Pharmacologic suppression of atrial flutter

induced by atrial stimulation

To examine the electrophysiologic properties of human atrial flutter and its response to various classes of antiarrhythmic drugs, 39 patients were identified as having inducible sustained atrial flutter with atrial extrastimulation techniques. Measurement of intra-atrial, interatrial, atrioventricular node and His-Purkinje-conduction intervals, atria1 refractory periods, and atrial flutter-cycle length were made before and after intravenous administration of verapamil, ouabain, or cedilanid, propranolol, and procainamlde in these 39 patients, as well as in seven control patients. Verapamil significantly shortened flutter-cycle length but suppressed atrial-flutter induction in only one of seven patients. Two of nine patients who received propranolol proved resistant to flutter provocation; the seven patients who remained nonsuppressible exhibited greater prolongation of interatrial-conduction time. Ouabain and cedilanid suppressed flutter inducibility in four of seven patients, and flutter-cycle length increased in those patients remaining inducible. Procainamide suppressed flutter induction in nine of 11 patients. These results suggest that procainamide is the most effective agent of those agents tested in suppressing atrial flutter induced by atrial extrastimulation. Verapamil and propranolol proved quite ineffective in suppressing inducible atrial flutter. (AM HEART J lgg2;123:681.)

William R. Davis, MD, and Stephen F. Schaal, MD. Columbus and Put-ma, Ohio

Electrophysiologic studies in both man and experi- mental models have provided important insights into the electrophysiologic mechanisms and myocardial substrates permitting atria1 flutter. As discussed by Boineau,’ controversy over the mechanisms of flutter has centered on the macro- versus microreentry issue, with the weight of evidence favoring macroreentry in humans. However, this understanding has had lim- ited clinical usefulness in providing a rational ap- proach to pharmacologic control, and therapy re- mains largely empiric.

Atria1 flutter can conveniently be induced for study purposes with the introduction of atria1 extrastimuli. Flutter induced by these techniques appears to cor- relate with the spontaneous occurrence of the rhythm.2 In this study, we describe the effects of sev- eral antiarrhythmic agents on atrial-conduction prop- erties and the reproduction of atria1 flutter in pa- tients found to have readily and repeatedly inducible atria1 flutter obtained with programmed atria1 stim-

From the Kaiser Permanente, Parma, Ohio, and Division of Cardiology, The Ohio State University Hospitals, Columbus, Ohio.

Received for publication Jan. 2, 1991; accepted Aug. 20, 1991.

Reprint requests: Stephen F. Schaal, MD, Division of Cardiology, The Ohio State University Hospitals, Room 657 Means Hall, 1654 Upham Dr., Columbus, OH 43210.

4/l/34408

ulation. The study was designed to (1) identify the atrial-conduction properties that permit or inhibit response to the antiarrhythmic agents, procaina- mide, verapamil, and propranolol, and the cardiac glycosides, ouabain and cedilanid, (2) assess the effectiveness of these agents in preventing the in- duction of atria1 flutter, and (3) describe the electro- physiologic response of the atria1 flutter to each agent.

METHODS

Patients. Thirty-nine patients undergoing electrophys- iologic study for various indications were identified as hav- ing readily and repeatedly inducible sustained atria1 flut- ter by atria1 extrastimulation. After identification of the response to atria1 extrastimuli, the patients were randomly assigned to a drug protocol. Patients with evidence of sig- nificant sinus node dysfunction, atrioventricular conduc- tion, abnormality or left ventricular dysfunction with an ejection fraction <40% were excluded from study. Seven patients received verapamil, nine patients received pro- pranolol, seven patients received either ouabain or cedi- lanid, and 11 patients received procainamide. The age, sex, and clinical diagnoses are detailed in Table I. Patients were excluded if atria1 enlargement (>4.0 cm) was present by M-mode echocardiography. An additional five patients with inducible flutter received dextrose with repeat stim- ulation performed 10 to 20 minutes after dextrose infusion. Seven patients with no history of tachydysrhythmia who had normal electrocardiogram and electrophysiologic pa- rameters served as control subjects. Of the control popula-

681

662 Davis and Schaal

Table I. Clinical features of study patients

Case No. Age (YrJl

sex Clinical diagnosis

Verapamil 1 43/F 2 55/M 3 24/F 4 54/M 5 21/F 6 47/M 7 44/F

Propranolol 1 21/F 2 34/F 3 55/F 4 25/F 5 81/F 6 54/F 7 46/M 8 19/M 9 30/F

Ouabainlcedilanid 1 38/F 2 71/M 3 26/M 4 28/F 5 38/F 6 38/F 7 62/M

Procainamide 1 2 3 4 5 6 7 8 9

10 11

Dextrose 1 2 3 4 5

Control 1 2 3 4 5 6 7 8 9

10 11

58/F MVP, palpitations 7oiM Dizziness, palpitations 66/M Atrial flutter 36/M Syncope 69/M Syncope, atrial flutter/fibrillation 46/E Syncope, CHD 47/M Syncope, PVCs, PACs 77/M CSD, atria1 flutter 66/M CHD, palpitations 33/M VT 81/F CHD, syncope

47/F MVP, syncope 59/M MVP, near syncope 48/M Near syncope, palpitations 60/M VT, CHD 78/F CSD. atria1 flutter

45/F 41/M 52F 55/M 55/M 58/F 61/F 62/M 63/M 64/M 74/M

None None

HT None None None None None

CHD

MVP, syncope, palpitations CHD, syncope, CSD MVP, tachyarrhythmias Syncope, CSD MVP, syncope MVP, palpitations MVP, palpitations

Syncope Near syncope CSD, palpitations MVP, syncope CHD, syncope Syncope, palpitations Syncope MVP, syncope CHD, VT

Palpitations, PVCs Syncope, palpitations Palpitations MVP, CSD VT PJT CHF, PACs, atria1 flutter

CHD, Coronary heart disease; CHF, congestive heart failure; CSD, conduc- tion system disease; HT, hypertension; MVP, mitral valve prolapse; PJT, paroxysmal junctional tachycardia; PVC, premature ventricular contrac- tions; VT, ventricular tachycardia.

March 1992

American Heart Journal

Table II. Atria1 conduction intervals: Patients with induc- ible atria1 flutter versus control subjects (mean t SD mil- lisecond)

Inducible Control

AA 834.8 +- 159.5 931.5 + 303.0

HRA-LRA 33.6 + 13.2 36.7 t 10.5 HRA-LA 55.4 + 18.6 43.7 5 12.2 AERP 225.9 f 40.8 315.0 -+ 87.8

AA, Sinus cycle length; HRA, high right atrium; LRA, low right atrium; LA, left atrium; AERP, atria1 effective refractory period.

tion, four were female and seven were male, with an age range of 45 to 74 (mean, 57.8) years. One patient had cor- onary heart disease, and one patient had a history of hypertension; control patients were otherwise free of known heart disease.

Procedure. All patients were studied in the postabsorp- tive, nonsedated state after obtaining written, informed consent. All medications were withheld for 48 hours before electrophysiologic study. Intracardiac catheters were placed fluoroscopically with two bipolar or a quadripolar catheter positioned at the high right atrium (HRA), and a hexapolar catheter placed to record the low right atria1 (LRA), His bundle, and ventricular electrograms. The left atria1 electrogram was obtained by placing a bipolar elec- trode in the esophagus 3 cm below the junction of the su- perior vena cava and the right atrium. Three surface elec- trograms were simultaneously recorded. The right intra- atria1 conduction time was measured as the interval from the onset of HRA activity to the onset of LRA activity. In- teratrial-conduction time was defined as the interval from the onset of HRA activation to the onset of left atria1 (LA) activation. Atrioventricular node and His-Purkinje-con- duction intervals were obtained by measuring A-H and H-V intervals, respectively. The atria1 effective refractory period (AERP) was defined as the interval from the last paced atria1 depolarization to the longest premature atria1 stimulus that did not result in atria1 depolarization.

Baseline measurements of HRA-LRA, HRA-LA, AH, HV, and AERP were made before drug administration. Atria1 premature depolarizations were inserted in sinus rhythm and after atria1 pacing at cycle lengths of 500 and 600 msec. The premature depolarization (AZ) was inserted by progressive decrements of 10 msec until either atria1 flutter was produced or atria1 refractoriness was encoun- tered. If flutter was not produced, a second atria1 prema- ture depolarization (AZ) was introduced at progressive 10 msec decrements after AZ that was applied 20 msec after the AERP. Approximately 30% of patients required two extrastimuli for induction of atria1 flutter. Atria1 flutter was required to be sustained (>30 seconds) and reproducibly provokable with the same morphology and cycle length on at least two occasions. The rhythm terminated spontane- ously or with atria1 overdrive pacing.

One of the four antiarrhythmic agents was then selected at random and administered by one of the following pro-

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Number 3 Pharmacologic therapy of induced atrial flutter 683

Table III. Atrial-conduction intervals and atrial-flutter induction

AA HRA-LRA HRA-LA A-H AERP FF

Pre

Verapamii

Propranolol

Ouabainlcedilanid

Procainamide

Dextrose

723.4 k291.1

760.8 t144.0

805.1 k 229.6

868.2 * 173.9

937.4 3z 80.9

Post

743.6 67.4

814.1 91.7

798.9

213.3

799.0

126.5

Pre Post

33.2 32.1 9.3 15.0

33.3 35.3 11.7 9.9 35.3 36.4 14.2 13.2 36.9 34.4 10.3 14.4 35.4 22.4

Pre Post Pre Post

53.6 49.6 76.8 13.1 11.9 13.2

45 47.6 84.5 18.0 18.4 19.3

63.2 67.7 101.8 21.6 19.0 13.0

68.3 69.3 91.8

15.8 13.8 27.8 53.0 119.8

16.6 62.1

119.4

42.5 99.0 28.1

116.0 27.2

101.1 29.9

Pre

220 35.8

207.4 38.0

218.6 45.6

241.4 34.4

256.7 49.3

Post Pre post*

228.3 20.4

186.7 50.1

204.3 31.0

247.1 30.4

208.0 192.0

9.8 16.0

200.3 212.1

15.1 23.1

200.0 220.0 20.0 26.5

255.0 260.0 7.1 14.1

228.0 226.0 13.0 8.9

A, Atrial; H, His bundle; AA, sinocycle length; HRA, high right atrium; LRA, low right atrium; AERP, atria1 effective refractory period; FF, flutter-cycle length; Pre, predrug administration; Post, postdrug administration. *FF postdrug values are presented for patients who remained susceptible to flutter induction.

tocols: verapamil was administered, 10 mg/kg, not to exceed 10 mg administered during 2 minutes. Atria1 ex- trastimulation was repeated 10 minutes after drug admin- istration (seven patients). Procainamide was administered, 7 mg/kg (total dose, 400 to 1000 mg) intravenously, at 50 mg/min with repeat extrastimulation repeated 10 minutes after administration (11 patients). Ouabain, 0.01 mg/kg intravenously, was administered to a total dose 10.7 mg with atria1 extrastimulation repeated 30 minutes after drug infusion (six patients). Because ouabain was subsequently not available, cedilanid, 0.8 mg intravenously, with extra- stimulation, was repeated in 25 minutes (one patient). Propranolol, 0.1 mg/kg, not to exceed 10 mg intravenously, was administered at 1 mg/min with atria1 extrastimulation remeasured 20 minutes later in 20 patients (nine patients). Dextrose, 5% intravenously, was administered with atria1 extrastimulation repeated 10 to 20 minutes after adminis- tration (five patients).

Statistical analysis. Results are expressed as the mean + standard deviation. Student’s t test for paired data was used to evaluate the statistical significance between pre- and postdrug intervals. Student’s t test for unpaired data was used in comparing study subjects with inducible flutter to the control population without flutter.

RESULTS

The mean interatrial-conduction time in patients with inducible atria1 flutter (55.4 f 18.6 msec) was significantly prolonged over that of noninducible control subjects (43.7 f 12.2 msec; p < 0.05) (Table II). Intra-atrial-conduction time did not differ sig- nificantly between the groups. The AERP in the in- ducible group (225.9 f 40.8 msec) was shorter than AERP in the control group (315.0 f 87.8 msec; p < 0.01). Atrial-conduction intervals and responses to drugs are summarized in Table III. A 6.0 mm Hg average decrease in systolic blood pressure was noted after procainamide administration. No significant

blood pressure changes were noted after other inter- ventions.

Verapamil. Of the seven patients studied, only in one patient was induction of atria1 flutter effectively suppressed after the administration of verapamil. Interatrial- and intra-atrial-conduction times and AERP in the one patient with suppressible atria1 flutter were not significantly different from values obtained from patients with nonsuppressed atria1 flutter. For the group, an atrioventricular nodal effect was evidenced by lengthening of the AH interval (76.8 & 13.2 to 119.4 f 42.5 msec), although this change did not reach statistical significance. The flutter-cycle length after verapamil administration was significantly shortened from 208.3 -+ 9.8 msec to 191.7 f 16.0 msec (p < 0.05). AERP remained unaf- fected by verapamil administration.

Propranolol. Nine patients received propranolol, two of whom proved resistant to provocation of flut- ter after drug. Atrioventricular node (AV) conduc- tion was prolonged as reflected by an increase in the AH interval from 81.0 ? 24.5 to 99.0 f 28.1 msec (p < 0.05). No significant effects were noted in intra- atria1 conduction, AERP, or flutter-cycle length after propranolol administration. Interatrial conduction in patients remaining inducible after propranolol was significantly prolonged compared to that in those patients suppressed (49.3 + 18.4 versus 30.0 f 0 msec; p < 0.05).

OuabainIcedilanid. Of the seven patients studied, four patients (three receiving ouabain and one pa- tient receiving cedilanid) were not susceptible to provocation of atria1 flutter after drug administra- tion. Intra-atria1 conduction, AV node conduction, and AERP failed to distinguish patients who re- mained susceptible from those who were not after

684 Davis and Schaal March 1992

American Heart Journal

digitalis administration. Digitalis administration ef- fected no consistent changes in intra- or interatrial conduction or AERP in these patients in whom flut- ter was suppressed with mixed responses among the four patients. A trend toward AV nodal blockade was evidenced by an increase in AH interval from 101.8 + 13.0 to 116.0 -+ 27.2 msec, although statisti- cal significance was not achieved. The flutter-cycle length increased from 200.0 + 20.0 to 220.0 +- 26.5 msec with digitalis administration.

Procainamide. Nine of the 11 patients administered procainamide proved resistant to provocation of atria1 flutter after receiving the drug. Procainamide decreased the cycle length of sinus rhythm from 868.2 f 173.9 to 799.0 +- 126.5 (p < 0.05). Intra-atri- al- and interatrial-conduction intervals, A-II inter- val, and flutter-cycle length were unaffected by pro- cainamide. Procainamide lengthened AERP in three patients, shortened AERP in one, and produced no change in three patients. Interatrial conduction was prolonged to a greater degree after procainamide ad- ministration in those patients with persistently pro- vokable flutter (85.5 +- 7.8 versus 62.5 2 13.3 msec; p < 0.05). Predrug flutter-cycle lengths were shorter in patients who subsequently proved nonprovokable after procainamide administration compared to the two patients who remained provokable (218.0 * 26.8 versus 255.0 + 7.1 msec; p < 0.01).

Dextrose. Atria1 flutter remained inducible in all five patients after dextrose administration with no change in the flutter-cycle length, AERP, intra-atri- al- or interatrial-conduction times.

DISCUSSION

Electrophysiologic properties conducive to atrial flut- ter. Previous work from this laboratory3 has demon- strated that patients with spontaneous atria1 flutter have prolonged intra- and interatrial-conduction times as compared to that of control subjects. Be- cause patients with atria1 enlargement were excluded from both groups, this finding served as presumptive evidence that atrial-conduction disease provided the electrophysiologic substrate permitting atria1 flutter. The present results in patients with inducible atria1 flutter suggest similar findings. Interatrial conduc- tion was significantly prolonged in patients who were susceptible to the provocation of flutter, although this was not to the degree found previously.4 Unlike previous results, intra-atrial-conduction delay did not distinguish patients with inducible flutter from control subjects. This finding can probably be attrib- uted to the difference in study populations. Sponta- neous flutter was present in many of the patients from previous studies but not commonly identified in

patients from the present study. This suggests that atria1 flutter may have been induced in patients with lesser degrees of atrial-conduction disease than would be found in patients with spontaneous occurrence of the arrhythmia. Nonetheless, it is clear from the present study that atrial-conduction delay is a pre- requisite to the development of atria1 flutter.

The longer AERP found in the control group com- pared to that in subjects in whom flutter was induced is consistent with the theory that a relative prolon- gation of refractoriness protects the myocardium from premature depolarizations that could poten- tially induce a reentrant cycle if the proper spatial and temporal orientation of surrounding refractori- ness were present. 5, 6 This phenomenon suggests that pharmacologic prolongation of the AERP is at least one means by which the atria1 capacity for flutter rhythmicity might be suppressed. Boyden has re- cently provided evidence for such a mechanism for the conversion of atria1 flutter using a canine model with surgically created right atria1 enlargement. Agents that increased atria1 refractoriness, such as procainamide, were more likely to cause conversion of atria1 flutter to sinus rhythm. The atria1 flutter provoked in those patients who had previous docu- mented atria1 flutter was identical to that observed spontaneously. Although a minority of patients stud- ied had previously demonstrated spontaneous flut- ter, the flutter was reproducibly provokable. In addi- tion, the atria1 flutter was many times reprovoked in all the patients who received intravenous glucose.

Suppression of inducible atrial flutter Verapamil. The results of this study indicated that

verapamil is an unreliable agent for the suppression of atria1 flutter induced with programmed stimula- tion, although delay of AV nodal conduction is con- sistent with its clinical usefulness in slowing the ven- tricular rate. Our results of suppression of inducible flutter bear similarities to the results reported by several groups on the conversion of spontaneous atria1 flutter by intravenous verapamil; the cumula- tive conversion rate (of the series distinguishing atria1 fibrillation from flutter) was 21% (nine of 42 patients).8-13 Verapamil produced no appreciable ef- fects on either atria1 conduction or atria1 refractori- ness in our patients. Thus, the absence of a change in inducibility would be expected. Interestingly, the flutter-cycle length was shortened after verapamil administration. Verapamil has been demonstrated to produce varying effects on flutter-cycle length in dogs with surgically created pulmonary stenosis and tri- cuspid regurgitation resulting in right atria1 enlarge- ment.l Three of the dogs studied by Boyden dem- onstrated termination of atria1 flutter, one with a

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Number 3 Pharmacologic therapy of induced atria1 flutter 685

slight increase in atria1 rate, one with no change in atria1 rate, and another dog with a decrease followed by an increase in rate before conversion. A possible explanation for the shortening of flutter-cycle length is a catecholamine rise in response to the fall in blood pressure induced by verapamil. Alternatively, this could be an intrinsic effect of the drug. Shortening of the flutter-cycle length might have some effect on the difficulty of interrupting the reentrant flutter cycle. Inoue et al.* have demonstrated the presence of an “excitable gap” in both spontaneous and experimen- tally induced atria1 flutter that comprises 14% to 25 % of the total flutter-cycle length. It is likely that, as the atria1 flutter-cycle length is abbreviated, the width of the excitable gap decreases as well. An increase in the atrial-flutter rate would therefore shorten the period of vulnerability of the flutter cy- cle to extraneous influences. Moreover, surrounding myocardium would likely tend to demonstrate greater inhomogeneity of recovery of refractoriness and con- tribute further to the perpetuation of the flutter cy- cle.6

Propranolol. Propranolol proved to be an ineffec- tive drug for the suppression of inducible flutter. Boyden had similarly demonstrated a lack of flutter termination after propranolol in dogs. No significant changes in atrial-conduction properties or AERP were noted after propranolol administration in most patients. Propranolol has previously been demon- strated to shorten the AERP with low and moderate doses and prolong the refractory period with high dose as measured by intracellular recordings of canine atria1 tissue.15 Two patients with interatrial- conduction time approximating that of the nonin- ducible control group demonstrated effective sup- pression of atria1 flutter after propranolol, whereas those patients remaining inducible had significantly prolonged conduction time. Beta blockade has been demonstrated to reduce the frequency of premature atria1 ectopics, especially in circumstances of auto- nomic dysfunction, such as that associated with mi- tral valve prolapse. Since a premature atria1 depolar- ization is almost always required for the onset of spontaneous tachycardia, P-blockade might be help- ful in preventing atria1 flutter in a small subset of patients.

Cardiac glycosides. The cardiac glycosides proved quite effective in the suppression of inducible atria1 flutter. However, no changes in atria1 conduction or refractoriness were noted that might account for the variable responses noted among patients receiving digitalis. Contrary to our results, Dhingra et al,le found that ouabain prolonged atria1 refractoriness in normal individuals, and Engel and Gonzalez17 re-

ported that ouabain induced prolongation of the AERP in patients with extrastimulus-inducible atria1 flutter or fibrillation. Studies of canine atria1 tissue have demonstrated that digitalis shortens the AERP with an intact vagal system but lengthens the AERP when the atria are denervated.ls The flutter-cycle length increased in our patients not suppressed by digitalis, although no change in cycle length after ouabain was found by Engel and Gonzalez.17 Our data are consistent with the theory that nonunifor- mity of refractoriness and conduction are likely fac- tors important in the genesis of atria1 flutter and fi- brillation.5, 6 Engel and Gonzalez l7 have reported that ouabain decreased the atria1 vulnerable period; this may be important in the reduction of the inho- mogeneity of atria1 refractoriness important in the induction of atria1 flutter.

Procainamide. Procainamide proved to be the most successful agent in suppressing the induction of atria1 flutter. Consistent with previous studies on the electrophysiologic properties of procainamide,lg, 2o sinus-cycle length was decreased and A-V node con- dution time increased. Wyse, et aL20 demonstrated that the AERP was prolonged with procainamide administration in human. Wu and Hoffman2’ re- ported a consistent prolongation of the AERP as well as flutter-cycle length response to procainamide in a canine surgically modeled for reproduction of reentry atria1 flutter. Boyden likewise reported a significant increase in flutter-cycle length after procainamide. Our results revealed no statistical prolongation of the AERP or atrial-conduction time after procainamide administration, primarily because one patient dem- onstrated marked shortening of the AERP and no change in atrial-conduction time. Nonetheless, pro- longation of the AERP effected by procainamide could provide and explanation for the lack of induc- ibility of atria1 flutter.

Procainamide did not change the flutter-cycle length in the patients who remained inducible. Cycle length before drug administration in patients re- maining inducible exceeded that of patients with suppressed flutter activity, suggesting either that procainamide is not as effective in the suppression of flutter activity by prolonging the time of reentry loop conduction and widening of the excitable gap and/or that atria1 flutter with cycle lengths >250 msec are apt to be resistant to procainamide-mediated sup- pression.

Clinical application. These results demonstrate that procainamide is much superior to propranolol and verapamil, whereas digitalis glycosides are modestly effective in the suppression of atria1 flutter induced by atria1 extrastimulation techniques. Watson and

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American Heart Journal

Josephsons have suggested that the capacity to induce atria1 flutter correlates closely with the ten- dency for spontaneous atria1 flutter. It is not clear from our results or previous studies whether phar- macologic suppression of induced flutter correlates with conversion of spontaneous atria1 flutter or maintenance of normal rhythm in the patient prone to atria1 flutter. However, the electrophysiologic similarities of atria1 flutter among study populations with inducible flutter such as ours and those of other groups with spontaneous flutter suggest that sup- pression of inducible atria1 flutter should correlate with pharmacologic control of the dysrhythmia. Pro- cainamide effectively abolished the atria1 capacity to maintain the flutter cycle, probably on the basis of increased atria1 refractoriness. Digitalis proved ef- fective in the control of atria1 flutter in more than one half of patients studied. Both verapamil and propra- nolo1 were ineffective agents in suppressing induc- ibility of atria1 flutter.

REFERENCES

1.

2.

3.

4.

5.

6.

Boineau JP. Atria1 flutter: a synthesis of concepts. Circulation 1985;72:249-57. Watson RM, Josephson ME. Atrial flutter. I. Electrophysio- logic substrates and modes of initiation and termination. Am J Cardiol 1980;45:732-41. Leier CV, Meacham JA, Schaal SF. Prolonged atria1 conduc- tion: a major predisposing factor for the development of atria1 flutter. Circulation 1978;57:213-6. Leier CV, Meacham JA, Schaal SF. Interatrial conduction de- lay in patients with atria1 flutter [Abstract]. Clin Res 1976; 24519. Boineau JP, Schuessler RB, Mooney CR, Miller CB, Wylds AC, Hudson RD, Borremans JM, Brockus CW. Natural and evoked atrial flutter due to circus movement in dogs: role of abnormal atria1 pathways, slow conduction, non-uniform refractory period distribution, and premature beats. Am J Cardiol 1980;45:1167-81. Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atria1 muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block, as studies with multiple microelec- trodes. Circ Res 1976;39:168-77.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Boyden PA. Effects of pharmacologic agents on induced atrial flutter in dogs with right atria1 enlargement. J Cardiovasc Pharmacol 1986;8:170-7. Sung RJ, Waxman HL, Elser B, Juma Z. Treatment of parox- ysmal supraventricular tachycardia and atria1 flutter-fibrilla- tion with intravenous verapamil: efficacy and mechanism of action. Clin Invest Med 1980;3:41-6. Aronow WS, Landa D, Plasencia G, Wong R, Karlsberg RP, Ferlinz J. Verapamil in atrial fibrillation and atria1 flutter. Clin Pharmacol Ther 1979;26:578-83. Tommasco C, McDonough T, Parker M, Talano JV. Atria1 fi- brillation and flutter: immediate control and conversion with intravenously administered verapamil. Arch Intern Med 1983; 143:877-81. Schamroth L, Krikler DM, Garrett C. Immediate effects of intravenous verapamil in cardiac arrhythmias. Br Med J 1972;1:660-2. Waxman HL, Myerburg RJ, Appel R, Sung RJ. Verapamil for control of ventricular rate in paroxysmal supraventricular ta- chycardia and atria1 fibrillation or flutter. Ann Intern Med 1981;94:1-6. Heng MK, Singh BN, Roche AHG, Norris RM, Mercer CJ. Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram. AM HEART J 1975;90:487-98. Inoue H, Matsuo H, Takayanagi K, Murao S. Clinical and ex- perimental studies of the effects of atria1 extrastimulation and rapid pacing on atria1 flutter cycle: evidence of macroreentry with an excitable gap. Am J Cardiol 1981;48:623-31. Iansmith DHS, Nash CB, Bandura JP. Biphasic nature of propranolol’s microelectrophysiologic effects. Am -7 Cardiol 1983;51:145-8. Dhingra RC, Amat-y-Leon F, Wyndham C, et al. The electro- physiologic effects of ouabain on sinus node and atrium in man. J Clin Invest 1975;56:555-62. Engel TR, Gonzalez ADC. Effects of digitalis on atria1 vulner- abilitv. Am J Cardiol 1978:42:570-6. Mendez R, Mendez C. The’action of cardiac glycosides on the refractory period of heart tissues. J Pharmacol Exp Ther 1953;107:24-36. Josephson ME, Caracta AR, Ricciutti MA, Lau SH, Damato AN. Electrophysiologic properties of procainamide in man. Am J Cardiol 1974;33:596-603. Wyse DG, McAnulty JH, Rahimtoola SH. Influence of plasma drug level and the presence of conduction disease on the elec- trophysiologic effects of procainamide. Am J Cardiol 1979; 43:619-26. Wu K, Hoffman BF. Effect of procainamide and N-acetylpro- cainamide on atria1 flutter: studies in vivo and in vitro. Circu- lation 1987:76:1397-408.