Author + information
- aDepartment of Cardiology, Lokmanya Tilak Municipal General Hospital, Mumbai, India
- bDepartment of Cardiology, Medanta Hospital, Delhi, India
- ↵∗Address for correspondence:
Dr. Yash Lokhandwala, Department of Cardiology, Lokmanya Tilak Municipal General Hospital, Sion, Mumbai 400022, India.
In the absence of significant heart disease, syncope is most commonly neurocardiogenic. A detailed clinical history and account of the witness (if available) is the most important diagnostic “tool” for determining the etiology and mechanism of syncope. Although there is a potential battery of diagnostic tests, none of them, with the exception of a long-term implantable loop recorder, have a high diagnostic yield. Sometimes, noninvasive tests like a simple treadmill test can unravel a subatrioventricular (sub-AV) nodal block.
In the presence of bundle branch block (BBB), unexplained syncope could be ominous. Such individuals, usually middle-aged or elderly, sometimes have paroxysmal AV block, with the syncopal episodes resulting in serious injury and even death. Evaluation of patients with intraventricular conduction defects and syncope was among the initial applications of invasive electrophysiological study (EPS) (1), helping identify patients with advanced conduction disease requiring permanent pacemaker, life-threatening ventricular tachycardia requiring implantable cardioverter-defibrillator, and bundle branch ventricular tachycardia requiring radiofrequency ablation. Using standard evaluation, EPS and implantable loop recorders, Moya et al. (2) showed that among 303 patients with BBB and syncope, this was due to bradyarrhythmias (in 202 patients), carotid sinus syndrome (in 20 patients), ventricular tachycardia (in 18 patients), neurally mediated (in 9 patients), and other causes (in 54 patients).
Patients with bifascicular block (BFB) with syncope can have disease of the sinus node, AV node, His, or infra-His conduction, the last being the most serious. The yearly incidence of progression to permanent high-grade AV block in an unselected population of patients with BFB is only 1% to 4%, but it is substantially higher in patients with a history of syncope (3). In patients with BFB and a prolonged His-ventricular (HV) interval, only a weak correlation between the result of the EPS and subsequent high-grade AV block was found (4). Levites and Haft (5) reported in 1974 that PR prolongation in the presence of right BBB and left-axis deviation suggested abnormality of the HV interval and hence, trifascicular delay; yet, 30% of patients with this finding had a normal HV interval. In patients with left BBB/right BBB and right-axis deviation, over 50% had a prolonged HV interval, although no significant correlation was found between the PR and HV intervals.
The positive predictive value of a complete EPS (including pharmacological challenge) to correctly identify patients who will require pacemaker implantation for AV block is ≥80% (6). However, a negative EPS does not rule out paroxysmal AV block as a possible underlying mechanism for syncope, and false negatives are not uncommon. If clinical suspicion for such a mechanism is high, an implantable loop recorder may be indicated thereafter. Several pharmacological agents such as disopyramide, ajmaline, procainamide, flecainide, and verapamil have been used to improve the diagnostic and prognostic yield of EPS. An infra-His block, induced by incremental atrial pacing is highly predictive of an impending high-grade AV block. A prerequisite for this finding is a normal AV nodal conduction. Atropine has been used in small studies to improve AV conduction and expose a diseased His-Purkinje system. The effects of class I drugs on a healthy His-Purkinje system are limited, whereas on diseased conduction system, they have a profound effect. Studies of class I antiarrhythmic drug testing to stress the His-Purkinje system likewise have limited patient numbers, lack adequate control groups or follow-up, and seem to indicate that pharmacologic testing has low predictive value.
Kaul et al. (7) studied 35 patients with BBB and unexplained syncope, using ajmaline 1 mg/kg for provocation; a positive test was seen in 12 patients (34%). Wunderlich and Hetze (8) reported on the provocation with ajmaline in 259 patients with intraventricular conduction disorders, of whom 235 patients had BFB. Among the 109 patients with previously documented high-grade AV block, the test was positive in 93 patients, that is, a sensitivity of 85%. In both these studies, a positive test was defined as a second- or third-degree AV block occurring spontaneously after ajmaline infusion; the protocol did not include His bundle recordings or atrial pacing.
Procainamide is the most common drug used to stress the His-Purkinje system. Tonkin et al. (9) first used procainamide to stress the His-Purkinje system in patients with BFB and unexplained syncope, administering 10 mg/kg in 42 patients. A positive test was defined as a His-Purkinje block during sinus rhythm or an HV prolongation >15 ms. Eleven patients (26%) in the syncope group had a positive test versus 3 of the 5 control subjects (60%). After a mean follow-up of 38 months, 2 patients in the syncope group, both with a positive test, had a documented high-grade AV block, whereas all patients in the control group remained in sinus rhythm. Although only a few control patients were included, the high percentage of patients with a false-positive test in this group raises concerns regarding the specificity of the test. Gang et al. (10) showed that procainamide causes a rate-dependent depressant effect on the His-Purkinje conduction. They proposed that atrial pacing should be part of a pharmacological stress test with procainamide in patients with intraventricular conduction defects.
Disopyramide is a class IA antiarrhythmic drug with anticholinergic properties. The anticholinergic influence on the AV node reduces the refractory period and theoretically allows exposure of the His-Purkinje system to higher stimulation rates during atrial pacing and thus, increases the stress on the distal part of the AV conduction system. It increases the refractoriness and the conduction time of the His-Purkinje system. Englund et al. (11) first studied disopyramide in patients with BFB and found it 75% sensitive with a positive predictive value of 80% for high-grade AV block or pacemaker-detected bradycardia during a 2-year follow-up. Flecainide and procainamide both predominantly block the fast sodium channel, but they can also block potassium channels; procainamide predominantly blocks the inactivated state of INa. Flecainide exhibits marked use-dependent depressant effects on the rapid sodium channel by decreasing Vmax; thus, marked drug effects can occur at physiologic heart rates. Flecainide was used for stress testing in patients with BFB and a history of unexplained syncope (11). Fifteen patients with BFB and syncopal attacks were given 2 mg/kg flecainide intravenously. The mean HV interval increased significantly and 2 patients developed infra-His block during rapid atrial stimulation. The study group was too small to assess the diagnostic accuracy of the method.
In this issue of JACC: Clinical Electrophysiology, Roca-Luque et al. (12) in a single-center study, compared procainamide (retrospectively) with flecainide in patients with a wide QRS complex and syncope, with preserved ventricular function. It is not clear whether clinically apparent neurocardiogenic or reflex syncope was excluded, especially because the mean number of syncopal episodes was 2.44; with true recurrent unexplained syncope in this setting, one would normally directly proceed for pacing. Flecainide had a higher diagnostic yield (14.5%) than procainamide (7.8%) due to a greater increase of the HV interval. However, there was no difference in infra-His block between the 2 groups. Drug-induced increase of HV interval >100 ms was seen in 9 patients (11.8%) in the procainamide group and 11 patients (14.5%) in the flecainide group (p = 0.04). Although the negative predictive value of flecainide was superior to procainamide, 19.2% of such patients in the former group went on to develop advanced AV block within just 3 years.
In summary, there are as yet several difficulties in accurately predicting AV block as the cause of syncope in patients with a wide QRS complex. Pharmacologically stressing the conduction system is useful in some of these patients. Among the drugs studied, flecainide seems to be preferable to unravel His-Purkinje disease in patients with BBB. Although we do not want to miss out on patients who are at risk of serious AV block, we certainly do not wish to unnecessarily implant pacemakers in patients who may never develop AV block in the future. Implantable loop recorders are the best available tool for patients with infrequent syncope and a wide QRS; yet sometimes, we may rather implant a pacemaker when the syncopal episode has been associated with injury. We must continue the search for an ideal sieve that will separate the wheat from the chaff.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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- 2019 American College of Cardiology Foundation
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