699 Silent Ischemia Matthew B. O’Steen and Neal S. Kleiman Key Points • Multiple mechanisms of silent ischemia have been proposed. • The incidence and clinical significance of silent ischemia and the need for screening and therapy vary depending on the population being studied. • Multiple methods for evaluating silent ischemia are available; each has utility in different clinical settings. Historical Perspective Since Heberden’s original description in 1772 1 of an exer- tional “disorder of the breast” and the subsequent recogni- tion that angina pectoris was associated with obstructive narrowing of the coronary arteries, clinicians caring for patients with coronary artery disease (CAD) have regarded angina as the benchmark by which to measure the prognosis and gauge the treatment of patients with coronary arterial atherosclerosis. However, reports of coronary atherosclero- sis, occasionally severe, in asymptomatic young soldiers killed in the First World War and the Korean War 1,2 and in pilots, 3 coupled with the increasing recognition that the elec- trocardiographic changes of infarction were often present in individuals with no history of chest pain, 4–6 led to the uneasy acceptance that interruption of blood supply to the myocar- dium was not necessarily heralded by angina pectoris. As the ability to recognize myocardial ischemia increased, so did the awareness that objective measures of detection were nec- essary in patients who were either asymptomatic or whose symptoms did not fulfill typical descriptions. It is now well accepted that a large proportion of patients has evidence of remote myocardial infarction (MI) but give no clinical history suggesting such an event. The development and acceptance of Masters’ two-step test from the 1920s through the 1950s, and later of the exercise treadmill test, led to the recognition that, as is seen in many other disease processes, not only MI and sudden death but also myocardial ischemia could occur in the absence of symptoms. The results of an early study by Twiss and Sokolow, 7 in which 21 of 66 patients with exertional angina pectoris underwent two-step exercise testing without developing chest discomfort, led the authors to state, “The electrocar- diographic changes after exercise are not dependent on the reproduction of pain while allowing that the percentage of positive results is much greater if pain is induced.” Eventu- ally, the use of more mechanistically based and hence more sensitive and specific nuclear and echocardiographic imaging adjuncts to stress testing reinforced the prognostic signifi - cance of decreased blood flow to viable areas of myocardium both in the presence and in the absence of symptoms. Simi- larly, the development of drugs that could delay the develop- ment of ischemia and of successful revascularization techniques that could prevent the development of previously demonstrable ischemia led to increased interest in studying and characterizing asymptomatic or “silent” ischemia. This effort was followed by attempts to determine whether treat- ment of silent or asymptomatic ischemia would improve the outcome of patients in whom it was present. Therefore, it was no longer clear that adequate control of symptoms con- stituted optimal treatment for all patients with ischemic heart disease. Mechanisms of Altered Pain Perception During Myocardial Ischemia It is likely that a multitude of mechanisms are responsible for the variability of individuals’ ability (or willingness) to sense pain as a result of myocardial ischemia. Experimental studies have demonstrated that activation of the baroreceptor reflex arc by pressor agents can induce hypoanalgesia in rats. Accordingly, stimulation of the efferent loop of this arc 3 1 Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Mechanisms of Altered Pain Perception During Myocardial Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Size of the Ischemic Area (“Ischemic Burden”) . . . . . . . 701 Hemodynamics and Left Ventricular Function . . . . . . . 702 Silent Ischemia in Patients with Diabetes Mellitus . . . 702 Detection and Documentation of Silent Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703 Prognosis in Patients with Silent Ischemia . . . . . . . . . . 705 Treatment of Silent Myocardial Ischemia . . . . . . . . . . . 707 Results of Suppressing Ischemia . . . . . . . . . . . . . . . . . . . 708 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708 700 chapter 31 (cardiopulmonary vagal pathways) may be responsible for the absence of pain in humans. 8 Because increases in the blood pressure repeatedly stimulates this pathway, it has been pos- tulated that hypertensive patients have a higher pain thresh- old than nonhypertensives. Patients with angiographically documented CAD and hypertension, for example, tend to have a higher mean dental pain threshold than normotensive patients, and experience fewer episodes of angina during daily life. 9 Patients with infiltrative autonomic neuropathies, such as that associated with diabetes, may also have dimin- ished afferent loop sensitivity. This group is discussed sepa- rately in a later section. Altered Central Nervous System Processing Mechanisms For a noxious stimulus to be perceived as pain, frontal cortical activation must occur. Cortical activation can be traced physiologically by detecting increased blood flow using positron emission tomography (PET). Comparison of changes in regional cerebral flow reveal equivalent degrees of thalamic activation in both angina as well as in silent ischemia, but a lesser extent of cortical activation in patients with painless ischemia. 10 This finding suggests differential gating of afferent stimuli at the thalamic level with only some impulses being allowed to pass through to the frontal cortex. Endorphins and Angina β-endorphins are recognized as modulators of pain; elevated plasma endorphins raise an individual’s threshold for expe- riencing pain. Since these endogenous compounds antago- nize the same central receptors that are blocked by opiates, which have been used successfully for a century to treat angina, it is tempting to consider that endorphin production or sensitivity may play a role in moderating the perception of angina. In patients with established coronary artery disease, β-endorphin levels in patients with silent ischemia have been reported to be almost twice as high as in asymp- tomatic individuals. 11 The same finding has been noted in patients undergoing percutaneous transluminal coronary angioplasty: Plasma levels of β-endorphins are lower in symptomatic patients and decrease significantly during balloon inflation. In patients with silent ischemia, plasma levels of β-endorphins have been reported to be higher before and to remain stable during balloon angioplasty when com- pared with patients who develop angina during ischemic symptoms, suggesting that endogenous opiate levels and their variation during ischemia are associated with individ- ual experience. 12 Investigation of percutaneous trans- luminal coronary angioplasty (PTCA)-induced ischemia, has suggested that there may be a threshold beyond which β-endorphins must increase in order to suppress anginal symptoms in response to ischemic stimuli. 13 However, when the induction of angina is compared to perception of other noxious stimuli, the same elevations in β-endorphin levels (as high as fivefold) that decrease perception of electrical pain stimuli 14 or of exogenous radiant heat 15 do not appear to affect the sensation of exercise-induced angina. It is possible that higher endorphin levels may affect the angina threshold. It remains fair to state that the role of endorphins in mediat- ing the perception of cardiac ischemia remains unresolved. Silent Ischemia and Inflammation Recent speculation has focused on the role of inflammatory processes in the perception of cardiac ischemia. Many inflammatory mediators have nociceptive properties; vascu- lar and perivascular inflammatory processes may stimulate or sensitize local afferent fibers. Patients with silent isch- emia have been noted to have an antiinflammatory pattern of cytokine production (increased levels of IL-4 and IL-10, and decreased monocytes expression of CD11b/CD18), which may increase the threshold for nerve activation and block the pain transmission pathway. 16 Mazzone and colleagues 16 eval- uated the expression of the peripheral benzodiazepine recep- tor on circulating leukocytes in 24 patients with and 33 patients without angina during exercise-induced myocardial ischemia. Flow cytometric determinations showed increased expression of peripheral benzodiazepine receptors on all classes of leukocytes in patients whose ischemia was silent compared with patients who developed symptoms during ischemia. It is unknown whether the presence of these recep- tors on leukocytes plays a causal role in the lack of symp- toms during myocardial ischemia or whether leukocytes merely represent one cell class in which peripheral benzodi- azepine receptor expression is upregulated. 17 Central Nervous System Processing: Evaluation of Pain Threshold Silent ischemia is induced daily in many patients undergoing coronary angioplasty of a vessel supplying viable myocar- dium. However, it has been estimated that 16% to 47% of patients do not experience pain during the procedure. Con- sequently, this procedure may provide a model for evaluating silent ischemia. Falcone et al. 18 evaluated pain threshold using dental stimulation in patients with and without angina during daily life undergoing PTCA. During pulpal stimula- tion, 66.2% of patients reported pain whereas 33.7% remained asymptomatic, even at maximal stimulation, recognizing that sedation and analgesia may also modify the sensation and reporting of pain. The study cohort was then divided into two groups according to the presence or absence of angina during myocardial ischemia. Although the two groups appeared demographically similar, dental pain could be pro- voked in 81% of patients with and 36% of patients without symptoms during PTCA. The authors concluded that indi- vidual profiles of generalized pain perception were likely to influence their perception of angina during episodes of myo- cardial ischemia. Duration or intensity of ischemia and left ventricular dysfunction were not absolute factors in deter- mining the occurrence of angina. However, it is worth noting that the same may not apply to angina during exercise or during daily living, possibly due to different pathophysio- logic mechanisms involved (Table 31.1). Psychological Aspects of Silent Ischemia In CAD as in most other disease states, psychological factors may influence the perception of discomfort as pain. These silent ischemia 701 factors may affect the response to therapy as well. The psy- chological comfort associated with increased medical sur- veillance as well as the perception that a medical strategy is being pursued may result in a significant “placebo effect.” For example, Amsterdam et al. 19 reported that in patients with silent ischemia, placebo therapy led to a 44% reduction of ischemic episodes and 50% reduction in total duration of ST depression. In an elegant study, Friedman et al. 20 showed a strong relation between silent ischemia and “type A” personality. When 10 patients with this behavioral trait underwent psy- chological counseling, which resulted in marked decreases in the feeling of “time urgency” and hostility (markers of type A personality), the mean frequency of ischemic episodes declined from an initial 6.6 to 3.1 ischemic episodes per 24 hours. Whether this decrease resulted from a truly altered perception threshold or reduction in endorphin secretion and in rate-pressure product is not known. Similarly, data from the Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) suggest that quantitatively determined high levels of daily psychological stress may reduce the threshold at which angina is reported in patients with clinically stable coronary artery disease. 21 Size of the Ischemic Area (“Ischemic Burden”) The relation between the amount of ischemic myocardium and the presence and severity of symptoms is hotly debated. In a study of 963 patients, Narins and coworkers 22 examined the differences between patients with silent ischemia and those with symptomatic ischemia during exercise testing 1 to 6 months after recovery from a coronary event. Compared with patients with symptomatic ischemia during testing, those with silent ischemia had less extensive reversible defects on stress thallium scintigraphy (Table 31.2), less func- tional impairment during treadmill testing (longer exercise duration and longer time to ST depression), and less frequent ST depression during ambulatory electrocardiographic moni- toring. In a similar study, Zellweger and colleagues 23 reported that when stress scintigraphy was performed on 356 patients 6 months after successful percutaneous coronary interven- tion (PCI), 62% of patients in whom ischemia was docu- mented were asymptomatic and the summed stress score (i.e., the degree of stress-induced ischemia) was substantially lower among asymptomatic compared with symptomatic patients. In another study of 300 consecutive patients with docu- mented CAD and reversible hypoperfusion on exercise ses- tamibi tomography, Marcassa and colleagues 24 compared the extent of hypoperfusion and the presence of symptoms during exercise stress testing. Patients with painful ischemia had lower values for workload, exercise time, and peak-rate pressure product. These patients more frequently had signifi - cant ST segment depression during exercise than did patients with silent ischemia. Patients with symptoms during isch- emia had more evidence of reversible hypoperfusion than did patients with silent ischemia (16% ± 10% vs. 11% ± 7%) despite comparable extent of stress hypoperfusion (22% ± 12% vs. 22% ± 13%). In contrast, Elhendy and associates 25 studied 224 con- secutive patients with limited exercise capacity and com- pletely or partially reversible perfusion abnormalities during dobutamine stress sestamibi single photon emission com- puted tomography (SPECT) and found no difference in the extent or severity of perfusion defects between symptomatic and asymptomatic patients. Discordant results have been reported in at least 10 studies that used myocardial perfusion scintigraphy to TABLE 31.1. Proposed mechanisms of silent ischemia Differences in somatic pain thresholds Increased endorphin levels Alterations in immunoinflammatory response to pain Autonomic neuropathy Abnormal central nervous system processing/gating of pain TABLE 31.2. Thallium-201 myocardial perfusion scintigraphic studies comparing the amount of ischemic myocardium in patients with or without chest pain during exercise testing First author Year No. of patients Method Selection criteria Reversible defects (% of patients) Amount of ischemia equal in patients with or without chest pain Hecht 27 1989 112 SPECT CAD; reversible defects 100% Gasperetti 28 1990 103 Planar Reversible defects 100% Heller 29 1990 234 Planar Reversible defects 100% Mahmarian 30 1990 356 SPECT Unselected 54% Bandu 131 1994 294 SPECT Unselected 94% Amount of ischemia greater in patients with than without chest pain Kurata 31 1990 471 SPECT Unselected 37% Galli 32 1990 200 Planar Old MI; reversible defects 100% Travin 33 1991 268 Planar Reversible defects 100% Hendler 34 1992 152 SPECT Ex ECG+ 83% Klein 26 1994 117 SPECT Ex ECG+ 80% Ex ECG+, positive exercise electrocardiogram; MI, myocardial infarction; Pts, patients; SPECT, single-photon emission computed tomography. 702 chapter 31 compare the amount of ischemic myocardium in patients with and without chest pain during exercise testing. 26–34 Several potential explanations exist for these discrepant findings. The earlier studies were conducted using widely different patient populations, ranging from clinically asymp- tomatic patients to only those with evidence of a marked ischemic response to exercise. Multivariable analysis was seldom performed in these studies, and varying definitions of silent ischemia were used. Hemodynamics and Left Ventricular Function In general, acute left ventricular dysfunction is a conse- quence of the extent of ischemia. Hence, findings relating the presence of ischemic symptoms to left ventricular func- tion might be expected to follow those related to the level of ischemic burden. Similar discrepancies exist in the literature concerning left ventricular performance during exercise testing in patients with silent and symptomatic ischemia. In a study that included 131 patients with angiographically documented coronary artery disease, Bonow and associates 35 found that patients with silent ischemia were less likely to develop a decrease in left ventricular ejection fraction during exercise radionuclide ventriculography than were patients who developed angina during testing. A similar observation was made by Matsubara et al. 12 : pulmonary artery wedge pressure at peak exercise was significantly lower and the cardiac index was significantly higher in patients with silent ischemia compared with patients who experienced angina. On the other hand, Cohn and associates 36 and Vassiliadis and colleagues 37,38 found no differences in global ejection fraction or regional wall motion abnormalities during exercise testing in symptomatic and asymptomatic patients. The inclusion of patients with prior myocardial infarction in the latter two studies may explain the differences from the former study. Silent Ischemia in Patients with Diabetes Mellitus Patients with diabetes represent a classic example of patients in whom the afferent loop of the cardiac sensory mechanism is altered. The afferent fibers that accompany the cardiac sympathetic nerves are felt to be responsible for transmission of cardiac pain. Using the synthetic radiolabeled norepineph- rine analog metaiodobenzylguanidine (MIBG), Langer and colleagues 39 demonstrated a decrease in cardiac catechol- amine uptake, indicative of cardiac sympathetic denerva- tion, in patients with versus those without diabetes. This abnormality was more severe in patients with clinically documented autonomic dysfunction and in patients in whom ischemia was asymptomatic. These findings suggest a direct link between worsening of cardiac sympathetic denervation in diabetics and silent ischemia. It is well established that CAD is a major complication of diabetes mellitus, representing the ultimate cause of death in more than half of all the patients with this disease. 40 Furthermore, myocardial infarction in people with diabetes is usually more extensive and more severe than in patients who have diabetes, and is associated with higher mortal- ity. 41– 46 The Detection of Ischemia in Asymptomatic Diabe- tes (DIAD) investigators evaluated patients with type II diabetes mellitus and no symptoms suggesting CAD; 522 patients underwent adenosine sestamibi SPECT. Sixteen percent of patients had evidence of abnormal myocardial perfusion; 6% had perfusion defects ≥5% of the left ventricu- lar mass. Predictors of these moderate to large defects included male sex, diminished heart rate response to the Valsalva maneuver, and symptoms of autonomic dysfunc- tion. 47 The cohort is currently being followed for clinical outcomes. Some authors have suggested that the occurrence of silent ischemic responses in patients with diabetes appears to be related to the severity of microvascular disease, partic- ularly as manifested by microalbuminuria. The combination of micro vascular disease and silent myocardial ischemia in patients with diabetes appears to be associated with a con- siderably greater likelihood of subsequent events. 47–50 Although it is commonly accepted that asymptomatic ischemia is more common among people with than among people without diabetes, there are conflicting data regarding the frequency of silent ischemia in individuals with diabetes mellitus. The Framingham Study investigators initially reported that in subjects with diabetes, the incidence of pain- less myocardial infarction was higher than in those without diabetes. 51 Several studies suggested that diabetic patients may have a high incidence of transient silent ST changes during ambulatory Holter monitoring. 52,53 In a well- controlled patient population, Nesto et al. 54 demonstrated that only 28% of patients with diabetes who had thallium scintigraphic indications of ischemia experienced angina pectoris during a treadmill test compared with 68% of patients without a diagnosis of diabetes. An analysis of patients with diabetes enrolled in the Asymptomatic Cardiac Ischemia Pilot (ACIP) database study revealed different results when patients with and without diabetes were com- pared. As expected, multivessel disease was more common in the group with diabetes (87% vs. 74%). However, the per- centage of patients without angina during the exercise test was similar in both groups (36% and 39%, respectively). The percentage of patients with only asymptomatic ST-segment depression during the 48-hour ambulatory electrocardiogra- phy (AECG) were also comparable (94% vs. 88%, respec- tively). An even more surprising finding was that despite more extensive and diffuse CAD, patients with diabetes tended to have less measurable ischemia during the 48-hour AECG monitoring period, perhaps related to lower achieved workloads. Among patients with diabetes, total ischemic time per 24 hours, ischemic time per episode, and maximum depth of ST-segment depression were also lower compared with nondiabetic individuals. 55 A study of 1737 people with type II diabetes and known CAD referred for nuclear stress testing found the frequency of scintigraphic evidence of CAD was no different in patients without angina (39%) from those with angina (44%). However, among patients presenting with the complaint of shortness of breath, the prevalence of CAD was 51%. 56 These disparate findings suggest that such factors as selection bias (particularly with regard to comorbidities), the degree of stress to which patients with diabetes are sub- jected during diagnostic testing, and the manner in which clinical histories are obtained may affect the frequency with which ischemia is reported. silent ischemia 703 Detection and Documentation of Silent Ischemia Exercise Stress Testing Exercise testing has been the hallmark of the detection of myocardial ischemia since the development of the two-step exercise test by Masters and Geller. 57 Although ST-segment deviation in individuals with previously undetected coro- nary artery disease is the sine qua non of a positive test when used for screening purposes in a large and generally asymp- tomatic population, much interest in silent ischemia has been focused on events in patients who are known to have CAD. This interest in patients with documented CAD who are already at higher risk than the general population is perhaps in part a necessary part of the enterprise of establish- ing that silent ischemia is a bona fide physiologic phenome- non rather than an artifact of the testing methods. In a retrospective analysis of 1698 patients with CAD who under- went exercise treadmill testing, Mark and associates 58 reported that ST-segment deviation occurred in 842 (50%). These electrocardiographic (ECG) changes were painless in 242 (14%) and were accompanied by angina in 600 (35%). In this study, as in a report from the Coronary Artery Surgery Study (CASS) registry, prior angina and more frequent epi- sodes of angina during daily activity were more common among patients who developed symptoms during ischemia. Patients with exercise-induced angina were more likely to have three-vessel CAD, a shorter peak exercise time, and a lower peak heart rate, although the median degree of ST- segment deviation observed with electrocardiography was not different. 59 These findings confirmed that the presence of angina during exercise testing was likely to reproduce symptoms that occurred during everyday life, and by exten- sion, suggested that patients in whom ischemia could be provoked without producing angina (or its equivalent) were likely to experience asymptomatic ischemia during daily activity. Ambulatory Electrocardiographic Monitoring Proof that silent ischemia is a common occurrence among patients at risk for coronary heart disease has relied largely on the use of AECG (Holter) monitoring, because it has extended the ability to detect ischemia from the clinic to the daily activities of life and because it has demonstrated that “ambulant” ischemia commonly occurs during daily activi- ties even in the absence of angina. Golding and coworkers 60 initially reported that transient elevation of the ST segment occurred in seven of 174 patients undergoing Holter monitor- ing for detection of arrhythmias. It is unlikely that all epi- sodes of ST-segment depression (particularly in a population in which the presence of disease is not established) represent myocardial ischemia. However, even in patients in whom exercise-induced ischemia can be demonstrated, it is rare to detect prolonged ST-segment depression in normal subjects if proper data acquisition techniques are used. Since tran- sient changes in position can produce brief periods of devia- tion in the ST segment, changes are usually required to last for at least 30 seconds before they are interpreted as repre- sentative of possible ischemic events. Studies of individuals with a low likelihood of CAD and without cardiac symptoms have revealed episodes of ST-segment depression exceeding 30 seconds in fewer than 5% of subjects. 61 In patients with CAD, it is considerably more common to detect ST-segment deviation on Holter monitoring. Other corroborating evidence of ischemia during daily life can be found during such episodes of asymptomatic ST-segment depression. Experience with a lightweight nonimaging radionuclide gamma camera that can be worn strapped to a patient’s chest has demonstrated frequent episodic asymp- tomatic reductions in left ventricular ejection fraction during daily activity, 62 especially during periods of mental stress. 63 These episodes are often, but not always, accompanied by ST-segment depression. 64 It is therefore likely that many epi- sodes of ST-segment depression that occur in patients with obstructive CAD represent actual ischemic events in the myocardium. Conversely, ST-segment depression without reduction in the left ventricular ejection fraction may repre- sent ischemia that does not involve an amount of myocar- dium sufficient to cause left ventricular dysfunction or may be nonischemic in origin. Painless depression of the ST segment on AECG has been reported in 40% to 85% of patients with CAD. 57,65–74 In patients with unstable rest angina or recent MI, reports from some centers have indicated that as many as 50% have evidence of ambulatory ischemia, 70–74 although considerable controversy exists concerning the frequency with which ambulant ischemia can be detected. For example, in the National Heart, Lung, and Blood Institute sponsored Thrombolysis in Myocardial Ischemia study (TIMI-3) of 1473 patients with unstable angina or non–Q-wave MI, ischemia exceeding 20 minutes in duration, observed during 24 hours of Holter monitoring with results interpreted in an experi- enced core laboratory, was present in fewer than 4% of patients. 75 In most cases when ischemia is detected, multiple daily episodes are present with considerable variation in each individual patient from day to day and week to week. 66 In most such studies, between two thirds and three quarters of such episodes in any given patient are not accompanied by angina. Limitations of Ambulatory Electrocardiographic Monitoring Several important limitations of AECG should be kept in mind. Studies have repeatedly shown that ischemic ST-T changes, even though strictly defined by the Minnesota code, are not specific for CAD and can be seen in healthy individu- als or in patients with documented coronary artery disease but without provocable ischemia. On the other hand, studies performed in patients hospitalized with acute coronary syn- dromes or MI have shown relatively high frequencies of silent ST-segment shifts, and have indicated that patients in whom such shifts occur are at significantly higher risk than are those in whom they are absent. 76 However it is important to recognize that such studies have been performed in patients with extremely high a priori risk (i.e., high pretest probability) of ischemia and the results may differ in ambula- tory patients in whom the risk is lower. As during PCI, the influence of sedation on the sensation of angina should also be considered. In addition, changes in left ventricular loading 704 chapter 31 conditions may also produce alterations in the surface elec- trocardiogram and in left ventricular function, particularly in patients with depressed ejection fractions, which may be interpreted mistakenly as representing ischemia. 11 Among the many causes are T-wave inversions recorded in young adults, electrolyte disturbances, valvular heart disease, car- diomyopathy, drugs, intracranial lesions, and recent food ingestion. 77 Boon and associates 78 demonstrated that the dis- crepancy in reported ischemia greatly depends on the spe- cific criteria used to define ischemia. In an analysis of Holter monitors of 194 asymptomatic hypertensive patients, 11.3% were reported to have silent ischemia as defined using the commonly used criterion of >0.1 mV of ST segment devia- tion. When baseline ECG abnormalities were accounted for and more stringent criteria were used to define ischemia, such as eliminating sudden ST segment deviation likely to be caused by body movement requiring down-sloping of the ST segment and duration of the shifts >1 minute, as well as requiring >0.2 mV ST segment shifts in the presence of resting ST deviation, the incidence of ischemia was reduced to 5.2%. In comparison with the standard ECG, the standard two- lead AECG is relatively insensitive for detecting ischemia, even when attempts are made to reproduce the leads used during standard 12-lead electrocardiography. When patients with CAD hospitalized for USA or surgery were monitored simultaneously using both a two-lead Holter monitoring system and a 12-lead microprocessor-driven real-time ECG monitor, the 12-lead microprocessor system detected signifi - cantly more ischemic events than did the two-lead monitor and produced no false-positive results in the normal control group. 79 The utility of AECG as a quantitative technique is also unclear. Neither the total duration of ischemic ST depression nor the total number of ischemic episodes corre- sponds well with the size of scintigraphic perfusion defects 80 or with the anatomic extent of angiographic coronary artery disease. 81 However, in patients hospitalized with MI and non-ST elevation acute coronary syndromes, use of con- tinuous 12-lead electrocardiogram and continuous vector- cardiography recording devices does allow quantitative measurement of ischemia, which appears to carry prognostic significance. 82–84 Relation Between Ambulatory Electrocardiographic Monitoring and Exercise Stress Testing The presence of painless ST-segment shifts on ambulatory ECG and symptomatic status during exercise testing should be viewed as providing complementary rather than redun- dant or even competing information. Differences between ischemic responses noted on treadmill testing and on ambu- latory monitoring ischemia may be related in part to dis- similarities in the provoking stimuli. Episodes of ambulatory ischemia often occur during sedentary activity and can be provoked by stressors as diverse as mental stress, 68,85 cold exposure, 69 or cigarette smoking. 86 Psychological stressors, especially situations that trigger emotional distress, cause increases in heart rate and blood pressure and may also trigger coronary vasoconstriction. 87–89 In addition, in patients who have painless ischemic responses on ambulatory ECG, ischemia induced during exercise testing may be accompa- nied by angina. Most patients exhibit a combination of both symptomatic and symptomless ST-segment changes, although the difference between ECG characteristics of silent and symptomatic episodes in a given patient is not well documented. Both the degree of ST-segment deviation and the duration of the episodes appear to be similar. When patients with CAD are subjected to differing exercise proto- cols, ischemic ST-segment depression usually occurs at similar rate-pressure products. However, the ischemic thresh- old on ambulatory ECG monitoring is considerably more variable 88,90 and usually occurs at a lower rate-pressure product than during treadmill exercise, 66,67,90–94 even in cir- cumstances when an increase in rate-pressure product pre- cedes the onset of ischemia. 95 Deanfield et al. 66 reported that among patients with ST-segment depression on exercise testing, the ST-segment changes noted during ambulatory monitoring occurred, on average, at heart rates of 20 beats per minute (bpm) less than the ischemic threshold detected on exercise testing. These episodes also occurred more frequently in the morning hours after rising, 91,95,96 following established circadian patterns for physiologic increases in plasma catecholamines 97 and plate- let aggregability, 98 as well as in blood pressure, 99 heart rate, 92 and for such clinical events as MI 100–102 and sudden cardiac death. 103 Assessment of asymptomatic ischemia is often used to evaluate the adequacy of medical therapy. However, despite the (very) roughly concordant information they provide con- cerning whether symptoms occur during ischemia, exercise testing and the AECG may detect different effects of anti- anginal treatments. For example, the CASIS investigators evaluated the influence of amlodipine and atenolol on myo- cardial ischemia during exercise stress testing and AECG monitoring. Ischemia during treadmill testing was more effectively suppressed by amlodipine, whereas ischemia during AECG monitoring was more effectively suppressed by atenolol. The combination of both drugs was more effec- tive than either drug alone in either setting. 104 Nuclear Scintigraphy The same issues of sensitivity and specificity that led to the introduction of nuclear imaging for detection of CAD also apply to detection of ischemia. Tomographic imaging is highly reproducible and has also allowed quantification of the amount of ischemic myocardium. When these studies are interpreted by competent readers, the variation in measuring the size of an ischemia defect is less than 10% in 95% of patients. 105 As a consequence, exercise SPECT has become accepted as a very accurate technique for the evaluation of ischemia suppression. 106–108 Adenosine-induced stress during SPECT can also be used to track changes in myocardial ischemia after medical therapy as well as after mechanical revascularization. 109 Relation Between Ambulatory Electrocardiographic Monitoring and Myocardial Perfusion Imaging As mentioned above, ambulatory electrocardiographic changes in a patient with CAD may not necessarily represent silent ischemia 705 active ischemia. In the Asymptomatic Cardiac Ischemia Pilot (ACIP) study, 106 patients with recent coronary angi- ography underwent both AECG monitoring and stress SPECT within 3 days. Seventy-four percent of patients with signifi - cant CAD had SPECT abnormalities, whereas 61% had isch- emia detected by AECG monitoring. The most important predictors of SPECT abnormalities were the severity of coronary stenosis, followed by total exercise duration, and patient age. The only predictor of AECG abnormalities was the presence of ST depression on the initial treadmill test. The concordance observed between the SPECT and AECG results was only 50%, and no relation was observed between the frequency or duration of AECG ischemia and the quanti- fied myocardial perfusion defect size as assessed by SPECT. Thus, these techniques may detect different pathophysio- logic manifestations of ischemia and may be complementary in more fully defining the functional significance of CAD. 80 Exercise and Dobutamine Stress Echocardiography Exercise and pharmacologic stimulation with catecholamine derivatives increase cardiac contractility in normal subjects. Consequently, when normal segments of myocardium are visualized using echocardiography, hyperkinetic wall motion is observed. In patients with obstructive CAD and normal wall motion at baseline, ischemia becomes manifest as an abnormality of local wall contractility. Stress echocardiogra- phy has been validated as a sensitive method of ischemia detection; however, the method of evaluating wall motion during stress test depends on a semiquantitative visual eval- uation with a limited scoring scale of different grades of dyssynergy. 110,111 Despite this limitation, several studies have shown that stress echocardiography and SPECT have similar sensitivity in detecting ischemia, ranging from 58% and 61% (with echocardiography and SPECT, respectively) for one- vessel disease to 94% for three-vessel disease. 112,113 The infu- sion of dobutamine during stress echocardiography increases the degree of left ventricular dysfunction in patients with functionally significant coronary artery disease and thus may be a more sensitive indicator of ischemia. 114 On the other hand, as stressors are compounded, the degree to which this intense combination of tachycardia and increased activity reproduces the stresses experienced by an individual during everyday life becomes questionable. Anginal chest pain is frequently induced in patients with stable coronary artery disease during stress testing. However, following MI, pain during stress testing may not be associated as clearly with an increased risk of adverse event compared with patients who did not experience angina despite a similar extent of CAD. 115 Prognosis in Patients with Silent Ischemia That asymptomatic episodes of ischemia occur in patients with CAD is now established. Subsequently most attention has become directed toward determining the prognostic implications of silent ischemia, its utility at expanding the number of patients who can be identified as being at risk for catastrophic events, and the ability to extend therapy to a previously unidentified group of patients. The frequency with which ischemia is detected and the outcomes of patients with silent ischemia are likely to depend on the extent of ischemic myocardium as well as other characteristics such as age, ventricular function, and the clinical setting in which the effort to detect ischemia is undertaken. In addition, the diagnostic techniques used to detect ischemia are likely to differ depending on the clinical setting. For these reasons, conclusions concerning silent ischemia are likely to differ among ambulatory patients in whom the presence of CAD is uncertain, and patients who are hospitalized with acute coronary syndromes. Consequently, the subsequent sections of this chapter will consider patients with known CAD sepa- rately from those in whom the presence of coronary athero- sclerosis has not been determined. Prognosis in the Patient with Known Coronary Artery Disease The Bypass Angioplasty Revascularization Investigation (BARI) trial offered a unique opportunity to follow patients with multivessel CAD systematically and serially following revascularization. Protocol-mandated symptom-limited exercise treadmill testing (ETT) was performed at 1, 3, and 5 years after revascularization with either angioplasty or coro- nary artery bypass surgery. At the time of the 1-year exercise test, 26% of patients had ST segment depression during exer- cise; 82% of these patients did not report angina during exercise testing; 69% (18% of the total) had angina neither before nor during the test. Only 1% of patients who did not experience angina between the time of revascularization and exercise testing required a further revascularization; more than half of these patients had a negative exercise test. Exer- cise time at the 5-year test was associated with decreased survival 2 years after the test, but exercise parameters deter- mined on the 1- and 3-year tests were poor predictors. This study pointed out a selection bias that plagues all attempts to relate stress-induced ischemia to clinical outcome: the strongest predictor of survival was not the result of exercise testing, but whether patients were able to undergo exercise testing at all. Mortality at 5 years was 25.9% in patients who did not exercise compared with 8.1% in the group that did take the test. These results do not support routine stress testing after revascularization for multivessel disease; however, they do not exclude the use of other diagnostic modalities in patients who are unable to undergo ETT due to comorbid illnesses. 116 Details from the ROSETTA Registry provide further insight in relation to the risk of recurrent disease after a revascularization procedure. In this registry, 791 patients who had undergone PCI were followed to determine the difference in cardiac events between patients who received “routine” (i.e., in the absence of angina) versus “selective” (clinically determined) functional testing after revascular- ization. After adjustment for baseline risk characteristics, routine functional testing allowed prediction of a composite of cardiac events at 6 months in patients who had undergone balloon angioplasty but not among patients who had under- gone coronary stenting. 117 The implication of these two studies is that in the initial period after revascularization, routine surveillance for ischemia in the asymptomatic 706 chapter 31 patient is likely to be fruitful only if the perceived risk of either graft failure or restenosis is high (e.g., after balloon angioplasty without stenting or after placement of bare metal stents over a long segment of coronary artery). However, the longer-term implications are less clear, particularly in patients with more severe disease or in patients who have received saphenous vein grafts at the time of bypass surgery. When 356 patients recruited in a Dutch study underwent routine follow-up angiography and scintigraphic stress testing 6 months after PCI, 62% of patients with target vessel reste- nosis were asymptomatic. Follow-up for 4 years revealed a risk gradient with the lowest risk for patients without isch- emia, greater risk of recurrent events in patients with silent ischemia, and the greatest risk in patients with symptomatic ischemia. 23 Prognosis in Asymptomatic Patients Without Known Coronary Artery Disease Elhendy and associates 118 evaluated the utility of exercise echocardiography in 1618 middle-aged patients (average age 55 years with low risk for CAD based on a prespecified algorithm). In this very low risk cohort, the rates of cardiac mortality and nonfatal MI were 0.1 and 0.25 per 100 person- years, respectively. In models used to predict cardiac events using clinical variables, exercise stress variables, and echo- cardiography variables in a sequential fashion, none of the exercise ECG features predicted future cardiac events. Changes in the wall motion score index predicted outcome; however, over half of the patients with subsequent cardiac events did not have abnormal stress echocardiographic results. Taken in aggregate, these findings call into question the routine use of exercise testing to screen low-risk asymp- tomatic patients. Marwick and associates 119 evaluated the utility of exer- cise stress echocardiography for predicting mortality in a cohort of 1859 patients without angina or other evidence of CAD. Only four (0.2%) patients developed angina during exercise and 215 (12%) patients developed ST-segment depres- sion during exercise, indicating that the vast majority of ischemic episodes in this cohort were silent. Overall annual- ized mortality was 0.9%, with annualized cardiac mortality of 0.2%. Although ischemia detected by stress echocardiog- raphy was a predictor of mortality at an average of 4.7 years, multivariate analysis revealed that only resting ejection frac- tion and Duke treadmill score (annualized mortality 2% for an intermediate- or high-risk score and 0.4% for patients with a low-risk score) were predictive of outcomes. These findings suggested that in a group with a low a priori risk of cardiac events, the detection of silent ischemia provides little prognostic information. A clearer perspective on the relation of basal risk to the prognostic value of silent exercise-induced ischemia comes from the Kuopio Ischemic Heart Disease (KIHD) risk factor study. Laukkanen and associates 120 performed bicycle ergome- try on 1769 asymptomatic middle-aged men with a broad spectrum of known risk factors for CAD. Eleven percent of participants had silent ischemia during exercise and an addi- tional 3.1% had silent ischemia after exercise. After adjust- ing for conventional risk factors, men with silent ischemia during exercise had an increased risk of acute coronary events and of cardiac death, 1.7- and 3.5-fold, respectively. Using men without ischemia as a reference group, there was a clear relationship between the presence of risk factors and the likelihood of cardiac death during follow-up. Viewed in light of the preceding studies, it appears that the prognostic information contained in the detection of silent ischemia increases as patients’ baseline risk increases. In one of the largest epidemiologic reports of silent ischemia published to date (Reykjavik study), 9139 randomly selected men were screened with a standard resting 12-lead ECG and followed for 4 to 24 years. Patients were categorized by the presence of ischemic symptoms and indications of ischemic heart disease on the resting ECG. The prevalence of ST-T changes (classified as ischemic by the Minnesota code) in the absence of angina among men without overt coronary artery disease was strongly influenced by age, increasing from 2% at age 40 years to 30% at age 80 years. Men with ST-T changes, but no symptoms were older and had higher serum triglyceride levels, more frequently were hypertensive, had left ventricular hypertrophy, and took antihypertensive medications, digitalis, or diuretics. The serum cholesterol level did not differ between the two groups. After adjustment for other risk factors, the risk ratio among men with silent ST segment shifts was 2.0 for death from CAD and 1.6 for subsequent MI in men with these ST changes when compared with asymptomatic men with no evidence of exercise-induced alterations in the ST segment. 121 Although the prognostic value of stress testing in women has also been assessed, 122,123 there are currently no data to indicate whether the frequency or prognosis of silent ischemia differs accord- ing to sex. Ambulatory Electrocardiographic Monitoring, Exercise Stress Test, and Prognosis The prognosis associated with asymptomatic myocardial ischemia detected using electrocardiographic means also appears to be related to the overall clinical risk group from which patients are selected. Ambulatory electrocardio- graphic findings in patients hospitalized in a coronary care unit with unstable rest angina are associated with a high likelihood of impending MI. On the other hand, studies in patients with stable manifestations of CAD tend to indicate that the risk associated with silent myocardial ischemia is more questionable. Quyyumi and colleagues 81 studied patients with CAD categorized as low risk (i.e., excluding patients with left main disease, three-vessel disease with left ventricular dysfunction at rest, three-vessel disease with inducible ischemia, two-vessel disease with impaired left ventricular function, and inducible ischemia). Among these “low-risk” patients, 39% had ST depression during AECG monitoring; 82% of those episodes were asymptomatic, which, however, did not predict higher risk for cardiac events in the future. In a retrospective analysis of 1402 patients with ECG evidence of ischemia during treadmill testing, Cole and Elle- stad 124 reported that coronary events (cardiac death, MI, or progression of angina) were twice as frequent in patients with symptomatic ischemia than those with silent ischemia. In reviewing the 5-year outcome of 842 consecutive patients in the Duke Cardiovascular Database who had angiographi- silent ischemia 707 cally documented coronary disease and abnormal exercise test results, Mark et al. 58 found that patients with silent ischemia during exercise testing had significantly better overall survival and infarct-free survival rates than did patients with angina. Similarly, among 1773 veteran patients referred for treadmill testing, a difference in mortality at 2 years was observed based on the development of angina during exercise. 125 The importance of asymptomatic ischemia on exercise testing after MI is often debated. Villella et al. 126 studied 6296 patients undergoing an exercise test an average of 28 days after intravenous thrombolytic therapy for a myocardial infarction. Residual ischemia was detected in 26% of patients, of whom 67% were asymptomatic. The 6-month mortality was 1.7% for those with a positive test, 0.9% for those who had a negative test, and 1.3% for patients whose test was not diagnostic. After adjustment for myocardial ischemia accom- panied by symptoms of angina, only symptomatic induced ischemia and low-work capacity were associated with an increased risk of death at 6 months, although asymptomatic ischemia was not. Even after analysis of silent ischemia by the occurrence of ST-segment depression at maximal or sub- maximal levels of exercise or on the degree of ST-segment depression, exercise-induced asymptomatic myocardial isch- emia was not significantly associated with a higher risk of death compared with exercise stress testing with negative results. The ability to exercise for more than 6 minutes was a predictor of good prognosis regardless of the associated ECG changes. The Asymptomatic Cardiac Ischemia Pilot (ACIP) trial contributed significantly to our understanding the impor- tance of silent ischemia. 127 Conti et al. 127 compared the outcome of patients who had angina either within the 6 weeks prior to enrollment or during the period of the study. These investigators reported that symptomatic patients in ACIP had a higher incidence of death, MI, or hospitalization for ischemic events (15.3% symptomatic vs. 7.8% asymptom- atic per 12 months). Interestingly, this difference was present mainly in patients who had angina within the 6 weeks pre- ceding the study period. Unlike patients who were symptom- atic during the period of recruitment, patients with angina occurring only during AECG or stress testing were not found to have a higher incidence of adverse cardiac events than asymptomatic patients. 128 Nuclear Imaging and Prognosis In recent years, tomographic myocardial scintigraphy has gained acceptance as the most widely used and reliable measure of the quantity of myocardium that is ischemic. Consequently, the relationship between ischemic defect size and prognosis has recently garnered much attention. There is consensus that, viewed on the background of other risk factors for mortality, the size of the ischemic defect is related to the likelihood of suffering a cardiac event. Reports from several large nuclear laboratories indicate a largely dichoto- mous relationship. Defects exceeding 15% to 20% of the myocardium are associated with a significantly higher likeli- hood of catastrophic events at 1 to 2 years than are smaller defects. While the concept that the quantity of myocardium at risk determines a patient’s outcome is not new, it is worth noting that several investigators have established that the si ze of a n ischem ic defe ct is a cr itic al deter mi na nt of outcome, independent of symptoms. 129 Treatment of Silent Myocardial Ischemia While the treatment of ischemia for the purpose of relieving angina or dyspnea has been established for several decades, the management of asymptomatic ischemia has been a matter of greater controversy. Only recently as revasculariza- tion techniques, particularly percutaneous coronary inter- ventions with the use of drug-eluting stents, have been refined, and the results become more robust, has consensus been reached about the use of revascularization strategies to treat ischemia in the asymptomatic patient. The ACIP trial was designed as a pilot study to determine precisely whether suppression of silent ischemia was possible using one of three strategies: angina-guided medical therapy, ischemia-guided medical therapy, or revascularization using balloon angioplasty or bypass surgery. Patients selected for this study had evidence of myocardial ischemia on both ambulatory and exercise treadmill testing. Ischemia sup- pression after a period of 12 weeks using medical therapy was performed using one of two regimens: (1) atenolol and nifedipine, or (2) diltiazem and isosorbide dinitrate. With a regimen of atenolol and nifedipine, ischemic changes on the AECG could be suppressed in 47% of patients. In the group treated with diltiazem and isosorbide dinitrate, ischemia was suppressed in 31% of patients. In the medical therapy group, the average doses (combined ischemia- and angina- guided therapy) of each medication at 12 weeks were as follows: atenolol 84 mg, nifedipine 34 mg, diltiazem 91 mg, and isosorbide dinitrate 36 mg. Thus, the degree of medical therapy can be described as moderately intense. The degree of ischemia suppression was similar in the ischemia- and in the angina-guided groups. The revascularization strategy led to suppression of ischemia in 70% of patients having bypass surgery versus 46% of patients undergoing angioplasty. It is likely that the prevalent use of drug-eluting stents would increase the latter figure significantly. The findings of other trials have been similar. In CASIS, patients were selected according to the presence of ischemia during treadmill testing and ambulatory monitoring and subsequently were assigned to receive either atenolol or amlodipine. Each group underwent a counterbalanced, cross- over evaluation of single drug and placebo, followed by evalu- ation of the combination. Suppression of ischemia during exercise testing and ambulatory monitoring was similar in patients with and without exercise-induced angina. Exercise time to angina improved by 29% with amlodipine, 16% with atenolol, and 39% with combination therapy. Similarly in the ASIST trial, after 4 weeks of treatment with atenolol of patients with Canadian Cardiovascular class I or II angina, the number and duration of ischemic episodes on ambulatory ECG decreased significantly compared with placebo. 104 In a similar study, Frishman and colleagues 130 were able to sup- press ambulatory ischemia as well as exercise-induced isch- emia using a long-acting preparation of verapamil, atenolol, or amlodipine. In a smaller study, Dakik et al. 109 compared intensive medical therapy to percutaneous revascularization 708 chapter 31 in minimally symptomatic patients with large ischemic defects (total defect ≥20% and ischemic defect ≥10% of the left ventricle) on thallium scintigraphy in patients after recent myocardial infarction. The medical regimen in this trial was much more intense compared with those in other studies. The average daily dose of medications was 113 ± 23 mg of isosorbide dinitrate, 131 ± 57 mg of metoprolol, 272 ± 58 mg of diltiazem, and the extent of ischemia was measured by highly reproducible adenosine thallium 201 SPECT. The above medical regimen resulted in a 12% ± 10% reduction in the ischemic defect size and was equally effec- tive as angioplasty. Results of Suppressing Ischemia The relationship between suppression of ischemia and clini- cal outcome still remains uncertain, particularly in patients with stable manifestations of CAD. However, in ACIP, at 1 year, mortality was 4.4% in the angina-guided group, 1.6% in the ischemia-guided group, and 0% in the revascularization group. There was a direct correlation between number of ischemic episodes on ambulatory ECG and event rate. However, it must be kept in mind that this trial was a pilot study with confidence levels too broad to allow definitive conclusions to be drawn. In ASIST, there was a nonsignificant trend for fewer serious events (death, resuscitation from ven- tricular fibrillation/tachycardia, nonfatal MI, or hospitaliza- tion for unstable angina) in atenolol-treated patients compared with those assigned to placebo. The most powerful univariate and multivariate correlate of event-free survival was the absence of ischemia on an ambulatory ECG 4 weeks after beginning therapy. Most data available thus far indicate that event-free survival is likely to be related to the reduction of the amount of ischemia present regardless of the presence or absence of symptoms and the treatment chosen. Large trials comparing revascularization to aggressive medical therapy (COURAGE, BARI 2D, INSPIRE) are currently nearing com- pletion. It is likely that these trials will contain substantial proportions of patients with asymptomatic ischemia and will provide guidance for selecting therapies in the future. Summary The clinical manifestations of CAD range from sudden death to transient asymptomatic ischemia noted on ambulatory ECG monitoring. Although the exact mechanism causing ischemia to be asymptomatic has not been elucidated, there is evidence that multiple mechanisms contribute. The clini- cal implication of silent ischemia varies depending on the setting in which it occurs. 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Arterioscler Thromb Vasc Biol 2004;24(7):1171–1179 Epub 2004 May 1176 106 Kuller LH Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women’s Health Initiative Arterioscler Thromb Vasc Biol... coronary angiography who underwent coronary reactivity assessment with a median follow-up of 48 months In this study, impaired coronary vasomotor response to acetylcholine was independently linked to adverse cardiovascular outcomes regardless of coronary artery disease severity.91 Reduced coronary vasodilator function and impaired response of resistance vessels to increased sympathetic stimulation, as seen... exogenous hormones likely play a role in their effects on coronary disease in women Hormone replacement treatment has both prothrombotic and antiatherogenic effects, and its failure in reducing the risk of cardiovascular events in postmenopausal women might be because of the stage of their atherosclerosis at the time of initiation of treatment.105 Furthermore, the early increased risk of CHD and stroke with . comparable extent of stress hypoperfusion (22 % ± 12% vs. 22 % ± 13%). 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