or sudden coronary death in patients with exercise-induced silent myocardial ischemia. A report from the Coronary Artery Surgery Study (CASS) registry

To evaluate whether patients with silent myocardial ischemia during exercise testing are at increased risk for developing a subsequent acute myocardial infarction or sudden death, the data on 424 such patients with proven coronary artery disease (CAD) from the Coronary Artery Surgery Study (CASS) registry were analyzed. These patients (group 1) were compared with 456 other patients with CAD (group 2) who had both ischemic ST depression and angina pectoris during exercise testing and with 1,019 control patients without CAD. The probability of remaining free of a subsequent acute myocardial infarction or sudden death at 7 years was 80 and 91%, respectively, for group 1, 82 and 93%, respectively, for group 2 (difference not significant, compared with group 1), and 98 and 99%, respectively, for the control patients (p less than 0.001), compared with group 1 or 2). Among patients in group 1, the probability of remaining free of myocardial infarction and sudden death at 7 years was related to the severity of CAD and presence of left ventricular (LV) dysfunction, and ranged from 90% for patients with 1-vessel CAD and preserved LV function to 38% for patients with 3-vessel CAD and abnormal LV function (p less than 0.001). Thus, patients with either silent or symptomatic ischemia during exercise testing have a similar risk of developing an acute myocardial infarction or sudden death--except in the 3-vessel CAD subgroup, where the risk is greater in silent ischemia. The risk of patients with silent myocardial ischemia is based primarily on angiographic variables.     

Role of beta-endorphins in silent myocardial ischemia

The reason for the absence of pain perception in silent myocardial ischemia is unknown. A role of increased endorphinic activity in patients with silent ischemia has been postulated. To further investigate this hypothesis, 10 men with documented coronary artery disease and previous positive electrocardiographic findings during exercise without anginal pain were studied. Six healthy volunteers served as control subjects. The protocol included 2 bicycle exercise tests, the first test serving as baseline and the second performed after administration of naloxone, a specific opiate antagonist. Plasma beta-endorphin levels were measured by radioimmunoassay in both tests at rest, at peak exercise level and after recovery. All patients underwent thallium-201 scintigraphy after coronary vasodilation to provide an additional independent marker of ischemia. All patients showed stress-induced reversible perfusion abnormalities. No patient reported pain after naloxone application. Exercise duration, blood pressure and heart rate were not significantly altered by naloxone. Plasma beta-endorphin levels ranged from 18 +/- 6 pg/100 microliters (mean +/- standard deviation) at rest to 22 +/- 6 pg/100 microliters during exercise in the patient group and from 20 +/- 5 to 27 +/- 9 pg/100 microliters in the control subjects. Thus, there was no significant increase of plasma beta-endorphins during exercise or after naloxone administration, nor was there any difference observed between patients and control group. These data support the view that endorphinic activity does not play an essential role in the pathophysiology of silent myocardial ischemia.     

Correlation between beta-endorphin plasma levels and anginal symptoms in patients with coronary artery disease

To verify whether beta-endorphin plasma levels influence the presence of anginal symptoms, 74 consecutive male patients were studied. All patients had previously documented coronary artery disease and reproducible exercise-induced myocardial ischemia. Thirty-five patients (Group I) had a history of angina and reported anginal symptoms during exercise stress testing; 39 patients (Group II) were asymptomatic and had documented silent myocardial ischemia during exercise. Baseline beta-endorphin plasma levels were measured in blood samples taken before exercise stress testing and analyzed by beta-endorphin-I125-RIA Kit-NEN (a radioimmunoassay method). The mean baseline beta-endorphin plasma level was 22.5 +/- 19 pg/ml in patients with anginal symptoms compared with 43.7 +/- 28 pg/ml in asymptomatic patients (p less than 0.001). Baseline blood pressure and heart rate-systolic pressure (rate-pressure) product at baseline and at ischemia threshold (1 mm ST segment depression) were similar in the two groups. Group II patients had a longer exercise duration (p less than 0.01), more pronounced ST segment depression (p less than 0.001) and a higher peak rate-pressure product (p less than 0.01). The extent of coronary artery disease, ejection fraction and left ventricular end-diastolic pressure were similar in the two groups. These data suggest that higher baseline beta-endorphin plasma levels may play a role in the decreased sensitivity to pain in patients with silent myocardial ischemia. In addition, different beta-endorphin levels can be associated with a different sensitivity to pain.     

The predictive value of silent ischemia at an exercise test before discharge after an episode of unstable coronary artery disease. RISC Study Group.

The prognostic value of silent ischemia during a symptom-limited predischarge exercise test (ET) was evaluated in 740 men after an episode of unstable angina or non-Q wave myocardial infarction. The 51% of patients with ST depression at the ET had a higher rate of myocardial infarction or death after 1 year (18%) compared with those without ST depression (9%; p less than 0.01). This increased risk was not influenced by the presence or absence of pain at the ET: 18.3% in patients with painful ischemia compared with 18.1% in patients with silent ischemia. However, ST depression combined with pain at the ET predicted a higher incidence of class III or IV angina at follow-up (43.9% compared with 16.7% in the group with asymptomatic ST depression; p less than 0.001). Because revascularization in addition to alleviating symptoms also enhances the prognosis in certain groups of patients, selections for coronary angiography and possible revascularization should not be made only on the basis of symptoms but also on the presence of myocardial ischemia, whether symptomatic or not.     

Effects of ischemia on QT dispersion during spontaneous anginal episodes.

Myocardial ischemia induced by pacing, angioplasty, or stress results in a significant increase in QT dispersion (QTd = QT maximum - QT minimum). This study investigated the effects of ischemia on QTd and the rate-corrected QTd (QT(c)d) during spontaneous anginal episodes in patients with coronary artery disease (CAD). Ninety-five patients with CAD and typical angina pectoris and 15 control subjects complaining of anginalike symptoms were studied. QTd and QT(c)d were calculated from 12-lead surface electrocardiograms recorded during and after the relief of pain. QTd and QT(c)d were significantly higher during the anginal episode (84+/-31 ms and 98+/-51 ms) compared to the painless conditions (69+/-24 ms and 71+/-24 ms) (P = .003 and P = .001 for QTd and QT(c)d, respectively) only in the 57 CAD patients who had a history of an old previous myocardial infarction. QTd and QT(c)d are significantly increased during spontaneous angina in patients with documented CAD and history of previous myocardial infarction.     

Myocardial perfusion in silent myocardial ischemia: investigation by exercise stress myocardial tomography with thallium-201

To investigate myocardial perfusion in silent myocardial ischemia, we performed exercise stress myocardial tomography with thallium-201 (T1) in 85 patients with coronary artery disease (CAD). Exercise stress myocardial tomography was obtained both immediately after exercise and three hours later. Patients were classified into two groups according to the presence (Symptomatic Group, n = 36) or absence (Silent Group, n = 49) of chest pain during exercise stress. Clinical features (age, gender and history of myocardial infarction) and arteriographically determined severity of CAD were the same in both groups. The extent of myocardial ischemia (% Ischemia) estimated by exercise stress myocardial tomography was the same in each group (30 +/- 10% in Silent Group, 28 +/- 12% in Symptomatic Group, NS). The severity of exercise-induced myocardial ischemia was expressed as a minimal value of myocardial T1 washout rate (minimal WOR) of each patient. Although exercise heart rate was identical in both groups, minimal WOR in Silent Group was significantly higher than that of Symptomatic Group (4 +/- 10% vs -16 +/- 14%, p less than 0.001). The study in patients who exhibited both silent and symptomatic ischemia showed same results. These findings suggest that the severity of ischemia is a fundamental factor in determining the presence or absence of pain during exercise induced ischemia.     

Prognostic implications of symptomatic versus asymptomatic (silent) myocardial ischemia induced by exercise in mildly symptomatic and in asymptomatic patients with angiographically documented coronary artery disease

Patients with coronary artery disease (CAD) may undergo periods of reversible myocardial ischemia without experiencing angina. To study the prognostic implications of "silent" myocardial ischemia induced by exercise, exercise electrocardiography and radionuclide angiography were performed in 131 consecutive patients with CAD, preserved left ventricular (LV) function at rest and mild or no symptoms during medical therapy. All patients who died during medical therapy were in the subgroup of patients with 3-vessel CAD in whom exercise-induced ischemia developed, which was characterized by both a decrease in LV ejection fraction and ST-segment depression. Patients in whom angina pectoris developed during exercise (54% of all patients) had a greater prevalence of this combined ischemic response to exercise than patients without angina (61% vs 27%, p less than 0.001) and also a greater prevalence of left main or 3-vessel CAD (59% vs 25%, p less than 0.001). However, when inducible ischemia was demonstrated, risk stratification and prognosis were the same whether the ischemic episode was symptomatic or silent. Among patients having both a reduction in ejection fraction and a positive ST-segment response, the likelihood of significant left main narrowing (13% vs 26%), 3-vessel CAD (56% vs 51%) and death during subsequent medical therapy (16% vs 9%) was similar in patients with silent compared to those with symptomatic ischemia. These data indicate that patients in whom angina develops during exercise have a greater prevalence of high-risk coronary anatomy and of inducible ischemia than patients without angina. However, once inducible ischemia is documented, the symptomatic response to exercise appears irrelevant for prognostic or risk stratification considerations.     

Study of silent myocardial ischemia using exercise stress test among diabetic and non-diabetic patients with documented coronary artery disease

IntroductionProspective studies have documented an increased likelihood of sudden cardiac death and unrecognized myocardial infarction in patients with diabetes.Aim of the workTo study silent myocardial ischemia using exercise stress test among diabetic and non-diabetic patients with angiographically documented coronary artery disease.Patients and methodsPatients with contra-indications to exercise test were excluded.All patients were subjected to treadmill test using modified Bruce protocol & were considered to have silent ischemia if ECG shows ischemic changes without chest pain.StatisticsData were collected & analyzed statistically.ResultsThe study included 80 patients with CAD (40 diabetics & 40 non-diabetics).Their mean age was 58 years old, including males (73.8%).According to stress test patients were classified:

• 1-Group 1: 28 patients (35%), showed no ST depression no chest pain during exercise test, 10 patients of them (35.7%) were diabetic.
• 2-Group 2: two patients (2.5%) who were diabetic showed chest pain without stress induced ST depression (only pain).
• 3-Group 3: 26 patients (32.5%) showed stress ST depression without chest pain (silent ischemia), 18 patients of them (69.2%) were diabetic.
• 4-Group 4: 24 patients (30%) showed ST depression and chest pain during exercise test (symptomatic ischemia), 10 patients of them (41.7%) were diabetic.

All patients underwent coronary angiography (100%) and all of them had significant coronary artery disease (more than 50% stenosis).ConclusionDiabetics with coronary artery disease have a higher prevalence of silent myocardial ischemia than non-diabetics.     

Clinical significance of exercise-induced silent myocardial ischemia in patients with coronary artery disease

Exercise-induced silent myocardial ischemia is a frequent feature in patients with coronary artery disease. The purpose of this study was to compare the clinical and angiographic characteristics of 269 patients who complained of chest pain during an exercise test (group I) with those of 204 who developed exercise-induced silent myocardial ischemia (group II). Group I patients more frequently had anginal symptoms of class III and IV of the Canadian Cardiovascular Society than did group II patients, who had milder symptoms (p less than 0.001). The only angiographic difference observed between the two groups was a slightly but significantly higher left ventricular end-diastolic pressure in group II patients (p less than 0.05), who also showed a longer exercise duration (p less than 0.01) with a higher heart rate-systolic pressure product (p less than 0.01) and more pronounced ST segment depression at peak exercise (p less than 0.001). Moreover, ventricular ectopic beats during exercise were more frequently observed in group II patients (p less than 0.05). Coronary bypass surgery was performed in 45% of patients of group I and in 24% of patients of group II (p less than 0.05). Survival curves of medically treated patients did not show any statistically significant difference between the two groups. Thus, although patients with a defective anginal warning system may have more pronounced signs of myocardial ischemia and a greater incidence of ventricular arrhythmias during exercise, their long-term prognosis is not different from that of patients who are stopped by angina from the activity that is inducing myocardial ischemia.     

Silent ischemia: evaluation by exercise and redistribution tomographic thallium-201 myocardial imaging

To compare the amount of myocardium jeopardized during silent ischemia and painful ischemia, 112 consecutive patients undergoing coronary arteriography with ischemia demonstrated by exercise and redistribution tomographic thallium-201 myocardial imaging (SPECT) were divided into two groups: 84 patients without anginal pain (silent ischemia) and 28 with pain (painful ischemia). The SPECT apical, mid and basal ventricular levels of the short-axis view and the apical portion of the long-axis view were divided into 20 segments. The results were 1) 7.4 +/- 4.7 ischemic segments in silent ischemia and 7.6 +/- 3.7 in painful ischemia (p = NS) with 4.7 +/- 3.6 segments in silent ischemia undergoing total redistribution compared with 5.4 +/- 3.4 in painful ischemia (p = NS); 2) no difference in the incidence of single, double or triple vessel disease between silent and painful ischemic groups; 3) similar anatomic distribution of ischemic segments between the two groups; 4) more positive exercise electrocardiographic (ECG) changes in painful ischemia (70%) than in silent ischemia (32%) (p less than 0.001) with equal amounts of ischemia associated with positive and negative exercise ECG findings. Conclusions: 1) Patients with silent and painful ischemia during exercise have similar amounts of ischemic myocardium demonstrated by tomographic thallium-201 imaging and similar extent of angiographically documented coronary artery disease despite the absence of pain and the lower incidence of positive exercise ECG findings in silent ischemia. 2) Positive and negative exercise ECG findings were associated with similar amounts of ischemic myocardium.