ABSTRACT: Silent myocardial ischemia increases the risk of sudden death and other adverse events in patients with coronary artery disease (CAD). The simplest, least costly way to detect ischemia-whether silent or symptomatic-is exercise testing with ECG monitoring. However, if no symptoms are associated with ST-segment abnormalities during the test, these ECG changes may represent false-positive results and further testing (eg, Doppler echocardiography or radionuclide ventriculography) is required. The optimal management strategy for patients with CAD and silent myocardial ischemia remains unclear. However, current evidence suggests that risk factor modification, medical therapy and, in appropriate patients, revascularization interventions (eg, percutaneous coronary interventions, coronary artery bypass graft surgery) reduce the risk of adverse cardiac events.
Only a small percentage of patients with coronary artery disease (CAD) have angina pectoris. In most patients, CAD is asymptomatic. Similarly, many patients with myocardial ischemia have no related symptoms; however, diagnostic studies reveal the characteristic findings, such as ST-segment changes, perfusion defects, and wall motion abnormalities.
Which patients are at risk for myocardial ischemia? Does silent ischemia have the same clinical significance as symptomatic ischemia? What is the optimal treatment strategy? Here I examine the available evidence to answer these questions; however, definitive answers await the results of future large-scale, long-term trials.
MANIFESTATIONS OF CARDIAC ISCHEMIA
During coronary angioplasty, ischemia is intentionally produced.1 Balloon occlusion of a coronary artery has been shown to reduce coronary blood flow and alter regional flow- demand ratios, resulting in the following abnormalities:
A decrease in coronary sinus oxygen concentration.
Relaxation failure and contraction failure.
A rise in left ventricular and diastolic pressures.
ECG changes (eg, ST-segment depression or elevation).
These abnormalities usually exist for only a short period, and chest discomfort may never even occur.
Although the mechanism that underlies asymptomatic myocardial ischemia is not known, several hypotheses have been set forth (Box).
WHEN TO SUSPECT MYOCARDIAL ISCHEMIA
Both symptomatic and silent myocardial ischemia can occur in patients with all types of ischemic heart disease, including:
Those with stable, unstable, variant, or post-infarction angina.
Cardiac arrest survivors.
Those who have undergone cardiac transplantation, coronary angioplasty, or coronary bypass surgery.
In addition, patients with multiple risk factors for CAD and some patients with diabetes are at heightened risk for myocardial ischemia.2 In most patients with symptomatic myocardial ischemia, ambulatory electrocardiography or exercise testing will demonstrate episodes of silent ischemia as well.3
HOW BEST TO DETECT AND CONFIRM SILENT ISCHEMIA
Table 1 lists the methods used to detect and confirm myocardial ischemia. The simplest, least costly way to detect ischemia-whether silent or symptomatic-is exercise testing with ECG monitoring. ST-segment deviation on a 12-lead ECG, either at rest or during exercise-induced chest discomfort, indicates myocardial ischemia (Figure). The ambulatory ECG also has been shown to be a useful method to detect ECG changes compatible with myocardial ischemia during activities of daily living.
However, if no symptoms are associated with ST-segment abnormalities during the test, these ECG changes may represent false-positive results. About 8% of apparently healthy American men aged 35 to 55 years will experience ST-segment depression during treadmill exercise, but only about half of the 8% will have proven CAD.4 In asymptomatic patients who have these ECG changes, further investigation is required to find additional evidence of myocardial ischemia, such as radionuclide perfusion abnormalities or regional wall motion abnormalities during echocardiography. The reversal of ST-segment depression or elevation following the administration of nitrates or after a revascularization procedure also suggests strongly that the ECG changes are related to myocardial ischemia.
CLINICAL SIGNIFICANCE OF SILENT MYOCARDIAL ISCHEMIA
Silent myocardial ischemia may result in sudden cardiac death. How often this occurs is not known. In the Framingham Study, half of the cases of sudden death during an acute myocardial infarction (MI) had been preceded by episodes of silent ischemia at least 2 weeks before the attack.5
Weiner and colleagues6 evaluated survival in the Coronary Artery Surgery Study Registry. Over a 7-year follow-up period, mortality was lower among patients with no evidence of ST-segment depression or angina than among those with angina and ST-segment depression, angina without ST-segment depression, or only ST-segment depression and no angina during exercise testing.Deedwania and associates7 showed that among patients with chronic stable angina, those with transient ST-segment depression on an ambulatory ECG had a poorer prognosis than those without this abnormality. Other investigators have made similar observations in patients with unstable angina,8,9 in those who had an MI,10,11 and in those who had recently undergone angioplasty.12
The optimal treatment of silent myocardial ischemia remains unclear. The evidence suggests that medical treatment or revascularization improves the prognosis.13 Two studies, the Asymptomatic Cardiac Ischemia Pilot (ACIP) Trial and the Atenolol Silent Ischemia Study (ASIST), assessed the effects of treatment in patients with silent myocardial ischemia and documented CAD.
The ACIP Trial. In this NHLBI-sponsored, multicenter, multinational trial, my colleagues and I compared 3 arms of therapy in 558 patients with CAD documented by coronary angiography, a positive stress test for myocardial ischemia, and ST-segment deviation on a 48-hour ambulatory ECG (one episode of which had to be silent).14 Patients with left main coronary artery stenoses, recent MI, or unstable angina were excluded. Of the patients included in the ACIP Trial, 41% had no history of angina, 48% had no angina during exercise-induced ST-segment depression, 90% had no angina during 48-hour ambulatory electrocardiography in which transient ST-segment depression was noted, and 29% had no angina in their history or during exercise testing or ambulatory electrocardiography.
Participants were randomized to an angina-guided strategy (medications to suppress angina), an ischemia-guided strategy (medications to suppress angina and evidence of ischemia on an ambulatory ECG), and a revascularization strategy (either percutaneous coronary interventions or coronary artery bypass graft surgery). Combination medical therapy consisted of either atenolol/nifedipine or diltiazem/isosorbide dinitrate. Active medication to control angina was available at any time during the study in all treatment groups.
At 12 weeks, 48-hour ambulatory electrocardiography was performed to assess patients in all 3 groups for ischemia; this was the primary outcome of the study. The ECG evidence of myocardial ischemia decreased regardless of the therapy used.15
In the medical therapy arms, the percentages of patients with no evidence of ischemia on the week-12 ambulatory ECG were nearly identical (38.9% in the angina-guided strategy group; 41.3% in the ischemia-guided strategy group). However, a higher percentage (54.7%) of patients in the revascularization arm had no ischemia demonstrated on the ambulatory ECG. The difference between the revascularization arm and both medical therapy arms was statistically significant (P < .001).
Coronary revascularization also reduced the average number of abnormal ECG leads and episodes of ST- segment depression during exercise-induced myocardial ischemia compared with the medical strategies. In addition, at 12 weeks, patients randomized to revascularization required fewer drugs than those randomized to either medical treatment arms of the trial. Thus, in the short term, revascularization reduced or eliminated ischemia better than either ischemia-guided or symptom-guided drug therapy.
Limitations of the trial design. The difference between the revascularization strategies and the medical therapy strategies may be related to the fact that the medications were not advanced to maximal dosages in most patients. Thus, many patients (60%) in the drug therapy groups continued to have evidence of ischemia on the ambulatory ECG. In the revascularization group, a significant percentage of patients (45%) also had persistent evidence of ischemia on the ambulatory ECG at 12 weeks. This may have been the result of incomplete revascularization.
In addition, although aggressive risk modification was recommended, there was no protocol-driven lipid-lowering therapy, blood pressure control, weight control, diabetes control, smoking cessation, or exercise programs.
Clinical outcomes in the ACIP Trial. The study was not powered to assess the end points of death, MI, or hospitalization for recurrent angina; however, these events were tracked over a 2-year period (Table 2). When the combined 2-year cumulative rates of death, MI, or hospitalization for cardiac disorders were assessed, the rate for angina-guided therapy was 41.8%; for ischemia-guided therapy, 38.5%; and for revascularization therapy, 23.1%. Thus, revascularization seemed to be the optimal strategy to relieve myocardial ischemia and decrease clinical events, given the caveat that much of the medical therapy was not guided by current protocols.
ASIST. This study included 306 patients with minimal or no angina pectoris, an abnormal exercise test result, and silent ischemia detected by ambulatory ECG monitoring. Patients were randomly assigned to receive atenolol (100 mg) or placebo.
After 4 weeks, the number and average duration of episodes of silent ischemia detected by ambulatory electrocardiography decreased significantly in those who received atenolol (P < .001). In addition, the risk of future adverse cardiac events at 1 year was reduced in the treatment group.16 n
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