Silent Myocardial Ischemia: Diagnosis, Treatment, and Prognosis

Silent myocardial ischemia is a major component of the total ischemic burden for patients with coronary artery disease (CAD); it is estimated that between 2 and 3 million persons with stable CAD have evidence of silent ischemia. Although statistically hard data are lacking on how treatment affects prognosis, management should aim to reduce or eliminate myocardial ischemia by risk factor modification, aggressive medical therapy and, if appropriate, myocardial revascularization.

Silent myocardial ischemia (SMI)— objective documented ischemia in the absence of chest discomfort or other anginal equivalents—is a major component of the total ischemic burden for patients with ischemic heart disease.¹ In the United States, an estimated 2 to 3 million persons with stable coronary artery disease (CAD) have evidence of silent ischemia. ² About 40% of patients with ischemic heart disease have acute episodes of myocardial ischemia during their lifetime; 75% of these episodes cause no symptoms and are considered “silent.”¹

Greater awareness of the incidence of silent ischemia in high-risk populations (eg, persons with diabetes) can help reduce cardiovascular events and death rates. In this review, we outline the evidence that supports the relationship between SMI and the risk of future cardiovascular events. We also offer recommendations for the diagnosis and management of SMI.

COHN CLASSIFICATION OF SILENT ISCHEMIA

Patients at increased risk for cardiovascular events include those with stable angina, unstable angina, postinfarction angina, or variant angina; those who have survived cardiac arrest or have had a heart transplant or percutaneous coronary intervention or bypass surgery; and those who have diabetes or multiple coronary risk factors.³

According to the Cohn classification,⁴ patients with silent ischemia are stratified into types I, II, or III:

• Type I silent ischemia is the least common form. It occurs in asymptomatic patients with obstructive CAD who do not experience anginal symptoms at any time.
• Type II silent ischemia most commonly occurs in patients with a documented previous myocardial infarction (MI).
• Type III is the most common form; it occurs in patients with chronic stable angina, unstable angina, or variant angina.

PROGNOSTIC SIGNIFICANCE OF SILENT MYOCARDIAL ISCHEMIA

In patients with ischemic heart disease, SMI occurs more often than does the typical episode of angina. A large body of evidence shows that cardiovascular outcomes for patients with SMI are similar to those with symptomatic ischemia.^5,6

SMI and cardiovascular risk. Weiner and colleagues⁵ evaluated a cohort of patients with CAD to determine whether SMI that occurred during exercise increased the risk of MI or sudden death. Of 880 patients who, within 1 month of undergoing catheterization, had a symptom-limited maximal exercise test using Bruce protocol, 424 evidenced ST-segment depression of 1 mm or more without angina. The investigators compared this group with 456 CAD patients who had ST-segment depression and angina during exercise testing, and with 1019 controls without CAD.

The percentages of CAD patients who experience subsequent MI or sudden death were similar in the silent ischemia and angina groups (20% and 9% vs 18% and 7%, respectively). However, the likelihood of MI or sudden death in patients with silent ischemia increased with the severity of CAD and left ventricular (LV) dysfunction. Of patients presenting with SMI, 62% had 3-vessel CAD with abnormal LV function and experienced subsequent MI or sudden death, compared with only 10% of patients with 1-vessel CAD and preserved LV function. The adverse event rate for patients with 3-vessel CAD and SMI was greater than that for patients with 3-vessel disease and angina. Of note, 48% of patients in the cohort had SMI during exercise testing; 65% had a history of angina at the baseline evaluation. Clinically, patients without warning signs of angina would be at increased risk.

Recently, Erne and colleagues,⁷ in the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I) randomized multicenter trial, enrolled 263 asymptomatic patients with 1 CAD risk factor, with silent ischemia identified by exercise treadmill testing (ETT) stress imaging. Fifty-one patients were randomized to antianginal drug treatment. Over the next 11 years, 3 patients in the medical treatment group experienced cardiac death, nonfatal MI, or acute coronary syndrome compared with 17 in the control group (P < .001).

SMI and chronic stable angina. Deedwania and Carbajal⁸ studied a small cohort of patients with documented CAD and chronic stable angina who underwent 24-hour ambulatory ECG monitoring while receiving antianginal medications prescribed by their primary care physicians. Forty-six patients (43%) had evidence of SMI during monitoring; 61 patients (57%) had no evidence of ischemia. In the first group, most ischemic events were silent (87%) and comprised 84% of the total ischemia time. Cumulative survival at 1 year and 2 years was significantly less (P = .023) for patients with SMI during ambulatory ECG monitoring.

In a more recent trial (the Heart and Soul Study), Gehi and associates⁹ evaluated self-reported angina by questionnaire and inducible ischemia using treadmill stress echocardiography in 937 outpatients with chronic stable angina during a 3.9-year followup period. They found that more than 80% of these patients did not report angina, with a 2-fold increase in recurrent MI or coronary heart disease (CHD) death (adjusted hazard ratio, 2.1; 95% confidence interval, 1.3 - 3.5) (P = .005)

SMI and unstable angina. Gottlieb and colleagues10 studied patients with unstable angina whose symptomatic ischemia had been nearly eliminated with therapy. In this population, persistent SMI evident on Holter monitoring was associated with more severe CAD. Compared with patients in whom SMI was absent, those with SMI were more likely to experience early (within 30 days) adverse outcomes of MI or recurrent symptoms requiring revascularization, as well as late (after 2 years) adverse outcomes including death or recurrent MI. Similar observations were evident in patients after recent angioplasty.^10,11

SMI following MI. Among patients about to be discharged following hospitalization for an MI, treadmill testing revealed that exerciseinduced ischemia with or without angina was associated with increased risk of coronary events and cardiac death.^12,13 In addition, a prospective study by Narins and associates⁶ that evaluated 500 patients who underwent ambulatory monitoring and stress thallium scintigraphy 1 to 6 months after an episode of unstable angina or MI found that 75% of the patients had evidence of SMI.

SMI without documented CAD or angina. Two studies have detected a significant association between exercise testing-induced SMI and mortality. The Lipid Research Clinics Coronary Primary Prevention Trial enrolled 3806 asymptomatic men with hypercholesterolemia who were randomized to cholestyramine or placebo treatment groups; 8.2% had a positive ETT and over the next 7.4 years (mean) the mortality rate from CHD was 6.7% (21/315) in the positive ETT group and 1.3% (46/3460) in the negative ETT group.¹⁴

The Multiple Risk Factor Intervention Trial (MRFIT) enrolled 12,866 middle-aged men who were asymptomatic and had 2 or more cardiovascular risk factors.¹⁵ During the next 6 to 8 years of follow-up, patients in the special intervention programs to reduce blood pressure, lipid levels, and cigarette smoking had a 7% lower CAD mortality rate than the control population. Global risk reduction was beneficial in this population of patients with an abnormal ETT who had no previous documented CAD.

The SWISSI I evaluated asymptomatic subjects without CAD but with at least 1 risk factor for CAD who had silent ischemia on ETT confirmed by stress imaging.⁷ These patients were divided into an antianginal drug group (included aspirin) (n = 26) and a risk factor control group (n = 28). During the next 11 years of follow-up, 3 (12%) of the medical treatment group versus 17 (61%) of the risk factor control patients (P < .001) experienced cardiac death, nonfatal MI infarction, or acute coronary syndrome requiring hospitalization or revascularization. The investigators concluded that patients with positive ETT and documented abnormal stress imaging should receive aspirin and global risk reduction.

In another population-based study of 2682 men without CAD, exercise- induced ischemia increased mortality and the risk of acute coronary syndrome by 5.9- and 3-fold in patients who smoked, by 3.8- and 1.9- fold in patients with hypercholesterolemia, and by 4.7- and 2.2-fold in those with hypertension.¹⁶ These observations underscore the importance of determining absolute cardiovascular risk.

CLINICAL ASSESSMENT

Although this review focuses on SMI, a large percentage of patients with ischemic heart disease have both symptomatic and silent episodes. Symptomatic ischemia may not present with classic anginal symptoms but with anginal equivalents such as dyspnea, fatigue, or palpitations. Dyspnea is a subjective symptom with several possible causes; it is typically associated with heart failure or chronic lung disease. However, when dyspnea occurs in a patient who has cardiovascular risk factors, consider a cardiac cause.²

Additional symptoms may include palpitations (or a subjective description of “rapid heartbeat”) and fatigue Patients may describe fatigue as an inability to walk long distances or as feeling a sudden onset of weakness. Obtain a detailed history, including subjective changes as detailed above, and note any cardiovascular risk factors. Patients who exhibit these symptoms may need to be evaluated for CAD.