Author + information
- Received October 29, 1998
- Revision received March 19, 1999
- Accepted June 21, 1999
- Published online October 1, 1999.
- Suneet Mittal, 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, New York Hospital–Cornell Medical Center, 525 East 68 Street, Starr 4, New York, New York 10021
We evaluated the long-term outcome of patients with coronary artery disease and unexplained syncope who were treated with an electrophysiologic (EP)-guided approach.
Electrophysiologic studies are frequently performed to evaluate unexplained syncope in patients with coronary artery disease. Patients with this profile who have inducible ventricular tachycardia are considered at high risk for sudden death and increased overall mortality, and therefore are often treated with an implantable cardioverter-defibrillator (ICD). The impact of this EP-guided strategy is unknown because there are no data comparing the long-term outcome of ICD recipients with that of noninducible patients.
We evaluated 67 consecutive patients with coronary artery disease and unexplained syncope. All patients were treated with an EP-guided approach that included ICD implantation in patients with inducible ventricular tachycardia.
Electrophysiologic testing suggested a plausible diagnosis in 32 (48%) of these patients. Inducible monomorphic ventricular tachycardia was the most common abnormality. Despite frequent appropriate therapy with ICDs, the total mortality for patients with inducible monomorphic ventricular tachycardia was significantly higher than for noninducible patients. The respective one- and two-year survival rates were 94% and 84% in noninducible patients and 77% and 45% in inducible patients (p = 0.02).
Electrophysiologic testing suggests an etiology for unexplained syncope in approximately 50% of patients and risk stratifies these patients with regard to long-term outcome. Patients who receive an ICD for the management of inducible ventricular tachycardia have a high incidence of spontaneous ventricular arrhythmias requiring ICD therapy. However, despite ICD implantation and frequent appropriate delivery of ICD therapies, patients with inducible ventricular tachycardia have a significantly worse prognosis than do those who are noninducible.
Electrophysiologic (EP) studies are frequently performed to identify an arrhythmic cause for unexplained syncope (1–12). Potential etiologies detected by EP testing include sinus node or His-Purkinje system dysfunction as well as sustained atrial or ventricular tachyarrhythmias. The greatest positive yield has been reported in patients with underlying structural heart disease (2,4,7–9,11,12).
Because patients with syncope and inducible ventricular tachycardia have an increased risk of sudden death as well as total mortality (4,11,13), implantable cardioverter-defibrillators (ICDs) are often implanted in these patients, despite absence of a clinically documented sustained ventricular arrhythmia. Follow-up of these patients has revealed a high incidence of spontaneous ventricular tachycardia requiring ICD therapy, suggesting that ICDs are efficacious in the management of these patients (14–17).
However, despite the purported utility of an EP-guided management strategy, several fundamental concerns limit interpretation of the available data. Specifically, prior studies have included a heterogeneous patient population with regard to cardiac diagnosis and have often included potentially nonspecific findings such as the induction of nonsustained ventricular tachycardia and ventricular fibrillation as positive study end points (2,5,8,13). In addition, the long-term follow-up of patients after EP testing has been confounded by the concurrent use of empiric antiarrhythmic drugs. Finally, the relative impact of ICD implantation in inducible patients is unknown because the follow-up of comparable noninducible patients has not been reported.
In this study we evaluated a homogeneous patient population with documented coronary artery disease and unexplained syncope. All patients were treated with an EP-guided approach, which included ICD implantation in patients with inducible ventricular tachycardia. The specific purposes of this study were 1) to evaluate the results of EP testing in these patients, 2) to compare the long-term outcome of inducible and noninducible patients and 3) to track the natural history of ICD recipients.
We evaluated 100 consecutive patients with structural heart disease and unexplained syncope who underwent an EP study between January 1994 and December 1997. We excluded 33 patients without coronary artery disease from further analysis. These included 20 patients with a nonischemic dilated cardiomyopathy, 3 patients with hypertrophic cardiomyopathy, 4 patients with a valvular cardiomyopathy and 6 patients with congenital heart disease. Patients with a documented sustained ventricular arrhythmia or those resuscitated from sudden cardiac death were also excluded.
All patients underwent an extensive evaluation including a history and physical examination, routine blood tests, 12-lead electrocardiography (ECG) and 24 h of in-patient telemetry or ambulatory ECG monitoring. In all patients, left ventricular (LV) ejection fraction was assessed by an echocardiogram, radionuclide ventriculography or LV cineangiography, and coronary artery disease was assessed 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 our previously published protocol (18).
After written informed consent was obtained, all patients underwent an EP study in the postabsorptive state. No patient was on an antiarrhythmic drug at the time of clinical presentation or the EP study.
Patients were locally anesthetized with 0.25% bupivacaine and lightly sedated with midazolam or morphine. Under fluoroscopic guidance, 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 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 4 times the diastolic threshold.
Sinus node dysfunction was evaluated by the corrected sinus node recovery time (at basic drive cycle lengths of 600, 500, and 400 milliseconds [ms]) and sinoatrial conduction time. Incremental atrial pacing was performed until atrioventricular (AV) nodal Wenckebach was reached. Atrial extrastimuli were delivered for the evaluation of dual AV nodal physiology and sustained atrial arrhythmias. Programmed ventricular stimulation included up to triple ventricular extrastimuli at two cycle lengths from two right ventricular sites. Patients with a negative baseline study received isoproterenol (1 to 5 μg/min titrated to increase heart rate by ≥20% over baseline), and the study was repeated from up to two right ventricular sites. Patients with inducible monomorphic ventricular tachycardia received intravenous (IV) procainamide (1000 to 1500 mg bolus followed by a continuous infusion of 4 to 8 mg/min) and underwent a repeat EP study according to the same protocol. No patient underwent stimulation from the LV. Sustained monomorphic ventricular tachycardia was the only positive end point of ventricular stimulation.
Coronary artery diseasewas defined as 1) ≥50% reduction in luminal diameter of at least one of the three major epicardial coronary arteries, 2) a documented myocardial infarction or 3) a perfusion abnormality on nuclear imaging in ≥1 coronary artery territory. Sinus node dysfunctionwas defined as a corrected sinus node recovery time ≥550 ms or a sinoatrial conduction time of ≥125 ms. Significant His-Purkinje system dysfunctionwas defined as 1) a HV interval of ≥100 ms at baseline or after IV procainamide or 2) the development of infra-Hisian block with rapid atrial pacing at a cycle length of ≥400 ms. Sustained monomorphic ventricular tachycardiawas defined as monomorphic ventricular tachycardia, regardless of cycle length, lasting ≥30 s or requiring termination due to hemodynamic compromise. Deaths were classified as cardiac, noncardiac or unknown based on the assessment of the referring physicians. Sudden deathwas defined as death occurring while the patient was asleep or within 1 h of the onset of symptoms.
Patients with inducible monomorphic ventricular tachycardia who were suppressed with IV procainamide underwent EP-guided serial antiarrhythmic drug trials. Patients who remained inducible despite IV procainamide received a tiered therapy ICD. Noninducible patients with isolated sinus node or His-Purkinje system dysfunction received a dual chamber pacemaker. Patients with a positive tilt-table test were treated with a beta-adrenergic blocking agent or pacemaker. No patient received empiric 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 not receiving a device were evaluated by telephone follow-up. Information was obtained regarding initiation of new antiarrhythmic drugs, recurrence of syncope or the identification of an alternative etiology for syncope by patients’ referring physicians.
All continuous variables are expressed as mean ± standard deviation. Comparisons of inducible 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). Kaplan-Meier survival curves were generated for 1) ventricular tachycardia/fibrillation-free survival in patients with inducible ventricular tachycardia who received an ICD and 2) total mortality between inducible and noninducible patients. Comparisons between survival curves were made using the log-rank statistic. A univariate Cox proportional-hazards regression model was employed to evaluate the effect of age, gender, number of syncopal episodes, history of myocardial infarction, history of nonsustained ventricular tachycardia, LV ejection fraction, presence of bundle-branch block, baseline (HV) interval, inducibility of monomorphic ventricular tachycardia and cycle length of induced tachycardia on mortality. A p value of <0.05 was considered statistically significant.
The study population consisted of 67 patients (57 male, 10 female) with documented coronary artery disease and unexplained syncope. The mean LV ejection fraction was 37 ± 13%. A history of myocardial infarction was present in 42 (63%) patients. Baseline demographics are outlined in Table 1.
On baseline ECG, the rhythm was sinus in 58 (87%) patients, atrial fibrillation or flutter in 8 (12%) patients and paced in 1 (1%) patient. First-degree AV delay was present in 9 (13%) patients. Bundle branch block was present in 24 (36%) patients and included a left-bundle branch block in 7 patients, right-bundle branch block in 3 patients, right-bundle branch block with a left anterior or posterior fascicular block in 9 patients and a nonspecific intraventricular conduction delay in 5 patients. Other findings included LV hypertrophy in 2 (3%) patients and pathologic Q waves in 25 (37%) patients.
Nonsustained ventricular tachycardia (9 ± 4 beats) was documented in 31 (46%) patients. The shortest cycle length during nonsustained ventricular tachycardia was 395 ± 46 ms. A signal-averaged ECG was performed in 26 patients, without underlying bundle branch block, and was abnormal (as previously defined ) in 15 (58%) of these patients.
Evaluation of coronary artery disease
Cardiac catheterization was performed in 50 (75%) patients. Of these 50 patients, 11 (22%) had single-vessel, 11 (22%) had double-vessel and 28 (56%) had triple-vessel coronary artery disease. In addition, 10 (15%) patients had a LV aneurysm. A diagnosis of coronary artery disease was made on the basis of nuclear stress imaging in the remaining 17 (25%) patients.
Eleven (16%) patients had previously undergone percutaneous transluminal coronary angioplasty (PTCA) and 37 (55%) had previously undergone coronary artery bypass grafting (CABG). Of the 37 patients with a history of CABG at the time of the EP study, 9 had undergone surgery during the same hospitalization. These patients presented with syncope and were discovered upon evaluation to have coronary artery disease requiring CABG prior to EP study.
The baseline HV interval was 56 ± 13 ms. Only one patient (HV = 100 ms) had severe His-Purkinje system dysfunction. Of the 58 patients in sinus rhythm, 7 patients had sinus node dysfunction. In addition, 10 of these 58 patients had dual AV nodal physiology but none had inducible AV nodal reentrant tachycardia. Table 2depicts the characteristics of patients with a positive EP study.
Sustained monomorphic ventricular tachycardia was inducible in 29 (43%) patients. The cycle length of induced ventricular tachycardia was 248 ± 37 ms; 15 (52%) patients had an induced ventricular tachycardia cycle length of ≤250 ms. All patients required either double or triple ventricular extrastimuli for induction of ventricular tachycardia. No patient required isoproterenol for induction of tachycardia. Four of the seven patients with sinus node dysfunction had concomitant inducible ventricular tachycardia, as did the one patient with severe His-Purkinje system dysfunction.
In an additional 11 patients, sustained ventricular fibrillation was the only induced ventricular tachyarrhythmia. Ventricular fibrillation was induced with double ventricular extrastimuli in one patient and with triple ventricular extrastimuli in the remainder. These 11 patients were considered to have a negative EP study.
Patients with inducible monomorphic ventricular tachycardia had greater LV dysfunction, greater likelihood of a prior myocardial infarction, and a longer baseline HV interval (Table 3). However, inducibility could not be predicted by other baseline demographic variables including age, gender, number of syncopal episodes, presence of bundle-branch block or nonsustained ventricular tachycardia or severity of coronary artery disease, including the presence of an LV aneurysm or history of prior revascularization with PTCA or CABG.
Procainamide was administered to 25 of the 29 patients with inducible monomorphic ventricular tachycardia. Of the four patients who did not receive procainamide, two had severe LV dysfunction with concomitant congestive heart failure and two others had moderate-severe His-Purkinje system dysfunction (HV interval of 79 and 90 ms). Ventricular tachycardia was suppressed following an infusion of procainamide in only one patient.
Positive EP study
The single patient with inducible monomorphic ventricular tachycardia that was suppressible with IV procainamide was treated with amiodarone after a repeat EP study confirmed drug efficacy. Of the remaining 28 patients with inducible monomorphic ventricular tachycardia, 26 received an ICD. One patient refused an ICD; the other patient died of ventricular fibrillation, which developed from sustained monomorphic ventricular tachycardia, on the fifth day post-EP study. This patient was awaiting resolution of PTCA-related acute renal insufficiency before receiving an ICD. Most ICDs (24/26) were implanted using a nonthoracotomy approach and transvenous leads. Twenty-three of the 26 ICDs had the capacity for stored electrogram retrieval. No mortality was associated with ICD implantation. Three patients with isolated sinus node dysfunction received a pacemaker.
Negative EP study
Four of 35 patients with a negative EP study received a pacemaker. Of these patients, one had tachycardia-bradycardia syndrome, one had a 4-s episode of AV block during atrial fibrillation and two patients had neurally mediated syncope during tilt-table testing, which did not respond to beta-blocker therapy. An additional two patients with a negative EP study had a positive tilt test and were treated with a beta-blocker. The remaining 29 (43%) patients with a negative EP study were discharged without the addition of any empiric therapy. Ten of these 29 patients also had a negative tilt test.
Follow-up was available in 60 (90%) patients at a mean of 448 ± 387 days (maximum 1430 days). During the follow-up period, six patients had recurrent syncope. Two of these patients had received an ICD for management of inducible ventricular tachycardia. In one patient, recurrent syncope was associated with ventricular fibrillation that was successfully defibrillated by the ICD. The cause of syncope in the other patient was unknown. Review of stored electrograms revealed no arrhythmia. The remaining four patients had been noninducible at the initial EP study. Two of these patients were later diagnosed with hypoglycemia, one patient was diagnosed with a seizure disorder and in another patient, the cause of syncope remains unknown.
Eleven patients (41%) with an ICD received appropriate therapy for sustained ventricular tachycardia (9 patients) or ventricular fibrillation (2 patients) at 155 ± 164 days (range: 1 to 522 days) post-ICD implantation. In the nine patients with spontaneous ventricular tachycardia, the cycle length of tachycardia was 293 ± 40 ms.
An antiarrhythmic drug was initiated in five patients during follow-up period. This included amiodarone in two patients, sotalol in two patients and azimilide in one patient. The indication for initiation of an antiarrhythmic drug was atrial fibrillation (leading to an inappropriate ICD discharge) in two patients and an appropriate ICD discharge for ventricular tachycardia in three patients.
Fifteen patients died during the follow-up period at a mean of 350 ± 287 days (range 5 to 960 days). Nine of these patients had inducible monomorphic ventricular tachycardia at the initial EP study, whereas six patients were noninducible. Table 4summarizes the mortality data for patients with available follow-up.
Of the five patients with a cardiac cause of death, two had sudden death without a documented arrhythmia. In addition, death due to recurrent documented ventricular tachycardia/fibrillation was observed in three patients. These included the patient who died awaiting an ICD implant, a patient who presented with an acute myocardial infarction and had recurrent ventricular tachyarrhythmias and a patient who had a protracted hospital course for multisystem organ failure. In the latter two patients, the ICD converted ventricular fibrillation to a supraventricular rhythm; however, both patients died of resulting electromechanical dissociation. Overall, four of the five deaths due to a presumed cardiac cause occurred in inducible patients; in contrast, five of the eight noncardiac deaths occurred in noninducible patients. Of the 11 patients in whom ventricular fibrillation was the only induced arrhythmia at EP study, 2 died over the follow-up period. In both cases, death was due to a noncardiac cause.
Survival without recurrent ventricular tachycardia or fibrillation was observed in only 47% and 21% of patients at one and two years’ post-ICD implantation, respectively (Fig. 1). Total mortality was significantly higher in patients with inducible monomorphic ventricular tachycardia despite therapy with an ICD (Fig. 2). The respective one- and two-year survival rates were 94% and 84% in noninducible patients and 77% and 45% in inducible patients (p = 0.02). Univariate Cox proportional-hazards regression modeling identified inducibility of monomorphic ventricular tachycardia as the only significant predictor of overall mortality (p = 0.03). Of note, no difference in outcome was observed between patients with an induced ventricular tachycardia cycle length of ≤250 ms and >250 ms at initial EP study.
The principal findings of this study are that in patients with coronary artery disease and unexplained syncope, EP testing suggests a probable arrhythmogenic cause in approximately 50% of patients. By identifying those patients with inducible monomorphic ventricular tachycardia, EP testing risk stratifies patients into high- and low-risk groups with respect to long-term cardiac and total mortality. In addition, patients who receive an ICD for the management of inducible ventricular tachycardia and unexplained syncope have a high incidence of spontaneous ventricular arrhythmias requiring ICD therapy. Most significantly, the results of this study suggest that, despite frequent appropriate ICD therapy, patients with inducible ventricular tachycardia are at high risk of cardiac and total mortality, with a two-year survival rate less than 50%.
Although our yield during EP testing was similar to rates previously reported in patients with unexplained syncope and structural heart disease, we excluded induction of nonsustained ventricular tachycardia and ventricular fibrillation as positive study end points because these findings may be nonspecific responses to the stimulation protocol (19,20). Induction of these arrhythmias accounted for approximately half the positive end points in prior studies (2,5,8,13). In the present study, induction of ventricular fibrillation failed to confer an increased mortality risk.
Patients with inducible monomorphic ventricular tachycardia had a markedly worse prognosis than did noninducible patients. Patients with a history of myocardial infarction and depressed LV function were most likely to have inducible ventricular tachycardia at EP study. However, other baseline demographic variables failed to predict inducibility. These findings demonstrate that inducibility of sustained monomorphic ventricular tachycardia is a marker of an extremely poor outcome in patients with ischemic heart disease and unexplained syncope.
Effects of ICDs
Because patients with unexplained syncope and inducible ventricular tachycardia have an increased risk of sudden death and total mortality (4,11,13), it has been suggested that ICD implantation is an effective management strategy in these patients (16,17). A high incidence of appropriate ICD therapies, similar to that in patients receiving ICDs for management of sustained ventricular tachycardia or fibrillation, has been observed in these patients and supports this approach (14,15). A similar finding was observed in our study, which confirms the potential utility of ICDs in the management of patients with syncope and inducible ventricular tachycardia.
However, despite receiving ICDs, seven patients died during the follow-up period. Unfortunately, in these patients, stored electrograms could not be retrieved. However, in three of these patients, death was presumed to have a cardiac etiology. Overall, despite the use of ICDs, the total mortality of inducible patients remained significantly higher than of noninducible patients. In this study, other risk factors for mortality could not be identified. It is important to note that the cycle length of induced ventricular tachycardia did not differentiate patients with respect to outcome. Therefore, in this patient cohort, induced sustained monomorphic ventricular tachycardia, regardless of cycle length, can be considered to be prognostically significant.
In the two prior studies that evaluated the utility of ICDs in patients with syncope and inducible ventricular tachycardia (16,17), data were provided for only a select group of inducible patients who received an ICD. Neither study reported data on the follow-up of patients with unexplained syncope who were either inducible and not treated with an ICD or noninducible during EP study.
Link et al. (16)reported on 50 patients who received an ICD after presenting with presyncope or syncope. Their patients had an appropriate ICD discharge rate of 22% at one year and 50% at three years’ post-ICD implantation. Only four patients died during the follow-up period of 23 ± 15 months. Their study differs from ours in several respects. First, their patients represented a heterogeneous group with differing underlying cardiac pathology, including patients with nonischemic cardiomyopathy. Second, therapy was not uniform as only 50 of the 82 inducible patients received an ICD. In addition, the follow-up data of inducible patients not receiving an ICD were not reported. Third, they considered nonsustained ventricular tachycardia and ventricular fibrillation as positive end points, which accounted for approximately 30% of “inducible” patients. The specificity of these findings in patients without a documented sustained arrhythmia is unknown. Finally, approximately 35% of the implanted ICDs lacked the capacity for stored electrogram retrieval and approximately 35% of patients were discharged with concomitant antiarrhythmic drug therapy, factors that complicate interpretation of the natural history in these patients.
Militianu et al. (17)reported on 33 patients who received an ICD after presenting with syncope. These patients were collected over a 10-year period from seven institutions. At least one appropriate ICD discharge was observed in 36% of patients over a follow-up period of 17 months. Similar to the previous study, patients were nonuniform with respect to cardiac diagnosis. Nearly one-half of patients receiving an ICD were inducible for only ventricular flutter or fibrillation or were noninducible. One-third of implanted ICDs lacked the capacity for stored electrogram retrieval, and a history of concomitant antiarrhythmic drug use was not reported.
Our study has several unique features. We evaluated only patients with documented coronary artery disease to eliminate the confounding contribution of differences in cardiac pathology in determining the ultimate long-term outcome in patients with unexplained syncope. We defined prespecified end points for a positive EP outcome. These end points did not include a baseline HV interval <100 ms or induction of nonsustained ventricular tachycardia or ventricular fibrillation because these may be nonspecific findings (7,20). The treatment of patients was uniform. On the basis of the results of the EP study, pacemakers were implanted in patients with isolated sinus node dysfunction and ICDs were implanted in patients with inducible monomorphic ventricular tachycardia that was not suppressible with procainamide. No patient was subject to empiric drug or device therapy. The implantation of ICDs with the capacity for stored electrogram retrieval and the absence of empiric therapy provide a unique opportunity to evaluate the natural history of these patients. Finally, to our knowledge, this is the first study to assess and contrast the outcome of inducible patients treated with an ICD with noninducible patients in a homogeneous cohort with unexplained syncope.
There are several limitations in this study. Because all our patients had coronary artery disease, the applicability of the data to patients with other forms of structural heart disease and unexplained syncope is unknown. Second, although inducible patients had a worse outcome than did noninducible patients, despite implantation of an ICD, the magnitude of the potential benefit of an ICD in inducible patients could not be determined from this study. To determine this benefit, patients with unexplained syncope and inducible ventricular tachycardia would need to be randomized to receive an ICD or no therapy. However, because important ethical issues could be raised if ICD therapy were withheld from patients with coronary artery disease, syncope and inducible ventricular tachycardia, we considered it prudent to treat all inducible patients with ICDs. Finally, although not readily accessible, the outcome of patients with coronary artery disease and unexplained syncope who were admitted to our institution during the course of this study but not referred for an EP study would have been of interest.
Electrophysiologic testing is an effective diagnostic test in patients with coronary artery disease and unexplained syncope. It provides an etiology for syncope in approximately 50% of patients, and it risk-stratifies patients with regard to long-term outcome. Patients who undergo ICD implantation for management of inducible ventricular tachycardia and unexplained syncope have a high incidence of spontaneous ventricular arrhythmias requiring ICD therapy. However, despite ICD implantation and appropriate delivery of ICD therapies, patients with inducible ventricular tachycardia have a significantly worse prognosis than do noninducible patients, with a two-year survival rate less than 50%. These results suggest that ICD therapy alone may not be sufficient for the management of inducible patients. In this context, the prognostic significance of the remaining ischemic burden, as well as other co-morbid diseases in these patients, needs to be prospectively examined.
☆ This work was supported in part by grants from the National Institutes of Health (RO1 HL-56139), the Rosenfeld Foundation and the Michael Wolk Foundation.
- coronary artery bypass grafting
- electrocardiogram, electrocardiography
- electrophysiology, electrophysiologic
- implantable cardioverter-defibrillator
- left ventricle, left ventricular
- percutaneous transluminal coronary angioplasty
- Received October 29, 1998.
- Revision received March 19, 1999.
- Accepted June 21, 1999.
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