effects of intravenous adenosine on verapamil-sensitive “idiopathic” ventricular tachycardia

ARRHYlHMlAS AND CONDUCTION DISTURBANCES

Effects of Intravenous Adenosine on Verapamil- Sensitive “Idiopathic9’ Ventricular Tachycardia

Michael J. Griffith, MD, Clifford J. Garratt, MB, Edward Rowland, MD, David E. Ward, MD, and A. John Camm, MD

The mechanism of ventricular tachycardia (VT) that occurs in the absence of structural heart disease (“idiopathic” VT) is unknown, but may in- volve triggered activity or reentry through calcium channel-mediated conduction pathways. It has been suggested that termination of V7 by adenosine is specific to ventricular arrhythmias caused by cyclic adenosine monophosphateme- diated triggered activity. The effects of vago- tonic maneuvers, and intravenous adenosine (up to 0.25 mg/kg in incremental doses) and Vera- pamil (0.145 mg/kg) administered to 9 patients with “idiopathic” VT were studied during electrophysiologic study. Seven patients had inducible fascicular VT and 2 had incessant right ventricular outflow tract tachycardia. Vagal maneuvers did not have any effect on any V7. Adenosine interrupted both right ventricular outflow tract tachycardias for a period (2 to 15 seconds) that was dependent on the dose of adenosine, but had no effect on VT in any patient with fascicular VT. Verapamil produced stuttering termination of right ventricular outflow tract tachycardia with no preceding change in RR interval in patients with this arrhythmia. Administration of ve1c apamil to patients with fascicular VT was followed by gradual slowing of the arrhythmia (cycle length increased from 397 f 45 to 506 -c 86 ms; p <O.Ol) in all 7 patients and by termination of V7 in 6.

In conclusion, the dHferential response of fascicular and right ventricular outflow tract tachy cardias to both adenosine and verapamil suggests that: (1) These 2 forms of idiopathic VT have different mechanisms. (2) Fascicular VT is unlikely to be due to cyclic adenoslne monophosphate-mediated triggered activity. These findings also have implications for the use of adenosine as a diagnostic agent in broadcorn- plex V7.

(Am J Cardiol1994;73:759-764)

From the Department of Cardiological Sciences, St. George’s Hospital Medical School, London, and the Department of Cardiology, Royal Brompton and National Heart Hospital, London, United Kingdom. Manuscript received April 5, 1993; revised manuscript received September 23, 1993, and accepted September 28.

Address for reprints: A. John Camm, MD, Department of Cardio- logical Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom.

T here is general agreement that reentrant mechanisms are responsible for ventricular tachycardia (VT) associated with chronic ischemic heart dis-

ease,‘,2 but the mechanisms underlying VT occurring in the absence of structural heart disease are unknown. Two distinct forms of “idiopathic” VT have been iden- tified: fascicular VT3-s and right ventricular outflow tract tachycardia.9-11 Several investigators have suggested that either triggered activity or reentry involving calcium channel-mediated conduction may be the underlying mechanism for VT in these patients, because both forms of idiopathic VT are terminated or suppressed by verapamil.4-9*‘2-14 Lerman et all5 described 4 patients with right ventricular outflow tract tachycardia terminated by vagal maneuvers and intravenous adenosine, and suggested that this response is specific to ventricular arrhythmias caused by cyclic adenosine monophosphate-mediated triggered activity. The purpose of the present study was to examine the effects of vagal maneuvers, adenosine and verapamil in 9 patients with idiopathic VT to: (1) assess the possible role of cyclic adenosine monophosphate-mediated triggered activity in fascicular VT, as well as right ventricular outflow tract tachycardia; and (2) define further the clinical role of adenosine in the diagnosis of broad-complex VT.i6

METHODS Patient selection: A series of 9 consecutive patients

presenting with spontaneous sustained episodes of idiopathic VT were admitted to the study. All patients had normal surface 12-lead electrocardiograms during sinus rhythm, chest radiographs, 2-dimensional echocardio- grams, left ventricular angiograms and coronary arte- riograms. Patients with nonsustained arrhythmias were excluded from the study. All patients gave informed con- sent. No patient was described in a previous study of fascicular VT.14

Electrophysiologic study: All antiarrhythmic ther- apy was stopped for 248 hours before the diagnostic electrophysiology study, and no patient had been re- ceiving amiodarone. Four quadripolar electrode cathe- ters were inserted percutaneously, and advanced under fluoroscopic guidance to the high right atrium, coronary sinus, right ventricular apex and atrioventricular junc- tion to record the His potential. Bipolar intracardiac sig- nals were recorded on paper simultaneously with 24 surface electrocardiographic leads (I, aVF, V, and V,). Atrio-His (AH) and His-ventricular (HV) intervals were measured by standard techniques.17 Programmed atria1 and ventricular stimulation was performed with a pro- grammable constant current stimulator that delivered rectangular pulses of 2 ms duration at 2 times the dia-

ADENOSINE AND IDIOPATHIC VENTRICULAR TACHYCARDIA 759

TABLE I Clinical Characteristics and Effects of Vagal Maneuvers, Adenosine and Verapamil on Idiopathic Ventricular Tachycardia

Patient Age (yr) & Sex BBB Morphology QRS Axis (“1 TCL (ms) Adenosine

Dose (mgl kg) CSMIVSM

Effects of

Adenosine Verapamil

1 20F Right -100 400 0.25 ST Termination 23M 45M 28M 33F 40M 30F 35F 28F

Right Right Right Right Right Right Leti Left

-90 -100

-90 -90

-100 -90

+120 +130

410 400 310 380 430 450 325 440

0.25 0.20 0.20 0.25 0.20 0.25 0.10 0.10

0 0 0 0 0 0

Termination Termination

Termination Termination Termination Termination Termination Slowed Termmation Termination

BBB = bundle branch block pattern; CSM = carotid sinus massage; ST = sinus tachycardia; TCL = tachycardia cycle @fth; VSM = v&alva maneuver; 0 = no effect; _ = not performed.

stolic threshold. The ventricular stimulation protocol consisted of the introduction of progressively premature ventricular extrastimuli at 2 drive cycle lengths (400 and 600 ms). If 1 extrastimulus did not induce VT, then a second and finally a third were introduced. Inducibility of VT was assessed also by atrial pacing: Progressively premature atrial extrastimuli were introduced at 2 cycle lengths (400 and 600 ms). If VT was not induced by 1 extrastimulus, then a second atria1 extrastimulus was introduced. Finally, induction of VT was attempted by rapid atrial pacing at a cycle length of 300 ms. The diagnosis of VT was obtained according to standard criteria.17 The diagnosis of fascicular VT was obtained on the basis of a right bundle branch block pattern with left- axis deviation in the frontal pla.ne,‘j in addition to the presence of a short HV interval during VT indicating early retrograde activation of the His bundle. The presence of an anterogradely conducting accessory atrioventricular connection or nodoventricular fiber was excluded by showing decremental AH conduction without change in the HV interval during the introduction of atria1 premature complexes in sinus rhythm or after an atrially paced drive train. l7 The diagnosis of right ventricular outflow tract tachycardia was obtained on the basis of a left bundle branch block pattern on the surface electrocardiogram with right-axis deviation in the frontal plane,” in addition to the criteria for VT

Vagal maneuvers: All vagal maneuvers were performed with the patient in a supine position, after the diagnostic electrophysiologic study and after reinduction of sustained VT Carotid sinus massage was performed according to standard techniques for 5 seconds on the right side and then repeated on the left side for an identical period after waiting approximately 30 seconds.18 Patients performed the Valsalva maneuver by blowing in a mouthpiece and maintaining a constant pressure of 30 to 40 mm Hg for 15 seconds.19 Tensing of the neck and abdominal muscles was considered as evidence that the maneuver was being performed correctly. This protocol was shown previously to be effective in terminat- ing approximately 50% of inducible junctional VTs.19

Drug administration: After attempted termination of VT by the Valsalva maneuver, intravenous adenosine was administered as a rapid bolus through a forearm vein at an initial dose of 0.05 m&g. If VT did not terminate after 2 minutes, incremental doses (increasing by 0.05

1 mg/kg) were given up to 0.25 mg/kg.16 Five minutes after the final dose of adenosine (after reinitiation or con- tinuation of VT), intravenous verapamil was administered at a dose of 0.145 mg/kg over 15 seconds.20

Statistics: All values are expressed as mean + SD. The paired t test was used to test for differences between means in the same patients. A p value co.05 was considered significant.

RESULTS The clinical details of the 9 patients (mean age 31

years; 5 women and 4 men) are listed in Table I. All patients had clinically documented, recurrent, broad-complex VT that had lasted 230 minutes. By design (see Patient selection), no patient had evidence of structural heart disease. Sustained (>lO minutes) VT was initiated reproducibly with programmed atrial or ventricular stimulation in all patients. All patients were hemodynami- tally stable during sustained VT Systolic blood pressure was maintained at >90 mm Hg in all patients, and mean VT cycle length was 394 ms (range 310 to 450). In all patients, the induced VT had surface electrocardiographic features identical to those of the spontaneous “clinical” arrhythmia.

Seven patients had fascicular VT and 2 had right ventricular outflow tract tachycardia. A retrograde His potential was recorded during VT in all 7 patients with fascicular VT, and the mean HV interval was -15 ms (range +lO to -25). The retrograde His potential could be dis- sociated from the QRS complex during VT by premature stimulation of the atrium or ventricle in all 6 patients in whom it was attempted. In all 7 patients, VT could be initiated or terminated by 1 or 2 ventricular extrastimuli. In 3 patients with fascicular VT, the arrhythmia could also be induced by rapid atrial pacing. Both patients with right ventricular outflow tract tachycardia had history of exertion-related arrhythmias, but VT could be initiated by ventricular extrastimuli without the need for isoproterenol infusion during the electrophysiologic study. These 2 patients developed “incessant” VT throughout the second half of the electrophysiologic study: The arrhythmia could be terminated temporarily by 1 or 2 ventricular extrastimuli, but recurred spontaneously within 1 or 2 seconds.

The effects of vagal maneuvers, adenosine and verapamil on VT are listed in Table I. Carotid sinus mas-

760 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 APRIL 15,1994

sage and the Valsalva maneuver were performed in 8 patients (6 with fascicular VT and both with right ventricular outflow tract tachycardia), but no VT was slowed or terminated as a result. Adenosine was administered to all 9 patients during VT at a mean dose of 0.2 mg/kg (range 0.10 to 0.25). Administration of adenosine did not terminate or slow fascicular VT in any patient with this arrhythmia. In 1 patient, administration of adenosine was followed by acceleration of sinus rate, resulting in cap- ture of the ventricles by sinus tachycardia. However, the fascicular VT appeared to continue uninterrupted and became apparent after the sinus rate returned to the level before adenosine (Figure 1). Adenosine consistently terminated right ventricular outflow tract tachycardia without first slowing the VT in the 2 patients with this arrhythmia; termination of VT was not associated with acceleration of sinus rate in either case. In 1 patient with retrograde ventriculoatrial conduction during VT, adenosine caused retrograde conduction block 3 seconds before termination of VT (Figure 2). In both patients with right ventricular outflow tract tachycardia, the arrhythmia spontaneously reinitiated after a few seconds of sinus rhythm. VT was interrupted for 1 to 2 seconds by 0.1 mg/kg of adenosine in both patients and for 10 and 15 seconds, respectively, after a dose of 0.2 mg/kg.

Intravenous verapamil was administered to all 9 patients. VT was terminated in 8 patients (6 with fascicular and 2 with right ventricular outflow tract tachycardia) (Figures 3 and 4) and was slowed without termination in 1 with fascicular VT In patients with

fascicular VT, there was a gradual but marked slowing of VT before termination, with a mean cycle length in- crease from 397 -t 45 to 506 + 86 ms (p ~0.01) (Figure 5), whereas those with right ventricular outtlow tract tachycardia showed no such change in cycle length before termination. Both patients with right ventricular outflow tract tachycardia showed a “stuttering” form of termination after verapamil (Figure 4): VT terminated intermittently, alternating with short periods of sinus rhythm, before stable sinus rhythm ensued.

DISCUSSION There is now considerable evidence that fascicular

and right ventricular outflow tract tachycardia are distinct subgroups of idiopathic VT, with characteristic clinical and electrophysiologic properties.3-15 The patients in this study have features typical of these types of VT in regard to absence of evidence of structural heart disease, classical electrocardiographic and electrophysiologic features, and marked response to verapamil.

Intravenous adenosine terminated both right ventricular outflow tract tachycardias in this study, confirming the findings of Lerman et a1.15 The latter investigators suggested that this finding was most consistent with the abolition of cyclic adenosine monophosphate-mediated triggered activity in individual myocytes of the right ventricular outflow tract. In previous work on isolated myocytes, adenosine was shown to have no direct electrophysiologic effect on ventricular myocardium; its only indirect effect was the abolition of catecholamine-in-

Follorlm~ imtrarrmomr mdomrlmr (O.tih~/k~).

FIGURE 1. Effect of intravenous adenosine on fascicular tachycardia in patient 1. Note appearance of sinus tachycardia and fusion beats, but fascicular tachycardia appears to be unaffected. CL = cycle length.


Following intravenous adenosine (0.20mg/kg)

FIGURE 2. Termination of right ventricular outflow tract tachycardia by adenosine (patient 9). Termination of tachy- cartlia is preceded by retrograde ventriculoatrial block and 1 ventricular premature complex (arrow], both of which are markers of action of adinoslne. HRA = high right atrial electrogram.

Vl CL 62omr

--.S

FlGURE 3. Effect of intravenous verapamil on fascicular tachycardia (patient 6). There is gradual slowing of tachycardia before termination occurs. CL = cycle length.

762 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 APRIL 15,1994

Bolur of

0.15 mg/b

Vcrapamil.

FlGlJRE 4. Effect of intravenous verapamil on right ventricular oufflow tract tachycardia (patient 8). Termination is stuttering, and there is no slowing of tachycardia before termination occurs. CL = cycle length.

duced (cyclic adenosine monophosphate-mediated) triggered activity. 21 The 2 right ventricular outflow tract tachycardias in the present study became incessant during the latter part of the electrophysiologic study: This behavior allowed the demonstration of the dose-related nature of the period of adenosine-induced suppression of right ventricular outflow tract tachycardia. In addition, these 2 arrhythmias differed from those of Lerman et alI5 in that they were not terminated by vagal maneuvers. Vagal maneuvers exert their action on the heart through acetylcholine release, which exerts its predominant electrophysiologic effect on the ventricular myocardium in a similar way to adenosine (i.e., antagonizing catecholamine-mediated increases in intracellular cyclic adenosine monophosphate). 22 The absence of any effect of vagal maneuvers on right ventricular outflow tract tachycardia in the present study does not exclude cyclic adenosine monophosphate-mediated triggered activity as the mechanism, but may indicate merely that they are not as powerful as adenosine in the suppression of such activity.

‘0°: 600 -

TCL ‘O” -

(ms)

400 -

It has also been suggested that triggered activity may be the underlying mechanism in some cases of fascicular VT23 This study showed an absence of effect of

2002 Before verapamil After verapamil

adenosine in all 7 patients with fascicular VT, despite L administration at a relatively high dosage. Studies on the

FIGURE 5. Effect of verapamil on tachycardia cycle

timing of adenosine-induced atrioventricular nodal length (XL) in patients with fascicular tachycardia (c/o& cim/es) and right ventricular oufflow tract

blockade suggest that adenosine acts on the atrioven- tachycardia (open circ~es~.


tricul~ node by the coronary circulation rather than by 1. we~lens HJJ, DWM DR, Lie H. Observations on mechanisms of venticu~ar

direct diffusion from the right ventricle.24 The finding tachycardia in man. Circularion 1976;54:237-244.

that adenosine-induced atrioventricular nodal blockade 2. Josephson ME, Horowitz LN, Farshidi A. Continuous local electrical activity: a

precedes adenosine-induced termination of right ven- mechanism of recurrent ventricular tachycardia. Circularion 1978;57:659-665. 2. Zipes DP, Foster PR, Troop PJ, Pedersen DH. Atrial induction of ventricular

tricular outflow tract tachycardia (Figure 2) supports an tachycardia: reentry versus triggered automaticity. Am J Cardiol 1979:44:1-S.

effect on right ventricular myocytes, which is also me- 4. Belhaasen B. Rotmensch HH, Laniado S. Response of recurrent sustained ventricular tachycardia to verapamil. Br Heart J 1981;46:679-682.

diated through the coronary circulation. Therefore, it is 5. German LD, Packer DL, Bardy GH, Gallagher JJ. Ventricular tachycardia in-

unlikely that the concentration of adenosine at the site duced by atrial stimulation in patients without symptomatic cardiac disease. Am J

of Ofi& Of faSCiCUlar VT WaS lower than that Of right Curdiol 1983;52:1202-1207. 6. Lin F-C, Finley CD, Rahimtoola SH, wu D. Idiopathic paroxysmal WII~~CULV

ventricular outflow tract tachycardia, and the higher tachycardia with a QRS pattern of right bundle branch block and left axis devia-

doses of adenosine administered during fascicular VT tion: a unique clinical entity with specific properties. Am J Cardiol 1983;52:95-100.

would indicate that the reverse was true (0.23 vs 0.10 7. Belhassen B, Shapira 1. Pelleg A, Coppermao I, Kauli N, Laniado S. Idiopathic recurrent sustained ventricular tachycardia responsive to verapamil: an ECG-elec-

mg/kg; Table I). Although the effects of adenosine on trophysiologic entity. Am Hean J 1984;108:103&1037.

fascicular VT were not reported previously, there have 8. Ohe T, Shimomura K, Aihara N, Kamakura S, Matsuhisa M, Sam I, Nakagawa

been 2 published cases of this VT which were unaffected H, Shimizu A. Idiopathic sustained left ventricular tachycardia: clinical and electrophysiologic characteristics. Circulation 1988;77:560-568.

by adenosine triphosphate>v25 This absence of response 9. Wu D, Kou H-C, Hung J-S. Exercise-triggered paroxysmal ventricular tachy-

to adenosine (and adenosine triphosphate) does not pro- cardia: a repetitive rhythmic activity possibly related to afterdepolarization. Ann 1nrern ,$&.d ]9s];95:4]&4]4.

vide support for triggered activity as a mechanism for 10. Palileo EV, Ashley WW, Swiryn S, Bauemfeind RA, Strasberg 8, Petropoulos

this arrhythmia, and it is likely that an alternative mech- AT, Rosen KM. Exercise provocable right ventricular outflow tract tachycardia.

anism such as calcium channel4ependent reentry is re- Am Hearr J 1982;104:185-193. ll. Buxton AE, Waxman HL, Marchlinski FE, Simson MB, Cassidy D, Josephson

sponsible. Several investigators have suggested that this ME. Right ventricular tachycardia: clinical and electrophysiologic characteristics.

arrhythmia may originate from a localized reentry cir- Circularion 1983:68:917-927,

cuit near or within the posterior fascicle of the left bun- 12. Sung RJ, Shapiro WA, Shen EN. Morady F, Davis J. Effects of verapamil on ventricular tachycardias possibly caused by reentry, automaticity, and triggered ac-

dle branch. tivity. J Clin Invest 1983;72:35@360.

The responses of the 2 forms of VT to intravenous i3. Belhassen B, Horowitz LN. Use of intravenous verapamil for ventricular tachycardia. Am J Cardiol 1984;54:1131-1133.

verapamil provide further support for the suggestion that 14. Ward DE, Nathan AW, Camm AJ. Fascicular tachycardia sensitive to calcium

their underlying mechanisms are probably different. antagonists. Eur Hear? J 1984;5:896-905.

Patients with fascicular VT showed a gradual but marked 15. Lerman BB, Belardinelli L, West GA, Beme RM, DiMarco JP. Adenosine- sensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated trig-

slowing of VT before termination, whereas those with gered activity. Circulation 1986:74:27&280.

right ventricular outflow tract tachycardia showed no 16. Griffith MJ, Linker NJ, Ward DE, Camm AJ. Adenosine in the diagnosis of

such change in cycle length before termination. In ad- broad-complex tachycardia. Lancer 1988;1:672-675. 17. Ward DE, Camm AJ. Clinical Electrophysiology of the Heart. London: Edward

dition, both patients with right ventricular outflow tract *mo]d, ]w. tachycardia showed a stuttering form of termination af- l8. Wellens HJJ, Brugada P, Bar F. Diagnosis and treatment of the regular tachy-

ter verapamil. Although these observations suggest that cardia with a narrow QRS complex. In: Kulbertus HE, ed. Medical Management of Cardiac Arrhythmias. London: Churchill Livingstone, 1986.

the 2 VTs have different mechanisms, neither type of re- 1% Mehta D, Wafa S, Ward DE, Camm AJ. Relative efficacy of various physical

sponse can definitely be attributed to either reentry or manoeuvres in the termination ofjunctional tachycardia. Lancer 1988;1:1181-1185.

triggered activity. 20. Gamatt CJ, Linker NJ, Griffith MI, Ward DE, Camm AJ. Comparison of adenosine and verapamil for termination of paroxysmal junctional tachycardia. Am J

Clinical relevance: Intravenous adenosine has been cardiO’ 1989~64~1310-1316~ suggested as a diagnostic test in patients with broad-

21. Isenberg G, Belatdinelli L. Ionic basis for the antagonism between adenosine and isoproterenol on isolated mammalian ventricular myocytes. Circ Res 1984;55:

complex VT of uncertain origin.16 Patients with fascic- 309-325.

ular VT have a QRS pattern in V6 that is in accordance 22. Linden I, Hollen CE, Pate1 A. The mechanism by which adenosine and cholin-

with a diagnosis of VT, and a QRS pattern in V] that is ergic agents reduce contractility in rat myocardium; correlation with cyclic adenosine monophosphate and receptor densities. Circ Res 1985;56:728-735.

reminiscent of supraventricular tachycardia.26 Absence 22. Lennan BB. Ventricular tachycardia unassociated with coronary artery disease.

of response to adenosine of an arrhythmia with these Prog CardiolVasc Dis 1988;1:255-279.

electrocardiographic features suggests the diagnosis of 24. Sylven C, Jonzon B, Edlund A. Angina pectoris-like pain provoked by i.v. bolus of adenosine: relationship to coronary sinus blood flow, heart rate and blood

fascicular VT rather than supraventricular tachycardia pressure in healthy volunteers. Eur Heart J 1989;10:48-54.

with aberrant conduction. The use of verapamil as the 25. Tai Y-T, Fang P-C, Lao C-P, Chow W-H, Cheng C-H. Reentrant fascicular tachycardia with cycle length altemans: insight into the tachycardia mechanism and

initial therapeutic agent in these cases will lead to ter- origin. PACE 1990;13:900-907.

mination of either form of arrhythmia, but will provide 26. Wellens HJJ, Bar FWHM, Lie Kl. The value of the electrocardiogram in the

no diagnostic information. differential diagnosis of a tachycardia with a widened QRS complex. Am J Med 1978;64:27-33.

764 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 APRIL 15, 1994

effects of intravenous adenosine on verapamil-sensitive “idiopathic” ventricular tachycardia

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