Author + information
- Received February 15, 2005
- Revision received March 27, 2005
- Accepted April 13, 2005
- Published online November 1, 2005.
- Abdou Elhendy, MD, PhD, FACC⁎ (, )
- Scott Chapman, MD,
- Thomas R. Porter, MD, FACC and
- John Windle, MD, FACC
- ↵⁎Reprint requests and correspondence:
Dr. Abdou Elhendy, 982265 Nebraska Medical Center, Omaha, Nebraska 68198-2265
Objectives We sought to assess the relation between myocardial ischemia during stress echocardiography and major events in patients with implantable cardioverter-defibrillator (ICD).
Background The association of myocardial ischemia with subsequent ICD therapy and mortality is unknown.
Methods We studied 90 patients (age 65 ± 13 years, 27 women) with history of coronary heart disease who received ICD for primary (53 patients) or secondary (37 patients) prevention of sudden cardiac death. Sixty-five (72%) patients had a previous coronary artery bypass surgery. Patients underwent exercise treadmill or dobutamine stress echocardiography. Ischemia was defined as new or worsening wall motion abnormalities. End points were death and appropriate ICD therapy.
Results Mean ejection fraction was 34 ± 12%. During a mean follow-up of 2.8 ± 1.5 years, 5 patients died and 19 patients had ICD therapy. Ischemia was detected in 20 of 24 patients with subsequent events and in 24 of 66 patients without (83% vs. 36%, p < 0.001). Events occurred in 17 of the 32 patients (53%) with both ischemia and inducible ventricular tachycardia (VT) on electrophysiologic (EP) studies. None of the 16 patients without ischemia or inducible VT on EP studies had events. In a Cox multivariate analysis model, independent predictors of events were a history of spontaneous sustained VT (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.3 to 3.8), inducible VT on EP studies (HR 1.7, 95% CI 1.2 to 4.5), and ischemia (HR 2.1, 95% CI 1.2 to 3.5).
Conclusions Ischemia during stress echocardiography is an independent predictor of death and ICD therapy in patients with coronary heart disease at high risk of arrhythmic death. Patients without inducible ischemia or VT on a previous EP study have a very low risk of events. A combination of ischemia and a positive EP study is associated with a very high risk of events.
Several randomized clinical trials have demonstrated the usefulness of the implantable cardioverter-defibrillator (ICD) for the prevention of sudden cardiac death caused by ventricular tachyarrhythmias (1–5). Recent advances in ICD technology have resulted in an increase in the number of ICD recipients and expansion of ICD indications (6). The occurrence of sustained ventricular arrhythmias with subsequent ICD therapy in these patients has major clinical implications (7–12). Implantable cardioverter-defibrillator shocks often cause major discomfort and psychological distress and might lead to more frequent hospital visits and necessitate addition of antiarrhythmic drugs with potential toxicities (7,8). Some studies have reported an association of multiple ICD therapy with increased risk of death (7). Identification of a precipitating factor for sustained ventricular arrhythmias might potentially lead to reducing the incidence and frequency of ICD therapy.
Coronary artery disease (CAD) is the underlying mechanism of left ventricular dysfunction and ventricular arrhythmias in the majority of ICD recipients (5). Amelioration of myocardial ischemia with revascularization procedures in the appropriate patients is attempted before or in conjunction with ICD implantation in patients with ischemic heart disease and sudden cardiac death or with high risk of arrhythmic death; however, incomplete revascularization, progression of native CAD, restenosis after percutaneous interventions, and graft occlusion might compromise myocardial perfusion in patients with ICD and contribute to further myocardial damage, arrhythmias, or worsening of heart failure symptoms.
Stress echocardiography is an increasingly used tool for functional evaluation of patients with known or suspected CAD (13–17). Myocardial ischemia assessed by this technique was shown to predict adverse outcome (13–17), although the association of myocardial ischemia with mortality and ICD therapy in patients at high risk of arrhythmic death has not been previously studied. The aim of this study was to find whether myocardial ischemia on stress echocardiography can predict mortality and major arrhythmic events in patients with an ICD.
The study population consisted of 90 consecutive patients with history of CAD, treated with an ICD for secondary or primary prevention of sudden cardiac death, who underwent dobutamine or exercise stress echocardiography for evaluation of myocardial ischemia between September 1997 and December 2002 at the University of Nebraska Medical Center, Omaha, Nebraska. A history of CAD was defined as previous myocardial infarction, myocardial revascularization, and/or >50% luminal diameter stenosis of >1 major epicardial coronary arteries in a previous coronary angiogram. Exclusion criteria were unstable chest pain and congestive heart failure functional class IV unresponsive to medical therapy. All patients gave an informed consent to undergo the stress echocardiography test. The Institute Review Board of the University of Nebraska Medical Center approved the protocol of the study.
Stress echocardiography protocols
Beta-blockers were discontinued at least 24 h before the stress echocardiogram. Other medications were not discontinued. Serum electrolytes were not routinely measured. Some particular precautions are required in our laboratory when stressing patients with ICD. All the stress studies in these patients are performed in the presence of a cardiologist and a nurse practitioner who is experienced in the management of an ICD device. The ICD is made in an inactive mode before the stress test and is activated after the recovery (18). In anticipation of any serious tachyarrhythmias, the patients should be continuously monitored and supervised. The ICD should be activated immediately to deliver a shock if the patient develops ventricular fibrillation or had ventricular tachycardia (VT) that is sustained and not responding to test termination, metoprolol, or lidocaine.
Symptom-limited exercise treadmill stress test was performed in 15 patients (17%) with the standard Bruce protocol. End points were significant symptoms reported by the patient (angina, fatigue, dizziness, dyspnea), >2 mV downsloping ST-segment depression measured 80 ms from the J point compared with baseline, symptomatic decrease in systolic blood pressure, and symptomatic or sustained ventricular or supraventricular tachycardia. Dobutamine stress test was performed in 75 patients (18). Dobutamine was infused at a starting dose of 5 μg/kg/min for 3 min, followed by 10 μg/kg/min for 3 min (low-dose stage). The dobutamine dose was increased by 10 μg/kg/min every 3 min up to a maximum dose of 50 μg/kg/min. Atropine (up to 2 mg) was administered intravenously if 85% of maximal predicted heart rate (220 − age) was not achieved. End points of dobutamine stress test were achievement of target heart rate, maximal dose of dobutamine and atropine, extensive new wall motion abnormalities, >2 mm downsloping ST-segment depression measured 80 ms from the J point compared with baseline, hypertension (blood pressure >240/120 mm Hg), symptomatic decrease in systolic blood pressure, symptomatic or sustained ventricular or supraventricular tachycardia, or any intolerable adverse effect considered to be the result of dobutamine. Metoprolol (1 to 5 mg) was used intravenously to reverse the side effects of dobutamine if these did not revert quickly after termination of dobutamine infusion. The ICD was reactivated 6 min after the stress test.
Echocardiographic imaging and interpretation
Images were acquired at rest and immediately after exercise stress. In patients who underwent dobutamine stress, images were acquired at rest, low dose, peak stress, and recovery. Images were recorded on videotapes, and the baseline and stress images were recorded in a quad-screen format. For segmental analysis of left ventricular function, a 16-segment model was used as suggested by the American Society of Echocardiography (19). Each segment was scored with a 5-point scale, with 1 = normal, 2 = mild hypokinesis, 3 = severe hypokinesis, 4 = akinesis, and 5 = dyskinesis. Ejection fraction at rest was measured with a previously validated modification of the method of Quinones et al. or by visual estimation (20,21). Ischemia was defined as new or worsened wall motion abnormalities during stress indicated by an increase of wall motion score ≥1 grade in ≥1 segment. Biphasic response to dobutamine in a dyssynergic segment was considered as an ischemic response. Akinesis becoming dyskinesis was not considered an ischemic response (22).
Follow-up was obtained by scheduled clinic visit to the electrophysiology (EP) clinic of our institute. Patients underwent a regular ICD interrogation at an average interval of six months or shorter if clinically required. Hospital records were also reviewed. Patients who underwent myocardial revascularization were censored at the time of revascularization. The end points considered were death and appropriate ICD therapy defined as an antitachycardia pacing therapy or shock for arrhythmia determined to be either VT or ventricular fibrillation. Death was considered cardiac if it was caused by acute myocardial infarction, significant cardiac arrhythmias, or refractory heart failure. Sudden unexpected death occurring without another explanation was included as cardiac death. Verification of events was performed by an investigator who did not participate in interpretation of the echocardiograms.
Continuous data are presented as mean values ± SD. The chi-square test was used to compare differences between proportions. The Student ttest was used for analysis of continuous data. Cox regression models were used to identify predictors of follow-up events. Variables included in the multivariate model were the variables that were significant (p < 0.05) in the univariate analysis. The probability of survival with freedom from ICD therapy was calculated with the Kaplan-Meier method. Event-free survival curves were compared in patients with and without ischemia by using the log-rank test. Differences were considered significant if the null hypothesis could be rejected at the 0.05 probability level.
Clinical data are presented in Table 1.Indications for stress testing were evaluation of chest pain in 50 patients, functional assessment after revascularization in 26 patients, and detection of a reversible cause of heart failure in 14 patients. The EP studies were positive for inducible sustained monomorphic VT in 62 (69%) patients. The ICD was placed in the remaining patients: those without inducible VT because of history of sudden cardiac death (16 patients), recurrent symptomatic VT patients who failed to tolerate or to respond to antiarrhythmic therapy (4 patients), and those with severe left ventricular dysfunction with spontaneous non-sustained VT (8 patients). Fourteen (16%) patients had atrial fibrillation as a baseline rhythm. The stress test was performed 3 ± 2.1 years after ICD implantation. Among patients with previous myocardial revascularization, the stress test was performed at a mean of 3.5 ± 2.8 years since the last revascularization procedure.
Stress test and echocardiographic data
There was a significant increase of heart rate (71 ± 14 vs. 137 ± 16 beats/min) from rest to peak stress. The target heart rate was reached in 81 (90%) patients. Systolic blood pressure increased with exercise (144 ± 26 vs. 165 ± 32 mm Hg), but not with dobutamine (142 ± 29 vs. 140 ± 35 mm Hg). There was no incidence of death, myocardial infarction, ventricular fibrillation, or sustained VT during or shortly after the stress test. Non-sustained VT occurred in six (7%) patients and supraventricular tachycardia occurred in two (2%) patients. One patient developed transient atrial fibrillation. Arrhythmias were terminated spontaneously, by stopping dobutamine infusion or by administration of metoprolol. Among the six patients with induced VT, two had inducible ischemia. Four of the six patients with stress induced VT had electrolyte levels measured within one week. None had a serum potassium level <3.6 mEq.
The mean dobutamine dose was 36 ± 9 μg/kg/min. Atropine was used in 35 (39%) patients; ST-segment depression occurred in 17 (21%) patients and angina occurred in 14 (17%) patients. Mean ejection fraction was 34 ± 12%. Ischemia was detected in 44 (49%) patients.
During a mean follow-up of 2.8 ± 1.5 years (range, 6 to 62 months), 5 patients died and 19 patients had appropriate ICD therapy (shock in 14 patients and antitachycardia pacing in 5 patients). Thirteen (14%) patients underwent revascularization during follow-up and were censored at the time of revascularization (10 of these patients had inducible ischemia). Among the 34 patients with ischemia who did not undergo revascularization, 10 patients preferred medical treatment, 3 patients had mildly obstructive CAD, 9 patients had angiographic stenosis of low feasibility for intervention, 5 patients had renal dysfunction and were considered at very high risk of contrast nephropathy requiring dialysis, and 7 patients were considered to have mild ischemia and were advised to continue medical treatment.
All of the five patients who died during follow-up had inducible ischemia. Four of these patients had both peri-infarction and remote ischemia, and one had only remote ischemia. Death was classified as cardiac in three patients. Other causes of death were stroke in one patient and complications of peripheral vascular disease in one patient. Clinical and echocardiographic data of patients with and without events (death and ICD therapy) are presented in Table 2.Patients who had events more often had a history of spontaneous sustained VT, inducible VT at EP studies, and ischemia on stress echocardiogram.
Thirty-two patients had both ischemia and positive EP study; events occurred in 17 (53%) of them. Thirty patients had positive EP study without ischemia; events occurred in 4 (13%) of them. Twelve patients had ischemia and negative EP study; events occurred in 3 (25%) of them. No events occurred among the 16 patients who had neither ischemia nor positive EP study.
Predictors of events
Significant variables from Table 2were considered in the Cox multivariate analysis model. The independent predictors of events in the Cox model were a history of spontaneous sustained VT (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.3 to 3.8, p < 0.01), inducible VT on EP studies (HR 1.7, 95% CI 1.2 to 4.5, p < 0.01), and myocardial ischemia (HR 2.1, 95% CI 1.2 to 3.5, p < 0.01). Age and resting ejection fraction were not significant in univariate analysis or after being forced in the Cox model. Survival curves with freedom of ICD therapy in patients with and without ischemia are presented in Figure 1.
Implantable cardioverter defibrillator therapy is a leading cause of hospital admission in ICD recipients (7,8). In addition to quality of life issues, multiple shocks were shown to act as potent predictors of survival independent of several other risk factors, particularly ejection fraction (7). Therefore, identification of reversible causes of sustained ventricular arrhythmias in these patients might have important clinical implications.
In this study, we assessed the relation between myocardial ischemia during exercise or dobutamine stress echocardiography and the occurrence of death or appropriate ICD therapy in 90 patients with history of CAD who received an ICD for primary or secondary prevention of sudden cardiac death. The majority of patients have received previous myocardial revascularization. The test was tolerated in all patients without serious side effects. During a mean follow-up of 2.8 years, 5 patients died and 19 had appropriate ICD therapy. A history of sustained VT, inducibility at EP studies, and myocardial ischemia during stress echocardiography were independently associated with increased risk of events. Myocardial ischemia remained an independent predictor of events, even after forcing age in the ejection fraction in the Cox model.
Our finding of an association of myocardial ischemia with adverse events in patients with ICD suggests that detection and appropriate treatment of myocardial ischemia in these patients might reduce the incidence or frequency of ICD therapy and thereby obviate the adverse effects of these events on patients’ quality of life, cost of health care, and need for additional antiarrhythmic therapy with potential side effects. The association of myocardial ischemia with events can be explained by the findings of previous studies, which have demonstrated that myocardial ischemia acts as a trigger of serious tachyarrhythmias when superimposed on a substrate of fibrotic myocardium (23–25). In our study, a combination of inducible VT on EP studies and ischemia on the stress echocardiogram was associated with a very high risk (53%) of events, whereas the risk was very low in the group of patients with neither ischemia nor inducible VT on EP studies. From these findings, it appears that ischemia might be a trigger of arrhythmias, particularly in patients with an existing substrate.
It is essential to emphasize that the results of this study apply to a largely symptomatic population, with the majority of patients studied at an intermediate follow-up after revascularization. This is, however, the group of patients in whom stress testing is clinically required to assess myocardial ischemia.
Stress testing in patients with an ICD
There are currently scarce data regarding the experience with stress testing in patients with an ICD. We have recently reported the safety and feasibility of dobutamine stress echocardiography for evaluation of myocardial ischemia in patients with an ICD (18). Gioia et al. (26) studied 101 patients with history of ventricular arrhythmias (31 patients after ICD implantation) with exercise or vasodilator single photon emission computed tomographic imaging. The extent of fixed (but not reversible) perfusion abnormalities was predictive of mortality during a follow-up of 29 months (27).
van der Burg et al. (27) studied 153 survivors of sudden death who underwent stress-rest perfusion imaging. Patients with ischemic/viable myocardium (n = 73) were revascularized if possible. Implantation of ICD was performed in 112 (72%) patients. During three-year follow-up, 15 cardiac deaths occurred and 42 (29%) patients had recurrent ventricular arrhythmias. Patients with events had a lower ejection fraction, more extensive scar, less ischemic/viability on perfusion imaging, and less frequently underwent revascularization. Multivariate analysis identified extensive scar and an ejection fraction ≤30% as the only predictors of death/recurrent ventricular arrhythmias. The discrepancy between their results and ours can be explained by the fact that stress testing was performed before revascularization in their study with possible amelioration of ischemia. In our study, ischemia was elicited after revascularization.
Clinical predictors of mortality and ICD therapy
Rinaldi et al. (9) studied 155 patients implanted with an ICD. Therapy occurred in 53 (34%) patients. Patients with therapy had a lower ejection fraction and more often had a positive EP study compared with patients without therapy. Patients with dilated cardiomyopathy had a high incidence of ICD therapy. In these patients EP results were poor predictors of ICD therapy. Anvari et al. (11) studied 200 patients with ICD during a follow-up of 27 ± 18 months, the actuarial incidence of appropriate shocks was 18%, 36%, and 72% at 1, 3, and 5 years, respectively. Coronary artery disease was the only significant predictor for shock occurrence. One possible explanation of these findings on the basis of the results of our study is the presence of ischemia among patients with CAD.
Pires et al. (28) reported that for many ICD recipients who sustained cardiac death, death ensued despite appropriate ICD therapy, suggesting acute adverse events as common terminal factors. Because the majority of their patients had CAD, it is possible that a major ischemic event was the underlying reason of sudden death in some of these patients.
One limitation of the study is the lack of data on diastolic left ventricular function. Therefore, it is not known whether ischemia is independently associated with events after adjustment for diastolic function. Although this study confirms our previous data on safety of dobutamine stress test in ICD patients (18), further studies including larger number of patients are required to clarify the safety of stress testing in these patients.
Summary and conclusions
Myocardial ischemia on stress echocardiography is associated with an increased risk of mortality and ICD therapy in patients with CAD at high risk of arrhythmic death. Therefore, myocardial ischemia should be thought of as a reversible cause of arrhythmic events in these patients. Patients without inducible ischemia or VT on a previous EP study have a very low risk of events. A combination of ischemia and a positive EP study is associated with a very high risk of events. Further studies are required to assess whether amelioration of ischemia can reduce the incidence of events in ICD recipients.
- Abbreviations and Acronyms
- coronary artery disease
- confidence interval
- hazard ratio
- implantable cardioverter-defibrillator
- ventricular tachycardia
- Received February 15, 2005.
- Revision received March 27, 2005.
- Accepted April 13, 2005.
- American College of Cardiology Foundation
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