Atriai Vulnerability and Electrophysiology Determined in Patients With and Without Paroxysmal Atriai Fihrillation VOLKER KUHLKAMP, RAINER HAASIS, and LUDGER SEIPEL From the Medizinische Klinik Abteilung III of the Eberhard-Karls-Universitat, Tubingen, Federal Republic of Germany KUHLKAMP, V., ET AL.: Atriai Vulnerability and Electrophysiology Determined in Patients With and
Without Paroxysmal Atriai Fibrillation. For elucidation of atriai electrophysiology and vulnerability an eiectrophysiologicai study was performed in 45 patients with documented paroxysmal atriai /ibriJIation and a control group (n =46). AtriaJ vulnerability was assessed by programmed atriaJ stimulation with up to two extrastimuli during sinus rhythm and paced cycle lengths of 600 msec, 430 msec and 330 msec. Sustained atriai fibriliation or flutter was induced in 37/45 patients with paroxysmal atriai /ibriJIation in contrast to 9/46 patients in tiie control group fP < 0.001). Left atriai diameter (M-mode echocardiogram), P wave duration, sinus cycle length, sinus node recovery time, and the effective refractory period of the right atrium were no( signi/icantJy different between the two study groups. Intraatrial conduction time from the high right atrium (HRA) to the basal right atrium (A] and the functional refractory period of the right atrium were significantly longer in patients with paroxysmal atriai fibrillation, (PACE, VoJ. 15, January 1992) atriai flutter, atriai fibrillation, electrophysiology, atriai vulnerability, paroxysmal atriaJ fibriiiation
Introduction Experimental studies indicate reentry as the electrophysiological mechanism of atriai tachyarrhythmias as atriai flutter and fibrillation.^"^ Accordingly clinical electrophysiological studies in patients seem to support the theory of reentry as the mechanism of atriai tachyarrhythmias.^"" The aim of the present study was the elucidation of atriai electrophysiology in patients with documented paroxysmal atriai fibrillation (PAF) or flutter compared to a control group without evidence for paroxysmal atriai tachyarrhythmias. Furthermore, we were interested in whether programmed atriai stimulation is useful to investigate atriai vulnerability. Programmed atriai stimula-
Address for reprints; Volker Kuhlkamp. M.D., Medizinische Klinik Abteilung III, Otfried Muller Str. 10, 7400-Tubingen, Federal Republic of Germany. Fax; 49-7071-291-293675. Received August 9, 1990; revision January 31, 1991; revision August 12, 1991; accepted September 3, 1991.
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tion was choosen because this is a well-defined technique for evaluation of tachyarrhythmias whose mechanism is thought to be reentry as for example in atrioventricuiar tachycardia, atrioventricuiar nodal tachycardia, and in the majority of cases with ventricular tachycardia. Methods In 45 patients with documented PAF (PAF group) and 46 patients without evidence for PAF (control group) by extensive history and 24 hour Holter monitoring (Pathfinder II, Reynolds Medical, Ltd., Hertford, United Kingdom) an electrophysiological study was performed. Patients in the control group did undergo electrophysiological testing for elucidation of syncope of unknown reason and ventricular tachycardia. In all patients of the PAF group PAF was documented by a resting ECG, the frequency of episodes of PAF were examined by history only. In the PAF group ten patients reported at least one episode of PAF per week, in 16 patients the frequency of PAF was estimated to
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be one episode per month and 14 patients reported < 1 episode of PAF per month. In the remaining five patients estimation of the frequency of PAF was impossible, since PAF was recorded by chance and patients did not recognize the episodes of PAF. Only patients in whom atrial fibrillation was converted to sinus rhythm by DC cardioversion were excluded from the study. Patient characteristics were similar in both study groups (Table I), patients with rheumatic heart disease, the mitral valve prolapse syndrome or the Wolff-Parkinson-White syndrome were excluded. All patients received a M-mode echocardiogram for determination of left atrial size, which was not different between the two study groups (Table I). Hyperthyroidism was excluded in all patients. After informed consent was obtained tbe electrophysiological study was performed in the nonsedated postabsorptive state. Prior to the electrophysiological study patients with PAF had to be in stable sinus rhythm for at least 48 hours, antiarrhythmic drugs including cardiac glycosides were withdrawn for five drug half-lives, no patient was receiving amiodarone. The intracardiac signals were filtered to pass 50 Hz to 1.000 Hz and recorded simultaneously with the surface ECG (I, III. and Vi) on a Siemens-Eiema Mingograf 62 (Siemens-Elema, Soina, Sweden] at a paper speed of 50 mm/sec and 100 mm/sec. Pacing stimuli were provided by a digital stimulator (Medtronic 5328,
Medtronic, Inc., Minneapolis, MN, USA) at twice diastolic strength and a pulse duration of 2 msec. A quadripolar electrode catheter (USCI, 10mm interelectrode distance [Div. of CR Bard, Billerica, MA, USA]) was advanced to the high right atrium (HRA), stimulation was performed via the distal electrode pair and recording of the right atrial electrogram by the proximal electrode pair. A hipoiar electrode catheter (Cordis [Miami. FL, USA], 10-mm interelectrode distance) was positioned in the atrioventricular junction to record activation of the basal right atrium (A wave) and the His bundle. A third electrode catheter was positioned in the right ventricular apex. Sinus node recovery time was estimated by atrial overdrive pacing for 30 seconds, initial rate of stimulation was selected just greater than the spontaneous sinus rate. The rate of stimulation was increased by 20 beats/min until a rate of 200/ min was attained. Sinus node recovery time was measured from the last paced atrial beat and the first beat of sinus origin. Frequency corrected sinus node recovery time was calculated by the difference between sinus node recovery time and sinus cycle length. ^^ The effective refractory period of the right atrium was defined as the longest attainable S1-S2 interval not evoking an atrial depolarization. Accordingly, tbe functional refractory period of the right atrium was the shortest attainable A1-A2 interval in the His bundle lead. Time intervals were measured between earliest deflections (45° deflection from the isoelectric line)
Table 1. Patient Characteristics PAF Group Age (years) Sex Left atrial diameter (mm) Left ventricular end-diastolic diameter (mm) CAD DCM Arterial hypertension No cardiac disease
(n -= 45)
Control Group
(n = 46)
56 ± 12 18 women 27 men 39 ± 9 (n - 43) 53 ± 1 6 (n - 39) 23
57 ± 13 22 women 24 men 37 H: 10 (n - 42) 51 ± 1 7 (n - 37) 21
9 17 3
11 12 2
CAD = coronary artery disease: DCM = dilated cardiomyopathy: n = number of patients.
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of atrial electrograms. Intraatrial conduction time was defined as the time interval from the earliest deflection of the HRA electrogram to the earliest deflection of the electrogram of the basal right atrium (A wave in the His-bundle lead) and was determined during sinus rhythm and paced cycle length of 600 msec, 500 msec, 430 msec, 375 msec, 330 msec, and 3OO msec after constant atrial pacing for at least 15 seconds and a paper speed of 100 mm/sec. Shorter paced cycle lengths were not used. Intraatrial conduction time was not measured during atrial flutter, since it was difficult to clearly relate an A-spike recorded in the HRA to an A-spike recorded in the basal right atrium. P wave duration and amplitude was measured in lead III and Vi of the surface ECG at a paper speed of 100 mm/sec and an amplification of 10 mm/mV. Atrial vulnerability was assessed by atrial overdrive pacing as described above and programmed atrial stimulation with up to two extrastimuli during sinus rhythm and after eight paced beats at cycle lengths of 600 msec. 430 msec, and 330 msec. First one extrastimulus S2 was introduced late in diastole and the coupling interval was shortened by steps of 10 msec until the effective refractory period of the right atrium was reached during sinus rhythm and each paced rate. Then, after increasing the coupling interval of the first extrastimulus by 10 msec, a second extrastimulus Sa was introduced and the coupling interval again shortened until no atrial depolarization was observed. If atrial flutter (cycle length ^ 240 msec) or fibrillation lasting for ^ 30 seconds was reproducibly induced tbe end point of the stimulation protocol was reached. The diagnosis atriai flutter or atrial fibrillation was only based on the high right atrial electrogram during the first 30 seconds after induction of the atrial arrhythmia; pacing studies or measurements of beat-to-beat atrial cycle lengths were not performed for further analysis of the induced atrial arrhythmia.^•*'^'' Atrial fibrillation: A-A interval < 165 msec, the spikes of the atrial electrogram are not separated by an isoelectric line Atrial flutter: A-A-interval > 165 msec and :< 240 msec, the spikes of the atrial electrogram are separated by an isoeiectric line.
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Atrial vulnerability was defined as follows: Normal atrial vulnerability was assumed if a maximum of six atrial premature depolarizations (cycle length < 240 msec) were evoked after completion of the stimulation protocol. The induced atrial arrhythmia was defined as nonsustained atrial flutter or fibrillation if more than six atrial premature beats (cycle length :< 240 msec) or atrial flutter (cycle length < 240 msec) or fibrillation lasting < 30 seconds was induced. Sustained atrial flutter (cycle length ^ 240 msec) or fibrillation was defined as an atrial tachyarrhythmia lasting longer than 30 seconds. All data are presented as mean ± standard deviation, further statistical analysis was done using the unpaired Student's t-test and the Chisquare test as appropriate.
Results Sinus Node Function Sinus cycle length, sinus node recovery time, and frequency corrected sinus node recovery time were not significantly different between the two study groups (Table II). Effective Refractory Period of the Right Atrium (Fig. 1) The effective refractory period of the right atrium was determined during sinus rhythm and paced cycle length of 600 msec, 430 msec, and 330 msec. There was no significant difference in the effective refractory period of the right atrium between the two study groups. For this comparison only the data of patients were included in whom the effective refractory period of the right atrium could be determined at each paced cycle length. For that reason the number of patients is smaller in botb groups, because in some of the patients a sustained atrial tachyarrhythmia was induced before the effective refractory period was determined at every paced cycle length. Functional Refractory Period of the Right Atrium (Fig. 2) The functional refractory period of the right atrium was obtained during sinus rhythm and
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KUHLKAMP, ET AL.
Table II. Data Obtained During the Electrophysiological Study PAF Group Sinus cycle length (R-R) Sinus node recovery time (SNRT) Frequency corrected sinus node recovery time {CSNRT) P wave duration during sinus rhythm P wave amplitude during sinus rhythm
872 1228 356 88 1.6
(n = 45)
Control Group (n = 46)
± 165 ± 356 ± 250 ± 23 ± 0.8
818 ± 152
1144 ± 203 332 ± 155 86 ± 21 1.4 ± 0.7
n = number of patients; data are given in msec or mV. ms 300 n
ms 350
250-
300-
200-
250-
control (n=42) PAF (n=22)
150-" SR
600
200-J 430
330
Figure 1, Effective refractory period afthe right atrium determined during sinus rhythm (SRJ and paced cycle lengths of 600 msec (600), 430 msec (430), and 330 msec (330) in pad'enfs with paroxysmal atrial /ibrilJation (PAFJ and without PAF (control). For this comparison only those patients were taken into account, in whom the effective refractory period of the right atrium could be determined during sinus rhythm and aJJ paced rates. paced rates of 600 msec, 430 msec, and 330 msec; however, the difference was significant [P < 0.05) between the two study groups only at a paced cycle length of 330 msec. Although it might have been of interest, shorter cycle lengths were not tested. Intraatrial Conduction Time The two study groups were not different in intraatrial conduction time (HRA-A) during sinus
74
control (n=42) PAF (n = 22) SR
600
430
330
Figure 2. Functional re/ractor>' period of the right atrium determined during sinus rhythm (SR) and paced cycle Jengths of 600 msec (600), 430 msec f430). and 330 msec (330] in patients with paroxysmal atriai fibrillation (PAFJ and without PAF (controlj. For this comparison only those patients were taken into account, in whom the functional refractory period of the right otrium could be determined during sinus rhythm and all paced rates. At the Shortest paced cycle length the functionaJ refractory period of (he right atrium was significantly longer in patients with PAF (* P < 0.05J.
rhythm. With continuous atrial pacing the delay in intraatrial conduction time was significantly (P < 0.01] more pronounced in patients with PAF as compared to the control group (Fig. 3). Intraatrial conduction time was not measured during atrial flutter, since it was impossible in the majority of
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ms 60-]
n 35.
50ZS.
40-
ffl , 15.
30-
10 . S.
20-
i
i
n.S
0
10-
t AF
control (n=46) PAF (n = 43)
0-
SR
600 500 430 375 330 300
Figure 3. Intraatrial conduction time from (he HRA to the basal right atrium during sinus rhythm and paced cycle Jengths of 600 msec, 500 msec, 430 msec, 375 msec, 333 msec, and 300 msec in patients with paroxysmal atriai fibrillation (PAF) and without PAF (control). During sinus rhythm intraa(rial conduction time was not different be(ween the two study groups, however, with right atrial pacing intraatrial conduction time was significantly f*P < 0.01) different between patients with PAF and the control group.
cases to relate an A-spike of the high right atrial lead to an A-spike in the basal right atrial lead. P wave duration as a second parameter of intraatrial conduction time was only determined during sinus rhythm and was not different between the two study groups (Table II]. P wave amplitude as a parameter of right atrial enlargement was determined in lead Vi of the surface ECG and was not different between the two study groups (Table II]. Atrial Vulnerability (Fig. 4) In 37 (82%) out of 45 patients with documented PAF sustained atrial flutter or fibrillation was reproducibly induced. In the control group sustained atrial flutter or fibrillation was initiated in only nine (20%) out of 46 patients (P < 0.001]. Induction of sustained atrial flutter or fibrillation in the PAF group had a sensitivity of 82%, that is 82% of the patients with PAF were correctly
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rwn lus AF
AF
Figure 4. Induction of non sustained (non sus) or sustained (sus) atrial flutter or fibrillation (AF) by programmed atria] stimulation in patients with fempty rectangJe) or without (hatched rectangle] paroxysmal atrial fibrillation or flutter.
identified by programmed atrial stimulation. The specificity of programmed atrial stimulation to correctly identify patients without PAF or flutter (control group) was 80%. The induction of nonsustained atrial fibrillation or atrial flutter was not significantly different between the two study groups (Fig. 4). The induction of sustained atrial flutter or fibrillation in the control group required two extrastimuli in six out of nine patients, whereas in patients with PAF a sustained atrial tachyarrhythmia was induced in 17 out of 3 7 patients by one extrastimulus, respectively, by continuous atrial pacing at a paced cycle length of 430 msec (one patient), 375 msec (one patient), and 330 msec (one patient]. In 17 patients of the PAF group two extrastimuli were necessary to induce atrial fibrillation or flutter (Fig. 5). Sustained atrial fibrillation was induced in 12 patients and atrial flutter in 25 patients of the PAF group. Atrial fibrillation was sustained by continuous atrial pacing (cycle length 375 msec] in one patient, by one extrastimulus in four patients and by two extrastimuli in seven patients. Basic drive cycle length was 523 ± 101 msec and the coupling interval of the extrastimulus inducing atrial fibrillation was 213 ± 39 msec. Atrial flutter was induced by continuous atrial pacing (cycle length 430 msec and 330 msec) in two patients, one extra-
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KUHLKAMP, ET AL.
o) control group n
tion initiating atrial flutter was 202 ± 2 7 msec (n = 6). If sustained atrial fibrillation was induced the coupling interval initiating atrial fibrillation was 220 ± 14 msec (n - 3, difference not significant). In 25 patients of the PAF group atrial flutter was the induced arrhythmia as stated above, although these patients had documented paroxysmal atrial fibrillation. In 11 (44%) patients with atrial flutter recorded in the HRA the surface ECG did not show any sign of atrial flutter, hut was instead typical for atrial fibrillation (Fig. 6). Furthermore, 21 of 37 patients (57%) with induced atrial fihrillation or flutter in the PAF group showed transition between atrial fibrillation and flutter and vice versa (Fig. 7).
4-
310 b) PAF group n 10-1
8-
6-
4-
2-
Discussion
Figure 5. Mode o/induction o/sustained atria] fibrillation or flutter in the controJ group (a) and the paroxysmal atrial /ibrilJaiton (PAF) group fb). n = number of patients; SiSi - continuous atrial pacing; SR = sinus rhythm; 600 ^ basic drive cycle length of 600 msec; 430 = basic drive cycle length of 430 msec; 330 ^ basic drive cycle iength of 330 msec; Sz ^ one extrastimulus; S2S3 = two extrastimuJi.
stimulus was required in 13 patients and two extrastimuli in ten patients. Basic drive cycle length was 481 ± 110 msec and the coupling interval of the premature atrial contraction initiating atrial flutter was 213 ± 39 msec. The mode of induction of atrial fibrillation was not significantly different from the mode of induction of atrial flutter. In the control group atrial fihrillation was induced by two extrastimuli in three patients. In three patients atrial flutter was induced by one extrastimulus and in three further patients by two extrastimuli. Basic drive cycle length was 499 ± 106 msec (n = 6) in patients with induced sustained atrial flutter and 487 ± 80 msec (n = 3] in patients with induced sustained atrial fibrillation. If sustained atrial flutter was the induced tachyarrhythmia the coupling interval of the premature atrial contrac-
76
The crucial point in our study was the selection of comparable patient groups in respect to underlying cardiac disease and left ventricular function (Table I) for the control and PAF group. We excluded all patients in the PAF group, in whom the occurrence of PAF might be influenced by additional factors as it is suspected for example in the Wolff-Parkinson-White syndrome^^ and in the mitral valve prolapse syndrome.^^ Several reports on atrial vulnerability and electrophysiology in patients with PAF have been presented,^^"^'* however, the results are inconsistent and the significance of an enhanced atrial vulnerability is unknown. ^^"^"^'^^"^^ In our patients in the control group PAF was thought to be unlikely if patients did not complain of palpitations and a baseline 24-hour Holter monitoring was without evidence for supraventricular tachyarrhythmias. Therefore, we excluded probably more patients from the control group than did EngeP" and Ohe.^^ In the study of Watson^^ 41 patients had inducible atrial flutter, in 31 patients atrial flutter or fibrillation was documented, the remaining ten patients with inducible atrial flutter had at least a history of palpitations. Therefore, the crucial point is the exclusion of PAF in the control group. However, even if patients do not complain of palpitations they may have PAF, since in five patients of the
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ATRIAL ELECTROPHYSIOLOGY AND VULNERABILITY
JG.70y
1s
Figure 6. Typical exampie of a patient in whom atria/ flutter was induced with a cycle length fA-A) of 200 msec, however the surface ECG leads I, HI, and V, do not show flutter waves. HRA = high right atrium; HBE = His bundie recording; RVA = right ventricuiar apex.
J
I
'
I
"
I
'
.
'
HBE KS.52yd' Figure 7. Continuous change between atrial flutter and atriai fibrillation in a patient in whom, primarily, atrial flutter with a cycle length (A-A) of 200 msec was the induced arrhythmia. HRA - high right atrium; HBE = His bundle recording.
PAF group PAF was recorded by chance only. Furthermore, it is unknown whether patients in the control group with an enhanced atrial vulnerability will develop atrial fibrillation in the future. The induction of atrial flutter in patients with
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PAF is of unknown significance. In our study atrial flutter was diagnosed by the intracardiac recordings only, pacing studies to differentiate between type 2 and type 1 atrial flutter or measurement of beat-to-beat trial cycle lengths have not been
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KUHLKAMP, ET AL.
performed.^^•^'' In some of the patients the intracardiac recordings were typical for atrial flutter, whereas the surface ECG did not show typical signs for atrial flutter (Fig. 7). Similar observations have been puplished.^° Hence the diagnosis of atrial flutter or fibrillation may depend on the type of recording available, and may even be more complicated with an increasing number of intracardiac recordings. Our definition of atrial flutter did not exclude patients with type 1 atrial fibrillation as defined by Wells and coworkers. ^^ However, there seems to be some overlap between type 1 atrial fibrillation and atrial flutter, since neither atrial cycle length or the change in beat-to-beat change atrial cycle length nor the separation of the atrial eiectrograms by an isoelectric baseline does clearly separate patients with type 1 atrial fibrillation from patients with type 2 atrial flutter.^^•^'' Furthermore, atrial flutter may degenerate to atrial fibrillation as it was seen in 21 patients with induced atrial flutter (Fig, 7) and vice versa, a finding seen by other investigators as well (type 4 atrial fibrillation, 14). We conclude that the significance of stimulation induced atrial flutter in patients with PAF is not established, it seems however, that atrial flutter may occur in these patients and is a clinical arrhythmia. The effective refractory period and conduction velocity are the determinants in the genesis of reentry arrhythmias according to the wavelength theory.^^ In the electrophysiological laboratory, measurement of the effective refractory period and conduction velocity within the reentry circuit is impossible. Several clinical studies stress intraatrial conduction delay as an important electrophysiological finding in PAF.^'^^-^^'^^'^^ In our study frequency dependent intraatrial conduction delay was significantly different between the two study groups although left atrial diameter was not significantly different. Hence, frequency dependent intraatrial conduction delay does not seem to be mainly a factor of an enlarged atrium rather than a primary electrical phenomenon. It has been suggested elsewhere that delayed conduction in diseased atrial tissue might be due to a shift from the sodium dependent fast response to the calcium dependent slow response domain.^^
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A point of criticism is that we measured right atrial electrophysiology but not right atrial diameter. However, a discrepancy between left and right atrial diameter is not very likely for patients in the PAF group or the control group, since right atrial enlargement is not a typical finding for the cardiac diagnosis seen in our patient population. P wave amplitude as a parameter of right atrial enlargement was not different between the PAF group and the control group. The clinical electrophysiological data concerning the effective refractory period of the right atrium are less definite^-^''-^^-^^"^^ than the data on intraatrial conduction delay. This may in part be due to an inhomogeneous patient population,^ selection of patients with the Wolff-ParkinsonWhite syndrome^^ and continuation of an antiarrhythmic therapy with cardiac glycosides.^^ In a further study^"* patients with enhanced and normal atrial vulnerability as defined by the electrophysiological study were compared irrespective of their clinical arrhythmia. Hence it is questionable if the obtained results can be transferred to diseased atria in patients with PAF. Several studies support our finding that there is no significant difference between the effective refractory period of the right atrium in patients with and without PAF or flutter.^^•^•'•^'^•^''•^^ Failure in rate adaption of the atrial effective refractory period^^ was not seen in the PAF group. However, similar to Attuel^^ we found a failure in rate adaption of the functional refractory period only in our PAF group. Since rate adaption of the effective refractory period was seen in the PAF group failure of rate adaption of the functional refractory period might represent delayed conduction. Limitations of the Study Since an enhanced atrial vulnerability was not a unique finding in patients with PAF it remains unknown in an individual patient whether an enhanced atrial vulnerability in the electrophysiological laboratory is related to PAF or not. For further elucidation of the value of an enhanced atrial vulnerability a follow-up of the patients with an enhanced atrial vulnerability but without evidence of PAF at the time of the electrophysiological study is necessary.
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References 1. Rosenblueth A, Garcia Ramos J. Studies on flutter and fibrillation: The influence of artificial obstacles on experimental auricular flutter. Am Heart J 1947; 33:677-684, 2. Moe GK, Abildskov JA, Atrial fibrillation as a self sustaining arrhythmia independent of focal discharge. Am Heart J 1959; 58:59-70. 3. Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. IIL The "leading circle" concept: A new model of circus movement in cardiac tissue without the involvement of an anatomic obstacle. Circ Res 1977; 41:9-18. 4. Allessie MA, Lammers WJEP, Bonke FIM, et al. Intraatrial reentry as a mechanism for atrial flutter by acetylcholine and rapid pacing in dog. Circulation 1984; 70:123-135, 5. Boineau JP, Schuessler RB, Mooney CR, et al. Natural and evoked atrial flutter due to circus movement in dogs. Am J Cardiol 1980; 45:1167-1181. 6. Boyden PA, Tilley LP, Albala A, et al. Mechanisms for atrial arrhythmias associated with cardiomyopathy: A study of feline hearts with primary myocardial disease. Circulation 1984; 69:1036-1047. 7. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. Circ Res 1986; 58:495-511. 8. Cosio FC, Arribas F, Barbero JM, et al. Validation of double-spike electrograms as a marker of conduction delay or block in atrial flutter. Am J Cardiol 1988; 61:775-780. 9. Cosio FG, Palacios J, Vidal JM, et al. Electrophysiologic studies in atrial fibrillation. Slow conduction of premature impulses a possible manifestation of the background for reentry. Am J Cardiol 1983; 51:122-130. 10. Disertori M, Inama G, Vergara G, et al. Evidence of a reentry circuit in the common type of atrial flutter in man. Circulation 1983; 67:434-440. 11. Waldo AL, Plumb VJ, Henthorn RW. Observations on the mechanism of atrial flutter. In B Surawicz, C Pratap Reddy, EN Prystowsky (eds.): Tachycardias. Martinus Nijhoff Publishing, The Hague, The Netherlands, 1984, pp. 213-229. 12. Breithardt G, Seipel L, Loogen F. sinus node recovery time and calculated sinoatrial conduction time in normal subjects and patients with sinus node dysfunction. Circulation 1977; 56:43-50. 13. Wells JL, McLean WAH, James TN, et al. Characterization of atrial flutter. Studies in man following open heart surgery using fixed atrial electrodes. Circulation 1979; 60:665-673. 14. Wells JL, Karp RB, Kouchoukos NT et al. Characterization of atrial fibrillation in man: Studies following open heart surgery. PACE 1978; 1:426-438. 15. Sharma AD, Klein CJ, Guiraudon GM, et al. Atrial fibrillation in patients with the Wolff-ParkinsonWhite syndrome incidence after surgical ablation
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of accessory pathway. Circulation 1985; 72: 161-169. Dobmeyer DJ, Stine RA, Leier CV, et al. Electrophysiologic mechanisms of provoked atrial flutter in mitral valve prolapse syndrome. Am J Cardiol 1985: 56:602-604. Bauernfeind RA, Swiryn SP. Strasberg B, et al. Electrophysiologic drug testing in prophylaxis of sporadic atrial fibrillation: Technique, application, and efficacy in severely symptomatic preexcitation patients. Am Heari J 1982; 103:941-949. Buxton AE, Waxman HL, Marchlinski FE. et al, Atrial conduction effects of extrastimuli with and without atrial dysrhythmias. Am J Cardiol 1984; 54:755-761. Cosio FG, Llovet A, Vidal JM. Mechanism and clinical significance of atrial repetitive responses in man. PACE 1983; 6:53-59. Engel TR, Luck JC, Leddy CL, et al. Diagnostic implications of atrial vulnerability. PACE 1979; 2:208-214. Haft JI, Lau SH, Stein E, et al. Atrial fibrillation produced by atrial stimulation. Circulation 1968; 37:70-74. Pop T, Fleischmann D, Effert S. The vulnerability of the right atrium. III. Electrophysiologic correlates of atrial vulnerability. Klin Wochenschr 1979; 57:31-36. Simpson R, Foster JR, Cettes LS. Atrial excitability and conduction in patients with interatrial conduction defects. Am J Cardiol 1982; 50:1331-1337. Simpson R, Amara I, Foster JR, et al, Thresholds, refractory periods, and conduction times of the normal and diseased human atrium. Am Heart J 1988; 116:1080-1090. Watson RM, Josephson ME. Atria! flutter 1. Electrophysiologic substrates and modes of initiation and termination. Am J Cardioi 1980; 45:732-741. Obe T, Matsuhisa M, Kamakura S, et al. Relation between the widening of the fragmented atrial activity zone and atrial fibrillation. Am J Cardiol 1983; 53:1219-1222. Chauvin M, Brechenmacher C. Atrial refractory periods after atrial premature beats in patients with paroxysmal atrial fibrillation. PACE 1989; 12:1018-1026. Attuel P, Childers R, Cauzemez B, et al. Failure in the rate adaptation of the atrial refractory period: Its relationship to vulnerability. Int J Cardiol 1982; 2:179-197. Luck JC, Engel TR. Dispersion of atrial refractoriness in patients with sinus node dysfunction. Circulation 1979; 60:404-412, Luca C, Petrescu LP. Atrial flutter with inapparent flutter waves on the surface electrocardiogram. Acta Cardiologica 1985; 40:477-483. Rensma PL, Allessie MA, Lammers WJEP, et al.
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KUHLKAMP, ET AL. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 1988; 62:395-410. 32. LeierCV, Meacham JA, Schaal SF. Prolonged atrial conduction. A major predisposing factor for the development of atrial flutter. Circulation 1978; 57:213-216. 33. Cadsby DC, Wit AL. Normai and abnormal electro-
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physiology of cardiac cells. In WJ Mandel (ed.); Cardiac Arrhythmias: Their Mechanisms, Diagnosis, and Management. Philadelphia, PA, ].B.Lippincott Company, 1980, pp. 55-82. 34. Debbas N, Butrous G, Mehta D, et al. Dynamic changes in endocardial monophasic action potential duration—a predictor of atrial vulnerability. (abstract) Eur Heart J 1988; 9(Suppl.):267.
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Without Paroxysmal Atriai Fibrillation. For elucidation of atriai electrophysiology and vulnerability an eiectrophysiologicai study was performed in 45 patients with documented paroxysmal atriai /ibriJIation and a control group (n =46). AtriaJ vulnerability was assessed by programmed atriaJ stimulation with up to two extrastimuli during sinus rhythm and paced cycle lengths of 600 msec, 430 msec and 330 msec. Sustained atriai fibriliation or flutter was induced in 37/45 patients with paroxysmal atriai /ibriJIation in contrast to 9/46 patients in tiie control group fP < 0.001). Left atriai diameter (M-mode echocardiogram), P wave duration, sinus cycle length, sinus node recovery time, and the effective refractory period of the right atrium were no( signi/icantJy different between the two study groups. Intraatrial conduction time from the high right atrium (HRA) to the basal right atrium (A] and the functional refractory period of the right atrium were significantly longer in patients with paroxysmal atriai fibrillation, (PACE, VoJ. 15, January 1992) atriai flutter, atriai fibrillation, electrophysiology, atriai vulnerability, paroxysmal atriaJ fibriiiation
Introduction Experimental studies indicate reentry as the electrophysiological mechanism of atriai tachyarrhythmias as atriai flutter and fibrillation.^"^ Accordingly clinical electrophysiological studies in patients seem to support the theory of reentry as the mechanism of atriai tachyarrhythmias.^"" The aim of the present study was the elucidation of atriai electrophysiology in patients with documented paroxysmal atriai fibrillation (PAF) or flutter compared to a control group without evidence for paroxysmal atriai tachyarrhythmias. Furthermore, we were interested in whether programmed atriai stimulation is useful to investigate atriai vulnerability. Programmed atriai stimula-
Address for reprints; Volker Kuhlkamp. M.D., Medizinische Klinik Abteilung III, Otfried Muller Str. 10, 7400-Tubingen, Federal Republic of Germany. Fax; 49-7071-291-293675. Received August 9, 1990; revision January 31, 1991; revision August 12, 1991; accepted September 3, 1991.
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tion was choosen because this is a well-defined technique for evaluation of tachyarrhythmias whose mechanism is thought to be reentry as for example in atrioventricuiar tachycardia, atrioventricuiar nodal tachycardia, and in the majority of cases with ventricular tachycardia. Methods In 45 patients with documented PAF (PAF group) and 46 patients without evidence for PAF (control group) by extensive history and 24 hour Holter monitoring (Pathfinder II, Reynolds Medical, Ltd., Hertford, United Kingdom) an electrophysiological study was performed. Patients in the control group did undergo electrophysiological testing for elucidation of syncope of unknown reason and ventricular tachycardia. In all patients of the PAF group PAF was documented by a resting ECG, the frequency of episodes of PAF were examined by history only. In the PAF group ten patients reported at least one episode of PAF per week, in 16 patients the frequency of PAF was estimated to
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be one episode per month and 14 patients reported < 1 episode of PAF per month. In the remaining five patients estimation of the frequency of PAF was impossible, since PAF was recorded by chance and patients did not recognize the episodes of PAF. Only patients in whom atrial fibrillation was converted to sinus rhythm by DC cardioversion were excluded from the study. Patient characteristics were similar in both study groups (Table I), patients with rheumatic heart disease, the mitral valve prolapse syndrome or the Wolff-Parkinson-White syndrome were excluded. All patients received a M-mode echocardiogram for determination of left atrial size, which was not different between the two study groups (Table I). Hyperthyroidism was excluded in all patients. After informed consent was obtained tbe electrophysiological study was performed in the nonsedated postabsorptive state. Prior to the electrophysiological study patients with PAF had to be in stable sinus rhythm for at least 48 hours, antiarrhythmic drugs including cardiac glycosides were withdrawn for five drug half-lives, no patient was receiving amiodarone. The intracardiac signals were filtered to pass 50 Hz to 1.000 Hz and recorded simultaneously with the surface ECG (I, III. and Vi) on a Siemens-Eiema Mingograf 62 (Siemens-Elema, Soina, Sweden] at a paper speed of 50 mm/sec and 100 mm/sec. Pacing stimuli were provided by a digital stimulator (Medtronic 5328,
Medtronic, Inc., Minneapolis, MN, USA) at twice diastolic strength and a pulse duration of 2 msec. A quadripolar electrode catheter (USCI, 10mm interelectrode distance [Div. of CR Bard, Billerica, MA, USA]) was advanced to the high right atrium (HRA), stimulation was performed via the distal electrode pair and recording of the right atrial electrogram by the proximal electrode pair. A hipoiar electrode catheter (Cordis [Miami. FL, USA], 10-mm interelectrode distance) was positioned in the atrioventricular junction to record activation of the basal right atrium (A wave) and the His bundle. A third electrode catheter was positioned in the right ventricular apex. Sinus node recovery time was estimated by atrial overdrive pacing for 30 seconds, initial rate of stimulation was selected just greater than the spontaneous sinus rate. The rate of stimulation was increased by 20 beats/min until a rate of 200/ min was attained. Sinus node recovery time was measured from the last paced atrial beat and the first beat of sinus origin. Frequency corrected sinus node recovery time was calculated by the difference between sinus node recovery time and sinus cycle length. ^^ The effective refractory period of the right atrium was defined as the longest attainable S1-S2 interval not evoking an atrial depolarization. Accordingly, tbe functional refractory period of the right atrium was the shortest attainable A1-A2 interval in the His bundle lead. Time intervals were measured between earliest deflections (45° deflection from the isoelectric line)
Table 1. Patient Characteristics PAF Group Age (years) Sex Left atrial diameter (mm) Left ventricular end-diastolic diameter (mm) CAD DCM Arterial hypertension No cardiac disease
(n -= 45)
Control Group
(n = 46)
56 ± 12 18 women 27 men 39 ± 9 (n - 43) 53 ± 1 6 (n - 39) 23
57 ± 13 22 women 24 men 37 H: 10 (n - 42) 51 ± 1 7 (n - 37) 21
9 17 3
11 12 2
CAD = coronary artery disease: DCM = dilated cardiomyopathy: n = number of patients.
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of atrial electrograms. Intraatrial conduction time was defined as the time interval from the earliest deflection of the HRA electrogram to the earliest deflection of the electrogram of the basal right atrium (A wave in the His-bundle lead) and was determined during sinus rhythm and paced cycle length of 600 msec, 500 msec, 430 msec, 375 msec, 330 msec, and 3OO msec after constant atrial pacing for at least 15 seconds and a paper speed of 100 mm/sec. Shorter paced cycle lengths were not used. Intraatrial conduction time was not measured during atrial flutter, since it was difficult to clearly relate an A-spike recorded in the HRA to an A-spike recorded in the basal right atrium. P wave duration and amplitude was measured in lead III and Vi of the surface ECG at a paper speed of 100 mm/sec and an amplification of 10 mm/mV. Atrial vulnerability was assessed by atrial overdrive pacing as described above and programmed atrial stimulation with up to two extrastimuli during sinus rhythm and after eight paced beats at cycle lengths of 600 msec. 430 msec, and 330 msec. First one extrastimulus S2 was introduced late in diastole and the coupling interval was shortened by steps of 10 msec until the effective refractory period of the right atrium was reached during sinus rhythm and each paced rate. Then, after increasing the coupling interval of the first extrastimulus by 10 msec, a second extrastimulus Sa was introduced and the coupling interval again shortened until no atrial depolarization was observed. If atrial flutter (cycle length ^ 240 msec) or fibrillation lasting for ^ 30 seconds was reproducibly induced tbe end point of the stimulation protocol was reached. The diagnosis atriai flutter or atrial fibrillation was only based on the high right atrial electrogram during the first 30 seconds after induction of the atrial arrhythmia; pacing studies or measurements of beat-to-beat atrial cycle lengths were not performed for further analysis of the induced atrial arrhythmia.^•*'^'' Atrial fibrillation: A-A interval < 165 msec, the spikes of the atrial electrogram are not separated by an isoelectric line Atrial flutter: A-A-interval > 165 msec and :< 240 msec, the spikes of the atrial electrogram are separated by an isoeiectric line.
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Atrial vulnerability was defined as follows: Normal atrial vulnerability was assumed if a maximum of six atrial premature depolarizations (cycle length < 240 msec) were evoked after completion of the stimulation protocol. The induced atrial arrhythmia was defined as nonsustained atrial flutter or fibrillation if more than six atrial premature beats (cycle length :< 240 msec) or atrial flutter (cycle length < 240 msec) or fibrillation lasting < 30 seconds was induced. Sustained atrial flutter (cycle length ^ 240 msec) or fibrillation was defined as an atrial tachyarrhythmia lasting longer than 30 seconds. All data are presented as mean ± standard deviation, further statistical analysis was done using the unpaired Student's t-test and the Chisquare test as appropriate.
Results Sinus Node Function Sinus cycle length, sinus node recovery time, and frequency corrected sinus node recovery time were not significantly different between the two study groups (Table II). Effective Refractory Period of the Right Atrium (Fig. 1) The effective refractory period of the right atrium was determined during sinus rhythm and paced cycle length of 600 msec, 430 msec, and 330 msec. There was no significant difference in the effective refractory period of the right atrium between the two study groups. For this comparison only the data of patients were included in whom the effective refractory period of the right atrium could be determined at each paced cycle length. For that reason the number of patients is smaller in botb groups, because in some of the patients a sustained atrial tachyarrhythmia was induced before the effective refractory period was determined at every paced cycle length. Functional Refractory Period of the Right Atrium (Fig. 2) The functional refractory period of the right atrium was obtained during sinus rhythm and
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Table II. Data Obtained During the Electrophysiological Study PAF Group Sinus cycle length (R-R) Sinus node recovery time (SNRT) Frequency corrected sinus node recovery time {CSNRT) P wave duration during sinus rhythm P wave amplitude during sinus rhythm
872 1228 356 88 1.6
(n = 45)
Control Group (n = 46)
± 165 ± 356 ± 250 ± 23 ± 0.8
818 ± 152
1144 ± 203 332 ± 155 86 ± 21 1.4 ± 0.7
n = number of patients; data are given in msec or mV. ms 300 n
ms 350
250-
300-
200-
250-
control (n=42) PAF (n=22)
150-" SR
600
200-J 430
330
Figure 1, Effective refractory period afthe right atrium determined during sinus rhythm (SRJ and paced cycle lengths of 600 msec (600), 430 msec (430), and 330 msec (330) in pad'enfs with paroxysmal atrial /ibrilJation (PAFJ and without PAF (control). For this comparison only those patients were taken into account, in whom the effective refractory period of the right atrium could be determined during sinus rhythm and aJJ paced rates. paced rates of 600 msec, 430 msec, and 330 msec; however, the difference was significant [P < 0.05) between the two study groups only at a paced cycle length of 330 msec. Although it might have been of interest, shorter cycle lengths were not tested. Intraatrial Conduction Time The two study groups were not different in intraatrial conduction time (HRA-A) during sinus
74
control (n=42) PAF (n = 22) SR
600
430
330
Figure 2. Functional re/ractor>' period of the right atrium determined during sinus rhythm (SR) and paced cycle Jengths of 600 msec (600), 430 msec f430). and 330 msec (330] in patients with paroxysmal atriai fibrillation (PAFJ and without PAF (controlj. For this comparison only those patients were taken into account, in whom the functional refractory period of the right otrium could be determined during sinus rhythm and all paced rates. At the Shortest paced cycle length the functionaJ refractory period of (he right atrium was significantly longer in patients with PAF (* P < 0.05J.
rhythm. With continuous atrial pacing the delay in intraatrial conduction time was significantly (P < 0.01] more pronounced in patients with PAF as compared to the control group (Fig. 3). Intraatrial conduction time was not measured during atrial flutter, since it was impossible in the majority of
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ms 60-]
n 35.
50ZS.
40-
ffl , 15.
30-
10 . S.
20-
i
i
n.S
0
10-
t AF
control (n=46) PAF (n = 43)
0-
SR
600 500 430 375 330 300
Figure 3. Intraatrial conduction time from (he HRA to the basal right atrium during sinus rhythm and paced cycle Jengths of 600 msec, 500 msec, 430 msec, 375 msec, 333 msec, and 300 msec in patients with paroxysmal atriai fibrillation (PAF) and without PAF (control). During sinus rhythm intraa(rial conduction time was not different be(ween the two study groups, however, with right atrial pacing intraatrial conduction time was significantly f*P < 0.01) different between patients with PAF and the control group.
cases to relate an A-spike of the high right atrial lead to an A-spike in the basal right atrial lead. P wave duration as a second parameter of intraatrial conduction time was only determined during sinus rhythm and was not different between the two study groups (Table II]. P wave amplitude as a parameter of right atrial enlargement was determined in lead Vi of the surface ECG and was not different between the two study groups (Table II]. Atrial Vulnerability (Fig. 4) In 37 (82%) out of 45 patients with documented PAF sustained atrial flutter or fibrillation was reproducibly induced. In the control group sustained atrial flutter or fibrillation was initiated in only nine (20%) out of 46 patients (P < 0.001]. Induction of sustained atrial flutter or fibrillation in the PAF group had a sensitivity of 82%, that is 82% of the patients with PAF were correctly
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rwn lus AF
AF
Figure 4. Induction of non sustained (non sus) or sustained (sus) atrial flutter or fibrillation (AF) by programmed atria] stimulation in patients with fempty rectangJe) or without (hatched rectangle] paroxysmal atrial fibrillation or flutter.
identified by programmed atrial stimulation. The specificity of programmed atrial stimulation to correctly identify patients without PAF or flutter (control group) was 80%. The induction of nonsustained atrial fibrillation or atrial flutter was not significantly different between the two study groups (Fig. 4). The induction of sustained atrial flutter or fibrillation in the control group required two extrastimuli in six out of nine patients, whereas in patients with PAF a sustained atrial tachyarrhythmia was induced in 17 out of 3 7 patients by one extrastimulus, respectively, by continuous atrial pacing at a paced cycle length of 430 msec (one patient), 375 msec (one patient), and 330 msec (one patient]. In 17 patients of the PAF group two extrastimuli were necessary to induce atrial fibrillation or flutter (Fig. 5). Sustained atrial fibrillation was induced in 12 patients and atrial flutter in 25 patients of the PAF group. Atrial fibrillation was sustained by continuous atrial pacing (cycle length 375 msec] in one patient, by one extrastimulus in four patients and by two extrastimuli in seven patients. Basic drive cycle length was 523 ± 101 msec and the coupling interval of the extrastimulus inducing atrial fibrillation was 213 ± 39 msec. Atrial flutter was induced by continuous atrial pacing (cycle length 430 msec and 330 msec) in two patients, one extra-
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KUHLKAMP, ET AL.
o) control group n
tion initiating atrial flutter was 202 ± 2 7 msec (n = 6). If sustained atrial fibrillation was induced the coupling interval initiating atrial fibrillation was 220 ± 14 msec (n - 3, difference not significant). In 25 patients of the PAF group atrial flutter was the induced arrhythmia as stated above, although these patients had documented paroxysmal atrial fibrillation. In 11 (44%) patients with atrial flutter recorded in the HRA the surface ECG did not show any sign of atrial flutter, hut was instead typical for atrial fibrillation (Fig. 6). Furthermore, 21 of 37 patients (57%) with induced atrial fihrillation or flutter in the PAF group showed transition between atrial fibrillation and flutter and vice versa (Fig. 7).
4-
310 b) PAF group n 10-1
8-
6-
4-
2-
Discussion
Figure 5. Mode o/induction o/sustained atria] fibrillation or flutter in the controJ group (a) and the paroxysmal atrial /ibrilJaiton (PAF) group fb). n = number of patients; SiSi - continuous atrial pacing; SR = sinus rhythm; 600 ^ basic drive cycle length of 600 msec; 430 = basic drive cycle length of 430 msec; 330 ^ basic drive cycle iength of 330 msec; Sz ^ one extrastimulus; S2S3 = two extrastimuJi.
stimulus was required in 13 patients and two extrastimuli in ten patients. Basic drive cycle length was 481 ± 110 msec and the coupling interval of the premature atrial contraction initiating atrial flutter was 213 ± 39 msec. The mode of induction of atrial fibrillation was not significantly different from the mode of induction of atrial flutter. In the control group atrial fihrillation was induced by two extrastimuli in three patients. In three patients atrial flutter was induced by one extrastimulus and in three further patients by two extrastimuli. Basic drive cycle length was 499 ± 106 msec (n = 6) in patients with induced sustained atrial flutter and 487 ± 80 msec (n = 3] in patients with induced sustained atrial fibrillation. If sustained atrial flutter was the induced tachyarrhythmia the coupling interval of the premature atrial contrac-
76
The crucial point in our study was the selection of comparable patient groups in respect to underlying cardiac disease and left ventricular function (Table I) for the control and PAF group. We excluded all patients in the PAF group, in whom the occurrence of PAF might be influenced by additional factors as it is suspected for example in the Wolff-Parkinson-White syndrome^^ and in the mitral valve prolapse syndrome.^^ Several reports on atrial vulnerability and electrophysiology in patients with PAF have been presented,^^"^'* however, the results are inconsistent and the significance of an enhanced atrial vulnerability is unknown. ^^"^"^'^^"^^ In our patients in the control group PAF was thought to be unlikely if patients did not complain of palpitations and a baseline 24-hour Holter monitoring was without evidence for supraventricular tachyarrhythmias. Therefore, we excluded probably more patients from the control group than did EngeP" and Ohe.^^ In the study of Watson^^ 41 patients had inducible atrial flutter, in 31 patients atrial flutter or fibrillation was documented, the remaining ten patients with inducible atrial flutter had at least a history of palpitations. Therefore, the crucial point is the exclusion of PAF in the control group. However, even if patients do not complain of palpitations they may have PAF, since in five patients of the
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JG.70y
1s
Figure 6. Typical exampie of a patient in whom atria/ flutter was induced with a cycle length fA-A) of 200 msec, however the surface ECG leads I, HI, and V, do not show flutter waves. HRA = high right atrium; HBE = His bundie recording; RVA = right ventricuiar apex.
J
I
'
I
"
I
'
.
'
HBE KS.52yd' Figure 7. Continuous change between atrial flutter and atriai fibrillation in a patient in whom, primarily, atrial flutter with a cycle length (A-A) of 200 msec was the induced arrhythmia. HRA - high right atrium; HBE = His bundle recording.
PAF group PAF was recorded by chance only. Furthermore, it is unknown whether patients in the control group with an enhanced atrial vulnerability will develop atrial fibrillation in the future. The induction of atrial flutter in patients with
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PAF is of unknown significance. In our study atrial flutter was diagnosed by the intracardiac recordings only, pacing studies to differentiate between type 2 and type 1 atrial flutter or measurement of beat-to-beat trial cycle lengths have not been
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KUHLKAMP, ET AL.
performed.^^•^'' In some of the patients the intracardiac recordings were typical for atrial flutter, whereas the surface ECG did not show typical signs for atrial flutter (Fig. 7). Similar observations have been puplished.^° Hence the diagnosis of atrial flutter or fibrillation may depend on the type of recording available, and may even be more complicated with an increasing number of intracardiac recordings. Our definition of atrial flutter did not exclude patients with type 1 atrial fibrillation as defined by Wells and coworkers. ^^ However, there seems to be some overlap between type 1 atrial fibrillation and atrial flutter, since neither atrial cycle length or the change in beat-to-beat change atrial cycle length nor the separation of the atrial eiectrograms by an isoelectric baseline does clearly separate patients with type 1 atrial fibrillation from patients with type 2 atrial flutter.^^•^'' Furthermore, atrial flutter may degenerate to atrial fibrillation as it was seen in 21 patients with induced atrial flutter (Fig, 7) and vice versa, a finding seen by other investigators as well (type 4 atrial fibrillation, 14). We conclude that the significance of stimulation induced atrial flutter in patients with PAF is not established, it seems however, that atrial flutter may occur in these patients and is a clinical arrhythmia. The effective refractory period and conduction velocity are the determinants in the genesis of reentry arrhythmias according to the wavelength theory.^^ In the electrophysiological laboratory, measurement of the effective refractory period and conduction velocity within the reentry circuit is impossible. Several clinical studies stress intraatrial conduction delay as an important electrophysiological finding in PAF.^'^^-^^'^^'^^ In our study frequency dependent intraatrial conduction delay was significantly different between the two study groups although left atrial diameter was not significantly different. Hence, frequency dependent intraatrial conduction delay does not seem to be mainly a factor of an enlarged atrium rather than a primary electrical phenomenon. It has been suggested elsewhere that delayed conduction in diseased atrial tissue might be due to a shift from the sodium dependent fast response to the calcium dependent slow response domain.^^
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A point of criticism is that we measured right atrial electrophysiology but not right atrial diameter. However, a discrepancy between left and right atrial diameter is not very likely for patients in the PAF group or the control group, since right atrial enlargement is not a typical finding for the cardiac diagnosis seen in our patient population. P wave amplitude as a parameter of right atrial enlargement was not different between the PAF group and the control group. The clinical electrophysiological data concerning the effective refractory period of the right atrium are less definite^-^''-^^-^^"^^ than the data on intraatrial conduction delay. This may in part be due to an inhomogeneous patient population,^ selection of patients with the Wolff-ParkinsonWhite syndrome^^ and continuation of an antiarrhythmic therapy with cardiac glycosides.^^ In a further study^"* patients with enhanced and normal atrial vulnerability as defined by the electrophysiological study were compared irrespective of their clinical arrhythmia. Hence it is questionable if the obtained results can be transferred to diseased atria in patients with PAF. Several studies support our finding that there is no significant difference between the effective refractory period of the right atrium in patients with and without PAF or flutter.^^•^•'•^'^•^''•^^ Failure in rate adaption of the atrial effective refractory period^^ was not seen in the PAF group. However, similar to Attuel^^ we found a failure in rate adaption of the functional refractory period only in our PAF group. Since rate adaption of the effective refractory period was seen in the PAF group failure of rate adaption of the functional refractory period might represent delayed conduction. Limitations of the Study Since an enhanced atrial vulnerability was not a unique finding in patients with PAF it remains unknown in an individual patient whether an enhanced atrial vulnerability in the electrophysiological laboratory is related to PAF or not. For further elucidation of the value of an enhanced atrial vulnerability a follow-up of the patients with an enhanced atrial vulnerability but without evidence of PAF at the time of the electrophysiological study is necessary.
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References 1. Rosenblueth A, Garcia Ramos J. Studies on flutter and fibrillation: The influence of artificial obstacles on experimental auricular flutter. Am Heart J 1947; 33:677-684, 2. Moe GK, Abildskov JA, Atrial fibrillation as a self sustaining arrhythmia independent of focal discharge. Am Heart J 1959; 58:59-70. 3. Allessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. IIL The "leading circle" concept: A new model of circus movement in cardiac tissue without the involvement of an anatomic obstacle. Circ Res 1977; 41:9-18. 4. Allessie MA, Lammers WJEP, Bonke FIM, et al. Intraatrial reentry as a mechanism for atrial flutter by acetylcholine and rapid pacing in dog. Circulation 1984; 70:123-135, 5. Boineau JP, Schuessler RB, Mooney CR, et al. Natural and evoked atrial flutter due to circus movement in dogs. Am J Cardiol 1980; 45:1167-1181. 6. Boyden PA, Tilley LP, Albala A, et al. Mechanisms for atrial arrhythmias associated with cardiomyopathy: A study of feline hearts with primary myocardial disease. Circulation 1984; 69:1036-1047. 7. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. Circ Res 1986; 58:495-511. 8. Cosio FC, Arribas F, Barbero JM, et al. Validation of double-spike electrograms as a marker of conduction delay or block in atrial flutter. Am J Cardiol 1988; 61:775-780. 9. Cosio FG, Palacios J, Vidal JM, et al. Electrophysiologic studies in atrial fibrillation. Slow conduction of premature impulses a possible manifestation of the background for reentry. Am J Cardiol 1983; 51:122-130. 10. Disertori M, Inama G, Vergara G, et al. Evidence of a reentry circuit in the common type of atrial flutter in man. Circulation 1983; 67:434-440. 11. Waldo AL, Plumb VJ, Henthorn RW. Observations on the mechanism of atrial flutter. In B Surawicz, C Pratap Reddy, EN Prystowsky (eds.): Tachycardias. Martinus Nijhoff Publishing, The Hague, The Netherlands, 1984, pp. 213-229. 12. Breithardt G, Seipel L, Loogen F. sinus node recovery time and calculated sinoatrial conduction time in normal subjects and patients with sinus node dysfunction. Circulation 1977; 56:43-50. 13. Wells JL, McLean WAH, James TN, et al. Characterization of atrial flutter. Studies in man following open heart surgery using fixed atrial electrodes. Circulation 1979; 60:665-673. 14. Wells JL, Karp RB, Kouchoukos NT et al. Characterization of atrial fibrillation in man: Studies following open heart surgery. PACE 1978; 1:426-438. 15. Sharma AD, Klein CJ, Guiraudon GM, et al. Atrial fibrillation in patients with the Wolff-ParkinsonWhite syndrome incidence after surgical ablation
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