Author + information
- Received November 19, 1997
- Revision received April 27, 1998
- Accepted May 8, 1998
- Published online September 1, 1998.
- Wolfram Grimm, MDa,*,
- Jürgen Hoffmann, MDa,
- Volker Menz, MDa,
- Kathrin Luck, MDa and
- Bernhard Maisch, MDa
- ↵*Address for correspondence: Wolfram Grimm, MD, Department of Cardiology, Hospital of the Philipps-University Marburg, Baldingerstraße, 35033 Marburg, Germany
Objectives. This study investigated the role of programmed ventricular stimulation (PVS) for arrhythmia risk prediction in patients with idiopathic dilated cardiomyopathy (IDC) and spontaneous nonsustained ventricular tachycardia (VT).
Background. Nonsustained VT in patients with IDC has been associated with a high incidence of sudden cardiac death.
Methods. Over the course of 4 years, 34 patients with IDC, a left ventricular (LV) ejection fraction ≤35%, and spontaneous nonsustained VT underwent PVS. All patients were prospectively followed for 24 ± 13 months.
Results. Sustained ventricular arrhythmias were induced in 13 patients (38%). Sustained monomorphic VT was induced in three patients (9%), and polymorphic VT or ventricular fibrillation (VF) in another 10 patients (29%). No sustained ventricular arrhythmia could be induced in 21 study patients (62%). Prophylactic implantation of third-generation defibrillators (ICDs) with electrogram storage capability was performed in all 13 patients with inducible sustained VT or VF, and in nine of 21 patients (43%) without inducible sustained VT or VF. There were no significant differences between the additional use of amiodarone, d,I-sotalol, and beta-blocker therapy during follow-up in patients with and without inducible VT or VF. During 24 ± 13 months of follow-up, arrhythmic events were observed in nine patients (26%) including sudden cardiac deaths in two patients and ICD shocks for rapid VT or VF in seven patients. Arrhythmic events during follow-up occurred in four of 13 patients with inducible ventricular arrhythmias compared with five of 21 patients without inducible ventricular arrhythmias at PVS (31% vs. 24%, p = NS).
Conclusion. PVS does not appear to be helpful for arrhythmia risk stratification in patients with IDC, a left ventricular ejection fraction ≤35%, and spontaneous nonsustained VT. Due to the limited number of patients, however, the power of this study is too small to exclude moderately large differences in outcome between patients with IDC with and without inducible VT or VF.
Implantable cardiac defibrillator (ICD) therapy has recently been shown to be superior to antiarrhythmic drugs for increasing overall survival in survivors of ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) causing severe symptoms (1). In addition, prophylactic ICD therapy has been demonstrated to improve survival in selected postinfarct patients with a left ventricular (LV) ejection fraction ≤35%, nonsustained VT on Holter, and inducible, nonsuppressible VT on electrophysiologic study (2). Prophylactic ICD implantation at the time of elective coronary bypass surgery, however, has failed to improve survival among patients with coronary heart disease, a depressed LV ejection fraction, and an abnormal signal-averaged electrocardiogram (ECG) (3)without previous programmed ventricular stimulation (PVS). Thus, for the present, electrophysiologic studies have a central role in identifying high-risk patients with coronary artery disease in whom prophylactic ICD implantation is indicated (2,3). In contrast to ischemic cardiomyopathy, very little information is available about the usefulness of PVS for arrhythmia risk prediction in patients with nonsustained VT in the setting of idiopathic dilated cardiomyopathy (IDC) (4–17). The purpose of the present study, therefore, was to prospectively examine the association between the result of PVS and subsequent arrhythmic events in patients with IDC and spontaneous nonsustained VT without a history of VT or VF.
From March 1993 until February 1997, 34 out of 172 screened patients (20%) presenting with IDC at our institution were enrolled in this study. Inclusion criteria for study enrollment were: 1) documented nonsustained VT on Holter with ≥3 consecutive ventricular premature beats with a rate >120 bpm; 2) LV ejection fraction ≤35% without >50% stenosis of any major coronary arteries during cardiac catheterization; 3) LV enlargement by angiography and echocardiography; and 4) absence of valvular heart disease, systemic hypertension, excessive alcohol abuse, or other conditions known to cause cardiomyopathy. One hundred and thirty-eight patients with IDC were excluded because they had an ejection fraction >35% (63 patients), had no nonsustained VT on Holter (50), had a history of sustained VT or VF (4), had chronic amiodarone therapy (9), or did not consent to study participation (12). In addition to diagnostic cardiac catheterization with coronary angiography and left ventricular angiography, endomyocardial biopsy was performed in 31 of 34 study patients (91%). The histologic findings of all these patients were abnormal, with varying degrees of hypertrophy and fibrosis. There was no evidence for acute myocarditis or specific heart muscle disease in any of these patients. The clinical characteristics of the 34 study patients and the 138 screened but not enrolled patients with IDC are summarized in Table 1.
Written informed consent was obtained from all patients. Electrophysiologic studies were performed in the nonsedated, postabsorbtive state after all antiarrhythmic agents had been discontinued for at least five drug half-lives. After local anesthesia had been obtained using 2% Novocaine, three 6-Fr quadripolar electrode catheters were inserted percutaneously through the femoral veins and advanced to the high lateral right atrium, across the tricuspid valve to record the His bundle electrogram and to the right ventricular apex in 26 of 34 study patients. In the remaining eight patients with continued oral anticoagulation with coumadine, a single 6-Fr quadripolar electrode catheter was inserted through the right or left basilic or cephalic vein and advanced under fluoroscopic guidance to the right ventricular apex and subsequently to the right ventricular outflow tract. No His bundle recordings were obtained in the latter eight patients. Surface electrograms from leads I, II, III, V1, and V6, and all intracardiac recordings were displayed simultaneously on a computer screen and continuously stored on optical disk (CardioLab; Prucka). Measurements of time intervals were performed manually at a screen speed of 200 mm/s. Stimulation was performed with a custom-designed, programmable stimulator (UHS 20; Biotronic) with stimuli 1 ms in duration at two times diastolic threshold. Programmed stimulation was performed with up to three extrastimuli at two basic drive cycle lengths (600 or 500 ms and 400 ms), starting at the apex, then at the outflow tract. Coupling intervals of extrastimuli were decreased in 10-ms intervals until coupling intervals of 200 ms were reached, refractoriness of all extrastimuli was reached, or a sustained ventricular arrhythmia was induced. The endpoint of stimulation was induction of a sustained ventricular arrhythmia or completion of the protocol. Of note, coupling intervals <200 ms were not tested in order to avoid nonspecific induction of polymorphic ventricular arrhythmias at very short coupling intervals. When a countershock was required to terminate an arrhythmia, no efforts were made to reproduce this arrhythmia by PVS. Incremental ventricular pacing, LV stimulation, or provocative maneuvers such as isuprel infusion or antiarrhythmic drug administration were not performed in any patient.
Sustained VT was defined as VT >30 seconds in duration or VT requiring countershock because of hemodynamic collapse. Sustained VT was defined to be monomorphic, if it had a well-defined QRS complex with constant axis and morphology on each of the 12-lead ECG, and the VT cycle length was ≥200 ms (18,19). Polymorphic VT was defined as VT in which the QRS axis or morphology was variable from beat to beat in at least one of the ECG leads. For the purpose of this study, no attempts were made to differentiate polymorphic VT, ventricular flutter, or VF.
All study patients were followed prospectively for 24 ± 13 months beginning at the time of electrophysiologic study until October 1997. Follow-up could be completed in all 34 patients. Arrhythmic events during follow-up were defined as: 1) spontaneous sustained VT or VF; 2) appropriate ICD shocks for spontaneous VT or VF with documentation of the rhythm leading to the shock by stored electrograms by the device; or 3) sudden cardiac death, i.e., death within 1 h after the onset of symptoms in a previously medically stable patient, death during sleep, or unwitnessed death. A total of 22 patients (65%) underwent prophylactic ICD implantation after PVS (Table 2). The following ICDs were used in this study: Medtronic Jewel 7202C, 7219C, 7220C, 7221C, or 7223Cx in 16 patients, CPI Ventak P2 Cardiac Pacemakers (Guidant Corporation, St. Paul, Minnesota) in four patients, and CPI Ventak AV in the remaining two patients in whom prophylactic ICD implantation was performed. All ICD systems had antibradycardia demand pacing and biphasic shock waveforms with a maximum shock energy of 29–34 J. For implantation of CPI devices exclusively Endotak DSP leads were used. Medtronic Jewel devices were implanted exclusively using transvenous Medtronic leads (models 6936, 6934S, and 6932). ICD implantation was completed successfully in all patients with nonthoracotomy lead systems with a mean intraoperative defibrillation threshold of 11 ± 5 J (range 3–24 J). All ICD patients were seen routinely in 3–4-month intervals or as soon as possible after spontaneous shocks at our defibrillator outpatient department for device interrogation and retrieval of stored ECGs. An ICD discharge was considered appropriate when stored ECGs showed an episode of sustained VT or VF preceding the shock using previously described criteria (20). The documented arrhythmia was considered “sustained” in the sense that it persisted up to the point of shock delivery. Since first shock energy was programmed to maximum output of 29–34 J in all prophylactically implanted ICDs in this study, each arrhythmia triggering device therapy had to sustain at least for 8–10 s before an ICD shock was delivered (Figs. 1 and 2). ⇓
All values are expressed as mean ± standard deviation, unless stated otherwise. Comparisons between groups were made by unpaired ttests, chi-square analysis, or Fisher’s exact test, as appropriate. A p value of <0.05 was considered significant. Due to the small number of patients enrolled, this study only had a 26% power (two-sided) to detect a twofold increase in arrhythmic events in patients with inducible VT or VF compared with patients without inducible VT or VF based on an assumed 2-year event rate of 30% (6).
Thirty-four patients with IDC, a LV ejection fraction ≤35%, and spontaneous nonsustained VT (8 ± 3 beats at a rate of 180 ± 26 bpm) were enrolled in the study. The baseline characteristics of the 34 study patients and the 138 screened but not enrolled patients are shown in Table 1. By definition, all 34 study patients had nonsustained VT on Holter compared with 28% of screened but not enrolled patients (p < 0.05). In addition, enrolled patients with IDC had a significantly lower LV ejection fraction and larger LV end diastolic diameters compared with screened but not enrolled patients.
Response to PVS
Sustained monomorphic VT was induced in three patients (9%), polymorphic sustained VT or VF in 10 patients (29%), and no sustained ventricular arrhythmia in 21 patients (62%).
Cycle length of induced monomorphic VT was 230, 240, and 250 ms, respectively. Induction of monomorphic VT required three extrastimuli in all three patients in whom monomorphic VT could be induced. Due to rapid hemodynamic deterioration, external cardioversion through preapplied autoadhesive pads was necessary to terminate induced monomorphic VT in all three patients.
Polymorphic VT or VF was induced with two extrastimuli in three patients and with three extrastimuli in the remaining seven patients. All episodes of induced polymorphic VT or VF had a rate >250 bpm and required external defibrillation with 200–360 J delivered through preapplied autoadhesive pads for termination.
The baseline characteristics and antiarrhythmic therapy following PVS of the 13 patients with inducible sustained VT or VF and of the 21 patients without inducible VT or VF are summarized in Table 2. His-bundle recordings were obtained in all 26 patients in whom the electrode catheters were introduced from the femoral veins, as described above. Mean HV interval in these 26 patients was 66 ± 13 ms (39–88 ms), with values >55 ms in 18 of 26 patients (69%).
Prophylactic ICD implantation and device programming
Implantation of third-generation ICDs with ECG storage capability was performed in all 13 patients with inducible sustained VT or VF and in nine of 21 patients (43%) without inducible sustained VT or VF at PVS (Table 2). Since none of the patients had pace-terminable arrhythmias induced on electrophysiologic study, all implanted defibrillators were programmed to single-zone devices for VF detection at cycle lengths below 312 ± 13 ms (range 330–290 ms). First shock energy was programmed to maximum output of 29–34 J in all devices at the time of hospital discharge without any preceding attempts of antitachycardia pacing (Figs. 1 and 2). An additional VT zone with antitachycardia pacing was programmed active later during follow-up in one patient who developed several episodes of pace-terminable monomorphic VT (Fig. 3). Of note, all devices used in this study had antibradycardia back-up pacing capability. The bradycardia escape rate was programmed in the VVI mode (n = 20) or in the DDD mode (n = 2) to 49 ± 5 bpm (range 40–60 bpm).
Arrhythmic events during follow-up
During 24 ± 13 months of follow-up after PVS, arrhythmic events were observed in nine of 34 study patients (26%). Two patients died suddenly, and seven patients received adequate ICD shocks for rapid VT or VF. Sudden death occurred 1 month after hospital discharge in one patient without inducible sustained ventricular arrhythmia at PVS. This patient had an LV ejection fraction of 20% and was discharged from the hospital without ICD and without antiarrhythmic drugs. Another patient with inducible polymorphic VT on electrophysiologic testing died suddenly at home 24 months after prophylactic ICD implantation while waiting for heart transplantation. Unfortunately, sudden death was unwitnessed in this patient and the device was not available for retrieval of stored ECGs after the patient deceased.
A total of seven patients experienced one or more ICD shocks for rapid VT or VF as documented by stored ECGs by the device (Figs. 1 and 2). Median follow-up duration between PVS and occurrence of the first appropriate ICD shock in these seven patients was 4 months (range 1–48 months). Mean cycle length of the most rapid episode of VT or VF triggering device therapy in each of the seven patients was 241 ± 31 ms (range 190–280 ms). In addition to shocks for rapid polymorphic VT, one patient also received shocks for spontaneous VT with a cycle length of 300–310 ms. Therefore, antitachycardia pacing was programmed active in this patient, which reproducibly terminated this arrhythmia (Fig. 3). Of note, sustained VT below the programmed rate cut-off for VF detection of 193 ± 8 bpm was not observed in any of the 22 study patients with prophylactic ICD implantation during median follow-up of 24 months (range 4–54 months).
Relation between the result of PVS and subsequent arrhythmic events
Baseline clinical characteristics and antiarrhythmic therapy following PVS for patients with and without antiarrhythmic events during follow-up are summarized in Table 3. Arrhythmic events occurred in four of 13 patients with inducible sustained ventricular arrhythmias compared with five of 21 patients without inducible sustained ventricular arrhythmias at PVS (31% vs. 24%, p = NS). There was no statistically significant difference in baseline clinical variables, result of PVS, and antiarrhythmic therapy at the time of hospital discharge in patients with, compared with patients without, arrhythmic events during follow-up. The incidence of deaths due to progressive heart failure was also not different between patients with and without arrhythmic events. Heart transplantation and dynamic cardiomyoplasty were performed in one patient each in the patient group without arrhythmic events until the end of follow-up in October 1997. One patient died from progressive pancreatic carcinoma 28 months after he had received the first appropriate defibrillator shock for ventricular flutter.
Prophylactic implantation of automatic defibrillators in asymptomatic postinfarct patients with spontaneous nonsustained VT, LV ejection fraction ≤35%, and inducible, nonsuppressible VT on electrophysiologic study has recently been shown to improve survival compared with conventional antiarrhythmic therapy in a prospective randomized trial (2). In contrast to postinfarct patients, arrhythmia risk stratification in patients with spontaneous nonsustained VT in the setting of IDC remains controversial (4–17). The present study investigated the role of PVS for arrhythmia risk prediction in a relatively homogeneous group of patients with IDC and spontaneous nonsustained VT in the presence of an LV ejection fraction ≤35%. In contrast to previous studies investigating the role of PVS for arrhythmia risk stratification in IDC, prophylactic implantation of ICDs with ECG storage capability was performed in the majority of patients in the present study. The major finding of our study is that inducibility of sustained monomorphic VT as well as inducibility of polymorphic VT or VF at PVS failed to predict subsequent arrhythmic events, i.e., sustained ventricular tachyarrhythmias or sudden death, which were observed in 26% of patients with IDC during a 2-year follow-up. Due to the limited number of patients, however, the power of our study is too small to exclude moderately large differences in outcome between patients with and without inducible VT or VF.
Comparison with previous studies using PVS for arrhythmia risk stratification in IDC
The results of previous studies investigating the role of PVS for arrhythmia risk prediction in patients with IDC without a history of sustained ventricular tachyarrhythmias are summarized in Table 4. Similar to our findings, sustained monomorphic VT was rarely inducible by PVS in the majority of previous studies and most investigators did not find PVS useful for arrhythmia risk stratification in patients with IDC in the absence of a history of sustained VT (4–11). The incidence of inducible sustained polymorphic VT or VF varied between 0% in the study of Stamato et al. (5)and 29% in the present study (Table 4). This discrepancy may simply reflect differences in patient selection and stimulation protocol with up to two extrastimuli in the study of Stamato et al. (5)and up to three extrastimuli in the present study. Although the clinical significance of inducible polymorphic VT or VF has never been evaluated in prospective studies with sufficient power, a large body of available data suggests that inducibility of sustained polymorphic VT or VF is merely a nonspecific response to aggressive stimulation protocols (18).
Of note, the present study differs from previous investigations in several important aspects. In contrast to all previously published studies (4–17), prophylactic ICD implantation with ECG storage capability was performed in the majority of patients with IDC and nonsustained VT following PVS. Although appropriate rhythm classification based on stored ECGs by a defibrillator can occasionally be difficult or even impossible (20), there is no doubt that it is generally less difficult and probably more accurate than classifying unwitnessed sudden death as an arrhythmic event (21,22). In addition, only patients with “idiopathic” dilated cardiomyopathy as defined above were included in our study, whereas a variety of underlying conditions including valvular heart disease and hypertensive heart disease were enrolled as “nonischemic” dilated cardiomyopathies in most previous reports. Similar to the inclusion criteria for postinfarct patients in the MADIT study (2), exclusively patients with IDC and spontaneous nonsustained VT with an LV ejection fraction ≤35% were included in the present study. In contrast to MADIT, however, syncope was not an exclusion criteria in this study.
Studies using prophylactic ICD implantation in IDC
Whether prophylactic ICD implantation is beneficial in patients with IDC with an LV ejection fraction ≤30% without previous symptomatic ventricular tachyarrhythmias is currently being investigated in the Cardiomyopathy Trial (23,24). All patients in the Cardiomyopathy Trial undergo extensive noninvasive and invasive tests, including 24-h Holter monitoring and PVS with up to three extrastimuli at two basic drive cycle lengths (24). The Cardiomyopathy Trial is a prospectively conducted multicenter study designed to randomize patients with IDC in NYHA functional class II or III with a LV ejection fraction ≤30% known for less than 9 months before study inclusion to either no antiarrhythmic therapy or implantation of an ICD. Of note, neither the result of Holter monitoring nor the result of PVS is allowed to influence randomization to ICD versus no ICD therapy in this trial. The trial started on July 1, 1991. At the time of this writing in February 1998, the pilot phase of the cardiomyopathy trial with enrollment of the first 100 patients has been completed, but no results have been reported so far.
Due to the limited number of patients, the power of our study is too small to exclude moderately large differences or to demonstrate equivalence in outcome between patients with and without inducible VT or VF at PVS with any confidence. Another limitation of the present study is that antiarrhythmic therapy including prophylactic ICD implantation following PVS was not standardized but left to the discretion of the attending physician and the patient. Therefore, it cannot be ruled out that the use of amiodarone, beta-blockers, and d,I-sotalol influenced the outcome, although there was no significant difference in the use of these drugs in patients with and without inducible ventricular arrhythmias as well as in patients with and without arrhythmic events during follow-up (Tables 2 and 3). Since monomorphic VT in all three patients in this study were hemodynamically not tolerated, requiring rapid cardioversion, no catheter repositioning to optimize His-bundle recordings and no stimulation maneuvers during VT were performed to diagnose or to rule out bundle branch reentry as the mechanism of VT in these patients (25). Furthermore, all ICDs used in this study provided antibradycardia demand pacing, which may have precipitated arrhythmias in some patients.
The results of our study support the hypothesis that PVS is not helpful for arrhythmia risk prediction in patients with IDC and spontaneous nonsustained VT. Unless larger prospective trials demonstrate that PVS might be useful for arrhythmia risk stratification in asymptomatic patients with IDC such as the cardiomyopathy trial (23,24), electrophysiologic testing has not been established for arrhythmia risk prediction with regard to prophylactic ICD implantation in patients with IDC. Novel, preferably noninvasive risk stratification strategies for sudden cardiac death should be sought in patients with dilated cardiomyopathy.
- implantable cardioverter defibrillator
- idiopathic dilated cardiomyopathy
- left ventricle
- programmed ventricular stimulation
- ventricular fibrillation
- ventricular tachycardia
- Received November 19, 1997.
- Revision received April 27, 1998.
- Accepted May 8, 1998.
- American College of Cardiology
- ↵Moss AJ, Hall J, Cannom DS et al. for the Multicenter Automatic Defibrillator Implantation Trial Investigators. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933–40.
- ↵Bigger JT Jr, for the Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary artery bypass graft surgery. N Engl J Med 1997;337:1569–75.
- Turitto G,
- Ahuja R.K,
- Caref E.B,
- El-Sherif N
- Tamburro P,
- Wilber D.J
- Wellens H.J.J,
- Brugada P,
- Stevenson W.G
- Avitall B,
- McKinnie J,
- Jazayeri M,
- et al.
- Hook B.G,
- Marchlinski F.E
- Hinkle L.E,
- Thaler H.T
- Epstein A.E,
- Carlson M.D,
- Fogoros R.N,
- et al.
- Caceres J,
- Jazayeri M,
- McKinnie J,
- et al.