Author + information
- Received July 31, 2000
- Revision received March 27, 2001
- Accepted April 10, 2001
- Published online August 1, 2001.
- Suneet Mittal, MD, FACCa,
- Steven C Hao, MDa,
- Sei Iwai, MDa,
- Kenneth M Stein, MD, FACCa,
- Steven M Markowitz, MD, FACCa,
- David J Slotwiner, MDa and
- Bruce B Lerman, MD, FACCa,* ()
- ↵*Reprint requests and correspondence:
Dr. Bruce B. Lerman, Division of Cardiology, The New York Hospital-Cornell Medical Center, 525 East 68th Street, Starr 4, New York, New York 10021
This study was designed to determine the incidence and prognostic significance of inducible ventricular fibrillation (VF) in patients with coronary artery disease (CAD) and unexplained syncope.
Current American College of Cardiology/American Heart Association practice guidelines recommend implantation of internal cardioverter-defibrillators (ICDs) in patients with unexplained syncope in whom either ventricular tachycardia (VT) or VF is inducible during electrophysiologic (EP) testing. Although the prognostic significance of inducible monomorphic VT is known, the significance of inducible VF remains undefined.
We evaluated 118 consecutive patients with CAD and unexplained syncope who underwent EP testing. Sustained monomorphic VT was inducible in 53 (45%) patients; in 20 (17%) patients, VF was the only inducible arrhythmia; and no sustained ventricular arrhythmia was inducible in the remaining 45 (38%) patients. The latter two groups of 65 (55%) patients make up the study population.
There were 16 deaths among the study population during a follow-up period of 25.3 ± 19.6 months. The overall one- and two-year survival in these patients was 89% and 81%, respectively. No significant difference in survival was observed between patients with and without inducible VF (80% power to detect a fourfold survival difference).
In 17% of patients with CAD and unexplained syncope, VF is the only inducible ventricular arrhythmia. Within the limits of this pilot study, long-term follow-up of patients with and without inducible VF demonstrates no difference in survival between the two groups. Therefore, the practice of ICD implantation in patients with CAD, unexplained syncope and inducible VF, especially with triple ventricular extrastimuli, may merit reconsideration.
Electrophysiologic (EP) testing is frequently performed to identify an arrhythmic cause for unexplained syncope (1–11). Because patients with syncope and inducible ventricular tachycardia (VT) have an increased mortality (12,13), they are often implanted with internal cardioverter-defibrillators (ICDs), even in the absence of a clinically documented sustained ventricular tachyarrhythmia (13–16). The rationale of this approach has been confirmed in follow-up studies demonstrating, in these patients, a high incidence of spontaneous VT requiring ICD therapy (13–16).
Although the adverse prognostic significance of inducible monomorphic VT in these patients is clear, the significance of inducible ventricular fibrillation (VF) is less certain because induction of this arrhythmia during EP testing (especially with triple ventricular extrastimuli) is generally considered a nonspecific finding (17,18). Nonetheless, according to current American College of Cardiology/American Heart Association practice guidelines, induction of “clinically relevant, hemodynamically significant sustained VT or VF induced at electrophysiology study” in patients with “syncope of undetermined origin” is a class I indication for ICD implantation (19).
In this study, we evaluated patients with coronary artery disease (CAD) and unexplained syncope who underwent EP testing. All patients were treated with an EP-guided approach, which included ICD implantation only in patients with inducible monomorphic VT. The specific aims of this study were 1) to determine the incidence of inducible VF in patients with CAD and unexplained syncope and 2) to study the natural history of these patients.
We evaluated 118 consecutive patients with CAD and unexplained syncope who underwent EP testing between January 1994 and December 1999. We excluded patients with a documented sustained ventricular arrhythmia or those resuscitated from sudden cardiac death.
Before undergoing EP testing, all patients underwent an extensive evaluation, which failed to identify a cause for syncope. This evaluation included at least 24 h of inpatient or ambulatory ECG monitoring, assessment of left ventricular ejection fraction (LVEF) by echocardiography, radionuclide ventriculography or LV cineangiography and assessment of underlying CAD by stress testing with nuclear perfusion imaging or cardiac catheterization. Patients with a negative EP study were advised to undergo tilt testing, which was performed according to one of our previously published protocols (20,21).
After written informed consent was obtained, all patients underwent EP testing as previously described (13). No patient was on an antiarrhythmic drug at the time of clinical presentation or EP testing. Patients were locally anesthetized with 0.25% bupivacaine and lightly sedated with midazolam and/or morphine. Under fluoroscopic guidance, two or three 5F or 6F quadripolar catheters with 5-mm interelectrode spacing (Bard EP, Billerica, Massachusetts; Daig, Minnetonka, Minnesota) were advanced to the high right atrium across the tricuspid valve to record a His-bundle potential and to the right ventricular apex and/or outflow tract. Bipolar intracardiac electrograms were filtered at 30 to 500 Hz and displayed on a digital monitor. Data were recorded on magnetic tape or optical disk (Prucka Engineering, Houston, Texas). Programmed stimulation was performed with an isolated current source (Bloom Associates, Reading, Pennsylvania), and stimuli were delivered as rectangular pulses of 2 ms duration at four times diastolic threshold with a minimum current of 2.0 mA.
Sinus node function was evaluated by the corrected sinus node recovery time and sinoatrial conduction time. Atrioventricular (AV) nodal function was assessed by atrial extrastimulus testing and incremental atrial pacing. Programmed ventricular stimulation included up to triple ventricular extrastimuli at two cycle lengths from two right ventricular sites. Extrastimuli were delivered until ventricular refractoriness was reached. Patients with a negative baseline study received isoproterenol (1–5 μg/min titrated to increase heart rate by >20% over baseline), and programmed stimulation was repeated. No patient underwent stimulation from the LV. Sustained monomorphic VT was defined as the only positive end point of ventricular stimulation.
Coronary artery disease was defined as 1) >50% reduction in luminal diameter of at least one of the three major epicardial coronary arteries, 2) a documented myocardial infarction (MI), or 3) a perfusion abnormality on nuclear imaging in ≥1 coronary artery territory. Sinus node dysfunction was defined as a corrected sinus node recovery time ≥550 ms or a sinoatrial conduction time of ≥125 ms. Significant His-Purkinje system dysfunction was defined as: 1) an HV interval of ≥100 ms at baseline, or 2) the development of infra-Hisian block with rapid atrial pacing at a cycle length ≥400 ms. Sustained monomorphic VT was defined as monomorphic VT, regardless of cycle length, lasting ≥30 s or requiring termination because of hemodynamic compromise. Patients with inducible VF included those with sustained polymorphic VT as well as VF. Deaths were classified as cardiac, noncardiac or unknown, based on the assessment of the referring physicians. Sudden death was defined as death occurring while the patient was asleep or within 1 h of the onset of symptoms.
Patients with inducible monomorphic VT (regardless of cycle length of induced tachycardia) received a tiered-therapy ICD. Noninducible patients with sinus node, AV node, His-Purkinje system dysfunction or carotid sinus hypersensitivity received a dual-chamber pacemaker. No other patient, including those with inducible VF, received antiarrhythmic drug or device therapy upon hospital discharge.
Patients with an ICD or pacemaker were followed in our arrhythmia clinic every three to six months. Stored electrograms were retrieved from ICD recipients. Patients who did not receive a device were followed by telephone contact. Information was obtained from referring physicians regarding initiation of new antiarrhythmic drugs, recurrence of syncope or the identification of an alternative etiology for syncope.
All continuous variables are expressed as mean ± SD. Comparisons of patients with inducible VF and noninducible patients were made using the chi-square or Fisher exact test (for categorical variables) and the Student ttest for independent samples (for continuous variables). A Kaplan-Meier survival curve was generated to compare the total mortality of patients with and without inducible VF. Comparison of survival between the two groups was made using the log-rank statistic. A p value <0.05 was considered statistically significant.
Of the 118 patients with CAD and unexplained syncope who underwent EP testing, 53 patients (45%) had inducible monomorphic VT. These patients were reported previously and were excluded from further analysis (13).
The remaining 65 patients (55%) (53 men, 12 women) make up the study population. The mean age of these patients was 69 ± 10 years, and the mean LVEF was 42 ± 13%. Twenty-seven patients (42%) had at least two syncopal episodes before diagnostic evaluation. Triple-vessel CAD was present in 36 patients (59%), and 34 patients (52%) had a history of MI. Nonsustained VT (9 ± 4 beats) was documented in 27 (42%) patients. Demographics of the study population are summarized in Table 1.
The baseline rhythm was sinus in 57 patients (88%), atrial fibrillation or flutter in seven patients (11%), and one patient (1%) was AV paced from a permanent pacemaker previously implanted for 3° AV block. Of the 57 patients in sinus rhythm, four patients (7%) had first-degree AV delay. Bundle branch block was present in 23 (35%) patients, which included left bundle branch block in seven patients, right bundle branch block with a left anterior or posterior hemiblock in 12 patients and a nonspecific intraventricular conduction delay in four patients. Additional findings included pathologic Q waves in 15 patients (23%) and LV hypertrophy in three patients (5%).
Cardiac catheterization was performed in 61 (94%) patients. Of these 61 patients, 11 (18%) had single-vessel coronary disease, 14 (23%) had double-vessel coronary disease, and 36 (59%) had triple-vessel coronary disease. A diagnosis of CAD was made on the basis of nuclear stress testing in the remaining four patients (6%). Prior percutaneous transluminal coronary angioplasty had been performed in 11 patients (17%), and 36 patients (55%) had undergone prior coronary artery bypass grafting.
Of the 57 patients with sinus rhythm in whom sinus node function could be evaluated, sinus node dysfunction was documented in 16 (28%). An additional two patients had carotid sinus hypersensitivity documented during EP testing. Neither AV nodal re-entrant tachycardia nor AV reciprocating tachycardia was inducible in any patient. The mean HV interval was 53 ± 10 ms. Only one patient had severe His-Purkinje system dysfunction. In this patient with underlying left bundle branch block, the HV interval increased from 63 to 150 ms during rapid atrial pacing.
Ventricular fibrillation was inducible in 20 (31%) of the 65 patients. These patients represent 17% of the 118 patients with CAD and unexplained syncope who underwent EP testing. Induction was achieved with double ventricular extrastimuli in two patients (10%) and with triple ventricular extrastimuli in the remaining 18 patients (90%) (Table 2). In one patient VF was induced only during infusion of isoproterenol. The remaining 45 patients (69%) had no inducible sustained ventricular arrhythmia. Patients with and without inducible VF were similar with respect to age, gender, LVEF, severity of CAD, underlying conduction system disease, ventricular effective refractory period and length of follow-up (Table 1).
Twenty-one (32%) of the 65 patients received a permanent pacemaker. Indications for pacemaker implantation included sinus node dysfunction in 13 patients, which was documented during EP testing in 12 patients. In one patient, despite normal sinus node function by EP parameters, an episode of symptomatic sinus bradycardia was documented on telemetry the day after the EP study. Four patients with documented sinus node dysfunction at EP testing did not undergo pacemaker implantation. These included three patients with minimal sinus node dysfunction (corrected sinus node recovery time of 579 ms and sinoatrial conduction time of 131 and 135 ms, respectively) and one patient (sinoatrial conduction time of 151 ms) who refused pacemaker implantation.
Additional indications for pacemaker implantation included AV node disease in two patients, manifest as atrial fibrillation with a slow ventricular response; carotid sinus hypersensitivity in two patients; His-Purkinje system disease in three patients and vasovagal syncope in one patient. Patients with His-Purkinje system disease included two patients with bifascicular block and recurrent syncope. The patient with vasovagal syncope had a positive tilt test and was treated with a beta-blocker. However, a pacemaker was ultimately required because the patient developed intolerable weakness and fatigue while on beta-blocker therapy. The incidence of pacemaker implantation in patients with inducible VF (four, 20%) was similar to patients without inducible VF (17, 38%, p = 0.16). No patient was discharged on an antiarrhythmic drug or received an ICD.
Follow-up was available in 61 patients (94%) at a mean of 25.3 ± 19.6 days (range one to 72.1 months). During this period, nine patients (15%) had at least one recurrence of syncope. In two patients, neurocardiogenic syncope was diagnosed on the basis of a positive tilt test, which was not performed at the initial evaluation. In an additional patient, syncope was attributed to hypotension induced by overdiuresis. A cause for syncope could not be determined in the other six patients. None of these nine patients died during the follow-up period.
Sixteen patients (26%) died during the follow-up period at a mean of 22.6 ± 18.5 months (range 1.1 to 61.6 months). The one- and two-year survival in these patients was 89% and 81%, respectively. Of these 16 patients, six had inducible VF, and 10 were noninducible for any ventricular tachyarrhythmia. There was no significant difference in the overall survival of patients with and without inducible VF (p = 0.39, Fig. 1). We also compared the overall survival in the subset of patients with an LVEF of ≤40%. In this group, the survival of patients with inducible VF (n = 10; LVEF: 34 ± 7%) was not different from patients without inducible VF (n = 24; LVEF: 33 ± 8%, p = 0.84).
Overall there were four cardiac deaths. Two deaths were sudden (one in each group), one resulted from congestive heart failure, and one resulted from an acute MI. There were eight noncardiac deaths, with etiologies including malignancy (n = 2), respiratory failure (n = 2), end-stage renal disease (n = 1), pancreatitis (n = 1), sepsis (n = 1) and suicide (n = 1). The causes of death were similar in patients with and without inducible VF. In four patients (all without inducible VF), the cause of death could not be determined.
The principal finding of this study is that in 17% of patients with CAD and unexplained syncope, VF is the only inducible ventricular tachyarrhythmia. Ventricular fibrillation is most commonly induced with triple ventricular extrastimuli. Long-term follow-up of patients with inducible VF and those without an inducible ventricular tachyarrhythmia demonstrates no difference in survival, suggesting that induction of VF with triple ventricular extrastimuli in these patients may have no discernible prognostic significance.
In patients with CAD and unexplained syncope, the induction of monomorphic VT appears to be a highly specific finding. Long-term follow-up of these patients has revealed a high incidence of spontaneous monomorphic VT requiring ICD therapy (13–16). In fact, the cycle length of the spontaneous VT is highly correlated with the cycle length of VT induced during EP testing (16). It is important to emphasize that, in contrast to some prior investigations (14,16), our definition of VF did not include patients with an induced monomorphic tachycardia cycle length ≤220 ms. We have previously demonstrated (13)that induction of monomorphic VT is of prognostic significance, regardless of the induced tachycardia cycle length.
The significance of inducible VF has been evaluated in a number of prior studies. None of these studies has demonstrated inducible VF to be of adverse prognostic significance. In patients with recent MI, VF is inducible in 14% to 33% of patients; however, the one- and two-year probability of remaining free from cardiac death or nonfatal VT or VF is virtually identical to that of patients without any inducible ventricular arrhythmia (22,23).
Findings in patients with syncope who undergo EP testing suggest a similar conclusion. For example, in an evaluation of 224 patients, including 137 patients who presented with presyncope or syncope, VF was inducible in 8% of patients, most commonly with triple ventricular extrastimuli (24). Patients with and without a history of presyncope or syncope had a similar incidence of inducible VF. No patient with inducible VF suffered a cardiac arrest or sudden death during a follow-up period of more than two years.
More recently, Link et al. (14)reported their experience in 282 patients with unexplained syncope who underwent EP testing. Their study population was heterogeneous with respect to underlying cardiac diseases. Of these 282 patients, 82 had an inducible ventricular arrhythmia, including 16 patients with inducible VF. An ICD was implanted in nine of these 16 patients; VF was induced with double ventricular extrastimuli in six of these patients and with triple ventricular extrastimuli in the remaining three patients. During follow-up, although three of the six patients in whom VF was induced with double ventricular extrastimuli had an ICD discharge, none of the patients in whom VF was induced with triple ventricular extrastimuli had an appropriate ICD discharge. However, because the ICDs were not capable of providing stored electrograms, it was not possible to determine the specific arrhythmia that precipitated the ICD discharge.
Finally, Buxton et al. (25)recently reported follow-up of patients with CAD, LVEF ≤40% and nonsustained VT who underwent EP-guided therapy. Over a five-year follow-up period, no difference in the arrhythmic event rate was observed between patients who were noninducible and those in whom polymorphic ventricular tachyarrhythmias were induced with triple ventricular extrastimuli.
This study has several important limitations. First, because all our patients had CAD, the applicability of the data to other forms of structural heart disease is unknown. In fact, several studies have suggested that, in contrast to patients with CAD, patients with nonischemic cardiomyopathy and unexplained syncope have a poor prognosis even when no ventricular arrhythmia is inducible during EP testing (26,27). Second, because VF was rarely induced with double ventricular extrastimuli, our study cannot determine whether there is a prognostic difference between induction of VF with double or triple ventricular extrastimuli.
Finally, this study is limited by its small sample size. Therefore, it is possible that a “real” difference in survival between patients with and without inducible VF may have inadvertently been missed. For example, based on the mortality data observed in these patients, our study had an 80% power to detect a fourfold difference in survival between patients with and without VF. A more clinically meaningful difference may be a 25% difference in survival between patients with and without inducible VF. However, to detect such a difference at a power of 80% (with an alpha level of 0.05), a prospective study would need to enroll approximately 2,500 patients. To date, the only study of this magnitude performed in the field of electrophysiology was MUSTT (25), which took nearly a decade to complete. Therefore, in the foreseeable future, decisions regarding management of patients with CAD, unexplained syncope and inducible VF need to be made on the basis of observational data from smaller studies.
Although the prognostic significance of inducible monomorphic VT in patients with unexplained syncope has been confirmed in several studies, the significance of inducible VF has not been established. Our data suggest that induction of VF in patients with CAD and unexplained syncope may be of limited prognostic significance. This finding is of significant clinical importance because VF is the only inducible ventricular arrhythmia at EP testing (using up to triple ventricular extrastimuli) in 17% of these patients. Therefore, the practice of ICD implantation in patients with syncope of undetermined origin in whom only sustained VF is induced during EP testing, especially with triple ventricular extrastimuli, may merit reconsideration.
☆ This work was supported in part by grants from the National Institutes of Health (RO1 HL-56139) and the American Heart Association, Grant-in-Aid, New York City Affiliate.
- coronary artery disease
- implantable cardioverter-defibrillator
- left ventricle, left ventricular
- left ventricular ejection fraction
- myocardial infarction
- ventricular fibrillation
- ventricular tachycardia
- Received July 31, 2000.
- Revision received March 27, 2001.
- Accepted April 10, 2001.
- American College of Cardiology
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