Sei Iwai, MD, Daniel J. Cantillon, MD, Robert J. Kim, MD, Steven M. Markowitz, MD, Suneet Mittal, MD, Kenneth M. Stein, MD, Bindi K. Shah, MD, Ravi K. Yarlagadda, MD, Jim W. Cheung, MD, Vivian R. Tan, MD, Bruce B. Lerman, 

Abstract

Introduction: "Idiopathic" ventricular arrhythmias most often arise from the right ventricular outflow tract (RVOT), although arrhythmias from the left ventricular outflow tract (LVOT) are also observed. While previous work has elucidated the mechanism and electropharmacologic profile of RVOT arrhythmias, it is unclear whether those from the LVOT share these properties. The purpose of this study was to characterize the electropharmacologic properties of RVOT and LVOT arrhythmias.

Methods and Results: One hundred twenty-two consecutive patients (61 male; 50.9 ± 15.2 years) with outflow tract arrhythmias comprise this series, 100 (82%) with an RVOT origin, and 22 (18%) with an LVOT origin. The index arrhythmia was similar: sustained ventricular tachycardia (VT) (RVOT = 28%, LVOT = 36%), nonsustained VT (RVOT=40%, LVOT=23%), and premature ventricular complexes (RVOT = 32%, LVOT = 41%) (P = 0.32). Cardiac magnetic resonance imaging and microvolt T-wave alternans results (normal/indeterminate) were also comparable. In addition, 41% with RVOT foci and 50% with LVOT foci were inducible for sustained VT (P = 0.48), and induction of VT was catecholamine dependent in a majority of patients in both groups (66% and 73%; RVOT and LVOT, respectively; P = 1.0). VT was sensitive to adenosine (88% and 78% in the RVOT and LVOT groups, respectively, P = 0.59) as well as blockade of the slow-inward calcium current (RVOT=70%, LVOT=80%; P = 1.00) in both groups.

Conclusions: Electrophysiologic and pharmacologic properties, including sensitivity to adenosine, are similar for RVOT and LVOT arrhythmias. Despite disparate sites of origin, these data suggest a common arrhythmogenic mechanism, consistent with cyclic AMP-mediated triggered activity. Based on these similarities, these arrhythmias should be considered as a single entity, and classified together as "outflow tract arrhythmias."

Introduction

The most common form of "idiopathic" ventricular tachycardia (VT) localizes to the right ventricular outflow tract (RVOT) and is referred to as RVOT tachycardia. Although less common, tachycardia arising from the left ventricular outflow tract (LVOT) is also observed. Up to 90% of outflow tract VT is thought to originate from the right ventricle, mainly from the RVOT but also from other regions of the right ventricle, including sites above the pulmonary valve.^[1]LVOT tachycardia can arise from endocardial sites, epicardial sites,^[2] the aorto-mitral continuity, as well as from foci accessible from the aortic sinuses of Valsalva.^[3,4]

RVOT tachycardia has been shown to have a unique arrhythmogenic substrate and electropharmacologic profile. In general, it is adrenergically mediated and sensitive to perturbations that lower intracellular calcium (e.g., adenosine and verapamil). These findings are consistent with VT due to cyclic adenosine monophosphate (cAMP)-mediated triggered activity dependent on delayed afterdepolarizations.^[5,6] It is unclear whether LVOT tachycardia shares a similar clinical phenotype, mechanism, and electrophysiologic properties, given its disparate location. To date, there has been no series comparing the clinical characteristics and electrophysiologic properties of LVOT and RVOT arrhythmias. Therefore, the purpose of this study was to fully characterize the electropharmacologic properties of these two entities in a large series of consecutive patients.

Methods

Study Population

We evaluated 122 consecutive patients with suspected outflow tract arrhythmias who presented to our laboratory for electrophysiologic evaluation, and underwent a complete electrophysiology study. Of note, 17 patients in our registry were excluded from this series due to incomplete electrophysiologic testing. For the purposes of this study, the LVOT includes foci in the aortic sinuses of Valsalva as well as the aortomitral continuity. Ectopy originating in nonoutflow tract sites (including epicardial foci) were excluded from this analysis. Reasons for referral included symptoms refractory to medical therapy, as well as suspected left ventricular dysfunction due to frequent ectopy. This analysis was approved by our institutional review board.

Noninvasive Evaluation

Patients underwent systematic evaluation of cardiac structure, function, and ectopy burden. When possible, this included cardiac magnetic resonance imaging (MRI) as well as 24-hour Holter monitoring and/or inpatient telemetry. The presence of coronary artery disease was assessed by stress testing and/or cardiac catheterization (defined as ≥70% stenosis of any major epicardial vessel). Left ventricular systolic function was quantified by echocardiography, radionuclide ventriculography, and/or ventricular cineangiography. Structural heart disease was defined as presence of coronary artery disease (defined above), left ventricular ejection fraction <40%, and/or moderate or severe valvular disease.

Electrophysiologic Testing

After giving informed written consent, patients underwent a standardized electrophysiologic testing protocol following an overnight fast. Patients were locally anesthetized with 0.25% bupivacaine and, if necessary, minimally sedated with intravenous midazolam and morphine or fentanyl. Quadripolar 6 F catheters were advanced to the high right atrium, His bundle position, and right ventricular apex and/or outflow tract. Bipolar intracardiac electrograms were filtered at 30–500 Hz. If further mapping and/or ablation in the left ventricle or sinuses of Valsalva was required, a retrograde aortic approach was used.

The stimulation protocol included burst atrial and ventricular pacing, and the introduction of single atrial and up to triple ventricular extrastimuli from up to two right ventricular sites. Stimuli were delivered as rectangular pulses of 2-msec duration at four times diastolic threshold. If necessary to facilitate induction of sustained tachycardia, programmed stimulation was repeated from at least one right ventricular site after isoproterenol or dobutamine (during a time period of national shortage of isoproterenol) was infused to decrease the sinus cycle length by approximately 20-30%.

When the systems were acquired, three-dimensional mapping was performed using one of two systems. The Biosense-CARTO electroanatomic mapping system (Biosense-Webster, Diamond Bar, CA, USA) was used in 86 patients, using previously described methods.^[7] The Endocardial Solutions noncontact mapping system (Endocardial Solutions, Inc., St. Paul, MN, USA) was employed in four patients, as previously described.^[8] All patients whose targeted ectopy had a left bundle inferior axis morphology initially had activation mapping performed in the right ventricle. If this failed to demonstrate an "early" (i.e., pre-QRS) site, mapping of the left ventricle via retrograde aortic approach was considered.

Evaluation of microvolt level T-wave alternans (TWA) was also performed, during atrial pacing at the time of the electrophysiologic study. TWA was not performed if the patient had incessant ectopy at baseline, or presented in an atrial arrhythmia. The current protocol (performed in 58 patients) involved recording at baseline and during right atrial pacing at 109 bpm for 5 minutes. TWA was analyzed using either the Cambridge Heart CH2000 or HearTwave system (Cambridge Heart, Inc., Bedford, MA, USA) according to standard criteria.^[9]

Pharmacologic Testing

Adenosine was given only when sustained VT (>30 seconds) was reproducibly induced during electrophysiologic testing. VT was considered adenosine sensitive if it terminated reproducibly within 20 seconds of administration of adenosine, in the absence of a premature ventricular complex (PVC). Adenosine (Adenocard; Astellas Pharma US, Inc., Deerfield, IL, USA) was administered as a rapid bolus through a central venous catheter, followed by a 10 mL flush of normal saline. The usual initial dose of adenosine was 6 mg, with the dose titrated incrementally by 6 mg until tachycardia terminated, suppressed, or ventriculo-atrial (VA) block occurred. Similarly, verapamil (5-20 mg i.v.) was also infused over 60 seconds when clinically appropriate/tolerated, to determine its effect on tachycardia.

Continuous variables were expressed as a mean standard deviation. Comparisons between groups were made using the independent samples t-test or Wilcoxon two-sample test where appropriate, according to normality of distribution. Categorical variables, expressed as numbers and percentages, were compared using Fisher's exact test or chi-square test, depending on the number of variables. All tests of significance were two-tailed, and P values of <0.05 were considered statistically significant.

Discussion

The principal finding in this study is that RVOT and LVOT tachycardias have similar electrophysiologic properties and underlying mechanism. The data in this study are unique, in that this is the largest single-center experience of outflow tract arrhythmias that utilizes a systematic approach to investigate the underlying arrhythmia mechanism. This included standardized electrophysiologic testing, pharmacologic perturbations, as well as TWA testing.

We found that both left and RVOT arrhythmias are inducible with programmed stimulation and are facilitated by catecholamine infusion. In addition, both forms of VT terminate in response to adenosine as well as verapamil. This pharmacologic profile distinguishes them from other forms of ventricular tachycardia,^[11] and suggests that arrhythmias from both of these sites appear to be caused by triggered activity due to cyclic adenosine monophosphate (cAMP)-mediated calcium-dependent delayed afterdepolarizations.^[6] Although there was a difference is cycle length of inducible sustained VT between the two groups, this cannot be easily explained. It is unlikely to have an underlying mechanistic etiology, and is possibly due to the small sample size of LVOT patients in combination with the slightly higher proportion of LVOT patients requiring catecholamine infusion to induce sustained VT.

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