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Prevalence and clinical significance of the repetitive ventricular response during sinus rhythm in coronary disease patients
Prevalence and clinical significance of the repetitive ventricular response during sinus rhythm in coronary disease patients The prevalence of the repetitive ventricular response (RVR) after single and double premature stimulation during sinus rhythm or a paced supraventricular rhythm at a rate of 85 bpm was assessed in 343 patients (group 1: 237 patients studied prospectively who were referred for coronary arteriography and ventriculography; group 2: 44 patients after; recent acute myocardial infarction; group 3: 61 patients with documented ventricular tachycardia and/or fibrillation). In group 1 patients, RVR testing was performed from both the right ventricular apex (n = 237) and outflow tract (n = lgO), whereas in the remaining patients only the apex was stimulated. In group 1, RVR after a single premature stimulus occurred in 21.9% and after two stimuli in 63.2%. In patients with normal left ventricular (LV) function (n = 63) the prevalence of RVR after a single stimulus was significantly less (9.5%) than in those with LV dysfunction (n = 174;26.4%,p < 0.01). However, after double stimulation, there was no longer any difference. In group 2, the prevalence of RVR was 25% after one and 34.1% after two premature stimuli. In group 3 patients, RVR was observed in only 14.8% after one and in 41% of patients after two premature stimuli. Ventricular tachycardia (2 10 QRS) was induced in nine patients during a supraventricular rhythm. Two hundred thirty-seven patients of group 1, who were prospectively studied in order to assess the prognostic significance of the RVR, were followed for a mean period of 27.2 + 10.7 months. No prognostic significance of the RVR could be shown in this group of patients, 160 of whom had chronic coronary artery disease. In conclusion, premature ventricular stimulation during sinus rhythm with the use of single and double stimuli was not able to provide a clinically useful differentiation between various groups of patients. It had no predictive value for the identification of patients prone to sudden death or ventricular tachycardia in patients with chronic coronary artery disease. (AM HEART J 107:22g, 1984.)
G. Breithardt,
R.-R. Abendroth,
M. Borggrefe, H. L. Yeh, K. Haerten,
and L. Seipel
Diisseldorf, West Germany
Ventricular echo beats, or the so-called repetitive ventricular response, are occasionaNy observed if programmed right ventricular stimulation is performed during either sinus rhythm or a driven atrial rhythm.‘-” In spite of several studies, the prevalence and the clinical significance of the repetitive ventricular response (RVR) for various groups of patients are still a matter of controversy. Recently, Greene et a1.2s3 reported a high prevalence of the RVR in patients with a history of recurrent ventricular
From the Medical Hospital B (Cardiology), The University of Diisseldorf. Supported by the Sonderforschungsbereich Kardiologie (SFB 30) of the Deutsche Forschungsgemeinschaft and the Minister fiir Wissenschaft und Forschung. Nordrhein-W&f&n, and a research fellowship (Dr. Yeh) of the Alexander van Humboldt-Stiftung. Received for publication Dec. 10, 1981; revision received Aug. 26, 1982; accepted Oct. 8, 1982. Reprint requests: Gunter Breithardt, M.D., Medizinische Klinik B, Universitgt Diisseldorf, Moorenstrasse 5, D-4000 Dtiseldorf, West Germany.
tachycardia and noted that the initiation of the RVR is of clinical significance for the identification of patients after recent acute myocardial infarction who are prone to sudden death. Further studies*-13 were not able to corroborate these data and to provide definite conclusions about the clinical significance of the RVR. Therefore, the purpose of the present study was to evaluate the prevalence of the RVR in different groups of cardiac patients with the use of the stimulation protocol suggested by Greene et al.* and extending it to the additional application of two premature stimuli. Furthermore, in a subgroup of patients the prognostic significance of the RVR was assessed prospectively. METHODS Patients. Electrophysiologic studies were carried out in three groups of patients (n = 343). Group 1 included 237 patients (mean age 50 -t 7.6 years) who were referred for coronary angiography and ventriculography to our hospi229
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I. Prevalence of RVR in the three groups of patients -___ No. of Table
Patients
Group 1 (n = 237) Group1A (n = 63) Group 1B (n = 174) Group2 (n = 44) Group3 (n = 61)
right oentricular sites tested 2
After 6)
S,
21.9
9.5
After
S,-S, 67) 63.2 60.3
26.4
64.3
1
25
34.1
1
14.8
41
tal and who were included in a prospective protocol after having given informed consent. The protocol was approved by the Ethical Committee of the Medical Faculty of this university. One hundred sixty patients had coronary heart disease(51 with one-vesseldisease,68 with two-vesseldisease,and 41 with three-vesseldisease).With regard to coronary angiography, coronary artery disease wasdefined ascoronary arterial narrowing of greater than 50% of vesseldiameter. One hundred thirty patients had a history of previous myocardial infarction with a mean interval between the infarction and the study of 31 months (range 2 to 171 months). The patients were subdivided according to their left ventricular function. Normal left ventricular function was defined as ejection fraction greater than 59%) end-diastolic volume index less than or equal to 100ml/m2 body surface area,and absence of regional contraction abnormalities (group 1A). However, if one or more of these parameterswere abnormal, the patients were categorized ashaving abnormal left ventricular function (group 1B). GFOU~ 2 included 44 consecutive patients (meanage55 years) after recent acute myocardial infarction (median day of study 25.5 days, range 16 to 81 days). Twenty-one patients had had anterior wall infarction and 23 had inferior wall infarction. The diagnosisof acute myocardial infarction was based on conventional ECG and enzymatic criteria, aswell ason history. GFOU~ 3 included 61 patients (mean age 54.3 f 12.3 years) with ECG-documented sustainedventricular tachycardia and/ or fibrillation. Eighteen patients had had one previous episodeof ventricular tachycardia, nine patients had had one episode of ventricular fibrillation, and 34 patients presented with chronic recurrent ventricular tachycardia without (n = 28) or with (n = 6) ventricular fibrillation. None of these latter patients had evidence of acute myocardial infarction associatedwith their arrhythmias. Programmed electrical stlmulation. All patients were informed about the nature of the study and had given their written consent. They were studied in the postabsorptive and nonsedated state. All ant&rhythmic drugs were withheld for at least four to five half-lives. Digitalis
1984
Heart Journal
wasdiscontinued 5 days before the study. In most group 1 and 2 patients, only one 4F (Cordis) bipolar electrode catheter (interelectrode distance 10 mm) was inserted percutaneously and positioned in the heart under fluoroscopy. In all group 3 patients, one additional quadripolar catheter was introduced into the high right atrium with the tip in the right auricular appendagefor stimulating and recording. Another bipolar electrode catheter (4F, Cordis, interelectrode distance 5 mm) was used to record His bundle activity. All signals were recorded simultaneously on an eight-channel, ink-writing recorder (modified Mingograph, Siemens-Elema)taking care to ensure appropriate isolation and grounding. In groups 1 and 2, lead, I, II, and V, were recorded, whereas in group 3, bipolar electrogramsfrom the bundle of His and from the high right atrium were recorded in addition. Programmed electrical stimulation was performed by means of the Conduction System Analyzer (Medtronic, 5325). The stimuli were 2 msec in duration and twice the diastolic threshold (always lessthan 2 mA). The stimulation protocol included the introduction of single and double ventricular extrastimuli during sinus rhythm or, in caseof sinusbradycardia (lessthan 60 bpm), during a paced supraventricular rhythm (rate 85 bpm). After every eighth supraventricular beat, one premature stimulus was introduced beginning in late diastole and moving progressively earlier until ventricular refractoriness was reached. Then, the coupling interval of the premature stimulus (S,) was prolonged again until effective capture of the ventricles was achieved. The second premature stimulus (SJ wasthen introduced beginning at a coupling interval that was about 150 mseclonger than S,-S, and decreasedin decrementsof 10 msec.In group 1 patients, the same stimulation procedure was also performed in the right ventricular outflow tract if the electrode catheter could be placed there in a stable position (which was possible in 217 patients, 92%). In group 3 patients, programmed ventricular stimulation with single and double premature stimuli was performed during both supraventricular rhythm and basic ventricular drive. at cycle lengths of 500,430, 370, and 330 msecuntil ventricular tachycardia (defined as 10 or more consecutive echo beats) was induced or the end of the stimulation protocol was reached. The ventricular responseto the introduction of premature stimuli was categorized as follows. A RVR was present if one or more nonstimulated premature ventricular depolarizations occurred. In the presenceof His bundle recordings, ventricular echo beats were considered to represent intraventricular or nonbundle branch reentry, if they met the criteria recently suggested.3,8In case of nonbundle branch reentry, the QRS complex is not preceded by a His potential and has a morphologic pattern different from the one of the paced QRS complex. Bundle branch reentry was consideredto be the mechanismof a RVR if it occurred after a critical V, H, delay and had an HZV, interval greater than or equal to the H-V interval of the conducted supraventricular complexes.In the absence of His bundle recordings (groups 1 and 2), a RVR was
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II. Crosstable relating the prevalence of the RVR during programmed premature stimulation with single and double stimuli introduced during a supraventricular rhythm (vertical columns) to a paced ventricular drive at cycle lengths of 500,430,370, and 330 msec(horizontal columns) in 61 patients with documented ventricular tachycardia or fibrillation (group 3)
Table
Stimulation protocol
Supraventricular Type
of response
Paced ventricular
0 VE 1 VE 2-3VE r4 VE
drive
(AT$RS)
VF All
0 VE
1 VE
2-3 VE
rhythm r4
VE
VT (r
10 QRS)
All
0 2 0
2 9
1
2
2
1
15
23 1 35
6
3
3
8
7
5
5
9
43 1 61 patients
Numbers indicate the number of patients with the specific response observed with each of the stimulation techniques. For instance, seven patients had one ventricular echo beat during a supraventricular rhythm; six of these seven patients had inducible VT and one had four ventricular echo beats during a paced ventricular drive. Abbrevations: VE = ventricular echo beats; VF = ventricular fibrillation.
classified as possible bundle branch reentry if it was present after early coupling intervals of the premature stimulus and the contour wassimilar to the QRS complex induced by right apical pacing. All other RVRs were interpreted as nonbundle branch reentry. Follow-up. Patients in group 1 were prospectively followed up after discharge from the hospital. Part of the protocol was that the results of programmed ventricular stimulation should not influence the treatment of the patients who participated in the prospective study. Therefore, the results of programmed ventricular stimulation were not communicated to the physician in charge of the patient. Follow-up data were obtained either by a questionnaire sent to the patients and their referring physicians or from the data of the outpatient clinic. Follow-up was done after a mean follow-up time of 27.2 f 10.7 months ( t-SD; II maximum 40 months). The end point of the study was to assessthe incidence of ventricular tachycardia or of sudden death during follow-up. The following causesof death were defined: sudden cardiac death (lessthan 1 hour from onsetof symptomsto death), nonsuddencardiac death, and noncardiac death. RESULTS Prevalence of RVR. The prevalence of the RVR in the various groups of patients is listed in Table I. Group 1. In 21.9% (52 of 237) patients, ventricular echo beats were induced during programmed
premature single stimulation during sinus rhythm.
After double premature stimulation, 63.2% (150 of 237) of patients exhibited ventricular echo beats. There was no significant difference in the prevalence of the RVR when the right ventricular apex (n = 237) or the outflow tract (n = 190) was stimulated. The maximal number of ventricular echo beats was two (mean + SD, 1.2 f 0.51) after single and seven (1.39 k 0.83) after double premature
stimulation. These echo beats were identical to the stimulated premature beat in four and 44 casesafter one and two premature stimuli, respectively, which
was considered as possible bundle branch reentry.3*8 In no patient was sustained ventricular tachycardia initiated. In patients with normal left ventricular function (group lA, n = 63), 9.5% had inducible ventricular echo beats after single premature stimuli which increased to 26.4% in patients with abnormal left ventricular function (group lB, n = 174; p < 0.01). After double premature stimulation, the prevalence of ventricular echo beats in patients with normal and abnormal left ventricular function was 60.3% and 64.3 % , respectively. There was no statistically significant correlation between the initiation
RVR and the age and sex of the patients, frequency of previous myocardial infarctions,
of the
the the
time interval between the study and the previous
myocardial infarction, the frequency and severity of angina pectoris, or exertional dyspnea. Group 2. Forty-four patients were studied after recent acute myocardial infarction. The overall incidence of the RVR during sinus rhythm after a single premature stimulus was 25 % (11 of 44 patients) and after two premature stimuli, 34.1% (15 of 44 patients). There was no significant difference in the prevalence of the RVR in patients with previous anterior versus inferior wall infarction. In 6 and 10 patients, respectively, only single echo beats were induced after one or two premature stimuli. In another four patients each, two ventricular echo beats were induced by single or double premature stimuli. Another patient exhibited three ventricular echo beats after double premature stimuli. In only
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one patient, sustained ventricular tachycardia was elicited by one premature stimulus. Group 3. Sixty-one patients with previously documented ventricular tachycardia and/or ventricular fibrillation were studied. As there were no significant differences in the response of the individual subgroups, these patients are considered together. During supraventricular rhythm, nine patients (14.8% ) demonstrated ventricular echo beats or ventricular tachycardia after one premature stimulus. Four patients had one and one patient each had three and six ventricular echo beats, respectively, whereas in another three patients, sustained ventricular tachycardia was initiated. After two premature stimuli, 25 patients (41%) had ventricular echo beats. Seventeen patients had between one and seven ventricular echo beats (one ventricular echo beat in nine patients, two to three in four patients, and four to seven echo beats in another four patients). In eight patients, ventricular tachycardia was induced being sustained (greater than 30 seconds) or requiring premature overdrive suppression in almost all patients. However, if an extended stimulation protocol was applied by using a basic ventricular drive at different cycle lengths (Table II), ventricular tachycardia was induced in 43 of 61 patients (70.5 % ) and four or more consecutive ventricular echo beats in another 15 of 61 patients (24.6%). In one patient, ventricular fibrillation was initiated. In two patients only, one ventricular echo beat was observed. Thus, the sensitivity of the extended stimulation protocol for the initiation of four or more ventricular echo beats was 96.7 % compared to 23 % during sinus rhythm. In all those patients in whom two or more ventricular echo beats were induced, these responses met the criteria for intraventricular reentry, whereas single echo beats of both types were often observed in the same patient. Prognostic significance. In 233 patients of group 1, sufficient follow-up data were obtained. In only four patients, no information was available. The mean follow-up period was 27.2 +- 10.7 months (range 1 to 40 months). During follow-up, seven patients died suddenly. All these patients had had abnormal left ventricular function. In three of these patients, no ventricular echo beats were induced, whereas in another three patients, one ventricular echo beat supervened. In only one patient were three consecutive ventricular echo beats initiated. Another seven patients died from heart failure or reinfarction. Two patients died from noncardiac death (one from carcinoma of the rectum and one during an accident). In 57 patients (24%), aortocoronary
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bypass grafting was performed during the follow-up time. In these patients, the follow-up period terminated at the time of surgery. During the follow-up period, 33 % of patients were on beta blockers, 9% on antiarrhythmic drugs, and 31% on digitalis. In 4% of patients, antiarrhythmic drugs were combined with beta blockers. The distribution of drugs in patients without and with ventricular echo beats was: beta blockers 29% and 35%) respectively; antiarrhythmic drugs 10% and 9% ; and digitalis 33 % and 27 % . These differences were not significant. Follow-up duration in patients without echo beats was 27.8 f 11.5 months and in patients with echo beats, 27.1 f 10.3 months. The duration of followup was shorter in those patients who were operated upon (6 + 8.8 months). However, the incidence of echo beats was not different in surgically and medically treated patients. No echo beats were induced in 32.8% of surgical and 31.8% of medical patients; one echo beat occurred in 44.8% and 48.9 % , respectively. More than one echo beat was observed in the remaining surgically and medically treated patients. DISCUSSION
The experimental initiation of a RVR after a single ventricular stimulus has been used as an index of ventricular electrical stability.5-7, 14-17Also, in the clinical electrophysiologic laboratory, programmed ventricular stimulation has gained increasing importance during recent years.18-26 It has mainly been used in patients with suspected or documented ventricular tachycardia to establish the diagnosis and the inducibility of this arrhythmia, and for control of the efficacy of antiarrhythmic drug therapy in patients with chronic recurrent ventricular tachycardia in whom these arrhythmias could be reproducibly initiated. 27-35The prognostic significance of this technique has remained controversial since Greene et a1.2 reported a positive correlation between the repetitive ventricular response (induced by one premature stimulus during sinus rhythm) and prognosis in patients with recent acute myocardial infarction. Several subsequent studies have addressed the problem of assessing ventricular vulnerability by using programmed ventricular stimulation. 1*8.13,20,22-24.3644 These studies have not yielded unequivocal results. Some confusion has arisen as the type of electrophysiologic testing has not been identical in all studies. This, however, seems to be important as experimental studies have shown that the prevalence of inducible arrhythmias during programmed
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ventricular stimulation depends on several factors, including the number of premature stimuli and the no ventricular type of basic rhythm. 5,7 Normally, echo beat can be induced by premature single stimuli of less than double diastolic threshold during sinus rhythm.‘, 5,41 However, in the presence of abnormally contracting myocardium, ventricular echo beats can be induced with different frequenCY.~,7 The prevalence of RVR is greatly increased if programmed ventricular stimulation is performed during a basic ventricular drive.‘, “9 l3
and abnormal left ventricular function (Table I). The patient population in the present study was comparable to those patients studied by Greene et al2 at a mean interval of 24 ? 19 days (*SD) after recent myocardial infarction. Nevertheless, the incidence of the RVR was higher in the latter study (39.6 % ) which cannot be explained. Introduction of two premature stimuli during sinus rhythm did not increase the prevalence of the RVR in contrast to the findings in patients without a history of ventricular tachycardia (group 1).
Prevalence of RVR in patients without history of ventricular tachycardia (group 1). In a recent retrO-
Prevalence of RVR in patients with history of ventrlcular tachycardia (group 3). A low prevalence of RVR
spective analysis of patients in whom electrophysiologic studies had been performed, Naccarelli et al.9 observed a RVR response in 2 of 21 patients (9.5% ) without a history of ventricular tachycardia after a single premature stimulus during sinus rhythm. In contrast, Fleischmann et al.4’ did not observe any RVR after single premature stimuli during sinus rhythm. This is similar to the results of Greene et al2 in 12 patients with normal coronary and left ventricular angiograms. The lack of RVRs during sinus rhythm probably is due to the fact that measurably prolonged intraventricular conduction times during a supraventricular rhythm can rarely be demonstrated never reaching the critical delay to exhibit reentry.41 In the present study, which is the only one to correlate the presence of the RVR to left ventricular angiographic findings in a large group of patients, a similarly low prevalence of the RVR was observed after one single stimulus in patients with normal left ventricular function (9.5%), whereas in patients with abnormal left ventricular function, the prevalence of the RVR increased to 26.4% (Table I). In those patients with previous myocardial infarction, the event was remote (range 2 to 171 months; mean interval 31 months). Introduction of two premature stimuli led to a marked increase in the prevalence of the RVR to 60.3% and 64.3%) respectively, in patients with either normal or abnormal left ventricular function. This had not yet been examined consistently in previous studies.
induced by single premature ventricular depolarizations during sinus rhythm in patients with a history of recurrent ventricular tachycardia has already been described by Josephson et al.23 They observed that ventricular tachycardia could be induced in only 3 of 21 patients during sinus rhythm. The relatively low prevalence of the RVR in these patients was later confirmed by other reports, mostly published in abstract form,8* 11-13although the prevalence of the RVR varied between 0% ,11 37 % , and a maximum of 47% .12In another study, Mason8 examined 59 patients with recurrent ventricular tachycardia in whom the RVR was initiated in only nine patients (15 % ). Ruskin et al.‘O studied 85 patients with serious ventricular arrhythmias. They observed a prevalence of the RVR of 16% in patients with recurrent sustained ventricular tachycardia, 6% in those with recurrent nonsustained ventricular tachycardia, and 12% in patients with recent ventricular fibrillation. Our own results of a 15% prevalence of the RVR in patients with a history of ventricular tachycardia are between these extremes. Introduction of two premature stimuli during sinus rhythm led to an increase in the prevalence of the repetitive ventricular response from 15% to 41% (Table I). This has not been studied consistently in other studies.
Prevalence of RVR after recent myocardial infarction (group 2). None of these previous studies, except for
the original study by Greene et al.2 and the present one, has addressed the prevalence of RVR in patients after recent acute myocardial infarction (AMI). In this group, which was studied at a median interval after AM1 of 25.5 days, the prevalence of the RVR (25% ) after one premature stimulus during sinus rhythm was not different from the one in patients without a history of ventricular tachycardia
Reasons
for differences
between
different
studies.
The reason for the differences in results of the various studies reported after the initial one by Greene et al.’ remains obscure. Several possible reasons that have been discussed elsewhere2ov45exist but they are not able to explain all differences. It has been argued20 that one possible reason for the greater incidence of the RVR in the study by Greene et al2 might be that these authors not only stimulated the right ventricle from the apex but also from the right ventricular outflow tract. This site might be more prone to the mechanical induction of echo beats as it is usually more difficult to obtain a stable position of the catheter. In our study, the same
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experience was obtained as far as the difficulties in obtaining a stable position are concerned. However, in those patients in whom the catheter was in a stable position during spontaneous rhythm, the overall incidence of subsequent induction of the RVR was not greater than from the right ventricular apex, thus excluding the argument of mechanical irritation. Nevertheless, in some patients a RVR was initiated at only one site and not at the other. Furthermore, patients were largely identical with regard to age, onset of myocardial infarction, and prevalence of anterior and inferior wall myocardial infarction. One difference, the importance of which remains debatable, was the shorter pulse duration used in the study by Greene et al2 (0.9 msec) and the higher maximum thresholds resulting (less than 4 mA). The greater incidence of a RVR in our patients without a history of ventricular tachycardia (group 1) compared to those after recent myocardial infarction (group 2) may possibly be explained by two sites of stimulation being tested in group 1 patients. The application of single or double premature stimuli is further limited by the fact that, at least during a supraventricular rhythm, the reproducibility is low.37 Mechanisms of RVR. Another question concerns the type of inducible reentrant beats. It has been accepted that echo beats probably caused by intraventricular reentrFs can be considered as a pathologic finding, whereas echo beats of the bundle branch reentrant type almost certainly represent a physiologic phenomenon. ~3,I3846In the present study, a clear definition of the type of RVR could only be made in patients with documented ventricular tachycardia or flbrillation.3*8 All those patients of this group who had two or more ventricular echo beats had those of the intraventricular reentrant type (besides some additional ventricular echo beats of the bundle branch reentrant type). Greene et a1.3 reported the results of 30 patients exhibiting a RVR after one premature stimulus during sinus rhythm. His bundle or right bundle branch deflections did not precede the repetitive complex in 29 of the 30 patients, which was regarded as evidence that the proximal His-Purkinje system was not involved in the reentry circuit. In 24 of 30 patients, the QRS axis of the repetitive complex was divergent 45 degrees or more from the stimulated complex. In 22 of 30 patients, the repetitive complex had a right bundle branch block configuration. Mason and Winkle32 observed a repetitive ventricular response in 9 to 59 patients with recurrent ventricular tachycardia after one premature stimulus. The repetitive ventricular response seemed to
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be the result of bundle branch reentry in four patients and possibly a result of other mechanisms in five. In the present study, which included a large cohort of patients, the protocol was designed to be as feasible as possible for routine application. In view of available reports that had suggested a very low incidence of bundle branch reentry after single premature stimuli during sinus rhythm,3’41 it was decided not to record His bundle potentials as this would have required the introduction of another catheter. This restriction was demanded by the Ethical Committee as the study was done in patients without symptoms caused by tachyarrhythmias. Prognostic significance. In 1978 Greene et al2 reported that within 1 year of follow-up, 15 of 19 patients with a positive RVR experienced ventricular tachycardia or sudden death, whereas only 4 of 29 patients without RVR developed ventricular tachycardia or sudden death. This study has been the only one that demonstrated a predictive value of the RVR for subsequent ventricular tachycardia or sudden death in patients after recent acute myocardial infarction. Later studies, in which a comparable stimulation protocol was used, could not substantiate these results.** ‘* Troup et a1.12studied 32 patients with documented ventricular tachycardia or fibrillation. The prevalence of the RVR in those surviving was 47 % and in those with sudden death 63% (NS). Mason,8 who studied 59 patients with recurrent ventricular tachycardia, was also not able to find a significant difference in the prevalence of sudden death in patients with and without repetitive beating. Similarly, in the present study, which yielded a mean follow-up duration of more than 2 years in 237 patients without previously documented ventricular tachycardia who were studied prospectively, there was no prognostic significance of the test. Although some patients received beta blockers or antiarrhythmic drugs, the distribution of these drugs among patients with and without a RVR was identical. Thus, it seems unlikely that a possible untoward prognostic significance of the RVR might have been obscured by these medications. Furthermore, the lack of predictive value cannot be explained by the fact that, in about one third of those patients with left ventricular contraction abnormalities (group lB), aortocoronary bypass grafting was performed during the follow-up period, which might have prevented sudden death as has been suggested previ0us1y.~~ However, aortocoronary bypass does not seem to have a salutary effect on ventricular arrhythmias.48*4p Furthermore, the low prevalence of the RVR in patients who previously had had malig-
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nant ventricular arrhythmias is noteworthy (Table I). Especially in this group of patients, one should be able tc elicit a RVR if it indeed could detect the risk of serious ventricular arrhythmias. However, the low prevalence of the RVR in this group of patients, which is in contrast to that of Greene et al.,’ is in accordance with the data of Mason et aLa Clinical implications. There is now considerable evidence that the RVR induced by single premature stimuli during a supraventricular rhythm is not able to differentiate between patients with or without documented ventricular tachycardia or patients with recent acute myocardial infarction. However, this study and others g*l*, 13,3*,3g have provided evidence that by a more extended stimulation protocol, which includes the application of single, and double premature stimuli during a basic ventricular drive at various cycle lengths, the sensitivity of the test can be greatly increased in patients with documented ventricular tachyarrhythmias. The only useful differentiation which was possible on the basis of single premature stimuli was between patients with normal or abnormal left ventricular function (Table I). However, this seems to be of minor clinical value. Introduction of two instead of one premature stimuli did not increase the differentiating potency of the test. Furthermore, this test does not have any prognostic significance as far as patients with chronic coronary artery disease are concerned. REFERENCES
1. Breithardt G, Seipel L, Loogen F: Der akute HerztodBedeutung elektrophysiologischer Stimulationsverfahren. Verh Dtsch Ges Herz Kreislaufforsch 46:38, 1980. 2. Greene HL, Reid PR, Schaeffer AH: The repetitive ventricular response in man. A predictor of sudden death. N Engl J Med 299:729, 1978. 3. Greene HL, Reid PR, Schaeffer AH: Mechanisms of the repetitive ventricular response in man. Am J Cardiol 45:227, 1980. 4. Jenzer H, Lohrbauer L, Lown B: Response to single threshold stimuli following acute myocardial infarction. Proc Sot Exp Biol Med 141:606, 1972. 5. Lown B, Kleiger R, Williams J: Cardioversion and dieitalis drugs: Changed digitalized animals. Circ Res 17:519, 1965. 6. Matta RJ, Verrier RL, Lown B: The renetitive extrasvstole as an index of vulnerability to ventricular fibrillation. Am J Physiol 230:1469, 1976. 7. Lown B: Electrical stimulation to estimate the degree of digitalization. II. Experimental studies. Am J Cardiol22:251, 1968. 8. Mason JW: Repetitive beating after single ventricular extrastimuli: Incidence and prognostic significance in patients with recurrent ventricular tachycardia. Am J Cardiol 45:1126, 1980. 9. Naccarelli GV, Prystowsky EN, Jackman WM, Heger JJ, Rinkenberger RL, Zipes DP: Repetitive ventricular response. Prevalence and prognostic significance. Br Heart J 46:152, 1981. 10. Ruskin JN, DiMarco JP, Garan H: Repetitive responses to single ventricular extrastimuli, in patients with serious ven~_I-----
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response in CAD
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tricular arrhythmias: Incidence and clinical significance. Circulation 63:767, 1981. Rinkenberger RL, Prystowsky EN, Jackman WM, Heger JJ, Zipes DP: Premature ventricular stimulation during sinus rhythm or atria1 pacing has low sensitivity in identifying patients with recurrent ventricular tachycardia or ventricular fibrillation (abstr). Clin Res 27:619, 1979. Troup PJ, Pedersen DH, Zipes DP: Effects of premature ventricular stimulation in patients with ventricular tachycardia (abstr). Circulation 58(Suppl 11):158, 1978. Farshidi A, Tyndall T, Batsford WP: Inducibility of recurrent sustained ventricular tachycardia, role of stimulation mode (abstr). Circulation 62(Suppl 111):261, 1980. Axelrod PJ, Verrier RL, Lown B: Vulnerability to ventricular fibrillation during acute coronary artery occlusion and release. Am J Cardiol 36:776, 1975. Han J, Garcia de Jalon PD. Moe GK: Fibrillation threshold of premature ventricular responses. Circ Res 18:18, 1966. Moore EN, Spear JF: Ventricular fibrillation threshold. Its physiological and pharmacological importance. Arch Int Med 135:446, 1975. Wiggers CJ, Wegria R: Ventricular fibrillation due to single, localized induction and condenser shocks applied during the vulnerable phase of ventricular systole. Am J Physiol 128:500,
1939/40.
18. Akhtar M, Damato AN, Batsford WP, Ruskin JN, Ogunkelu JB, Vargas G: Demonstration of re-entry within His-Purkinje system in man. Circulation 50:1150, 1974. 19. Akhtar M, Damato AN, Ruskin JN, Ogunkelu JB, Reddy CP, Leeds CJ: Characteristics and coexistence of two forms of ventricular echo phenomena. AM HEART J 92:174, 1976. 20. Akhtar M: Editorial: The clinical significance of the repetitive ventricular response. Circulation 63:772, 1981. 21. Breithardt G, Seipel L, Abendroth R-R, Haerten K, Loogen F: Initiierung und Terminierung ventrikuhirer Tachykardien durch Elektrostimulation. Z Kardiol 68:575, 1979. 22. Denes P, Wu D, Dhingra RC, Amat-y-Leon F, Wyndham C, Mautrer RK, Rosen KM: Electrophysiological studies in patients with chronic recurrent ventricular tachycardia. Circulation 54:229, 1976. 23. Josephson ME, Horowitz LN, Farshidi A, Kastor JA: Recurrent sustained ventricular tachycardia. I. Mechanisms. Circulation 57:431, 1978. 24. Kastor JA, Horowitz LN, Harken AH, Josephson ME: Clinical electrophysiology of ventricular tachycardia. N Engl J Med 304:1004, 1981. 25. Wellens HJJ, Diiren DR, Lie KI: Observations on mechanisms of ventricular tachycardia in man. Circulation 54:237, 1976. 26. Wellens HJ, Schuilenburg RM, Durrer D: Electrical stimulation of the heart in patients with ventricular tachycardia. Circulation 46:216. 1972. 27. Breithardt G, Seipel L, Abendroth R-R, Loogen F: Serial electrophysiological testing of antiarrhythmic drug efficacy in patients with recurrent ventricular tachycardia. Eur Heart J l:ll, 1980. 28. Fisher JD, Cohen HL, Mehra R, Altschuler H, Escher DJW, Furman S: Cardiac pacing and pacemakers. II. Serial electrophysiologic-pharmacologic testing for control of recurrent tachyarrhythmias. AM HEART J 93:658, 1977. 29. Fisher JD: Ventricular tachycardia-practical and provocative electrophysiology (editorial). Circulation 58:1000, 1978. 30. Horowitz LN, Josephson ME, Farshidi A, Spielman SR, Michelson EL, Greenspan AN: Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 58:986, 1978. 31. Hartzler GO, Maloney JD: Programmed ventricular stimulation in management of recurrent ventricular tachycardia. Mayo Clin Proc 52:731, 1977. 32. Mason JW, Winkle RA: Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic
236
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34.
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36.
37.
38.
39.
40.
41.
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drug therapy for recurrent ventricular tachycardia. Circulation 58:971, 1978. Scheinman MM: Induction of ventricular tachycardia: A promising new technique or clinical electrophysiology gone awry (editorial)? Circulation 58:998, 1978. Schaeffer AH, Greene HL, Reid PR: Suppression of the repetitive ventricular response: An index of long-term antiarrhythmic effectiveness of aprindine for ventricular tachycardia in man. Am J Cardiol 42:1007, 1978. Seipel L, Breithardt G: Electrophysiological effects of mexiletine in man: Influence on stimulus-induced ventricular arrhythmias. In Sandoe E, Julian DG, Bell JW, editors: Management of ventricular tachycardia-role of mexiletine. Amsterdam, 1978, Excerpta Medica, pp 219-232. Ahendroth R-R, Breithardt G, SeipeI L, Bleses H-P: Auftreten und prognostische Bedeutung ventrikuhirer Echoschlage bei Patienten mit und ohne koronare Herzkrankheit (abstr). Z Kardiol 70:333, 1981. Abendroth R-R, Seipel L, Breithardt G: Reproduzierbarkeit ventrikuliirer Echoschlage bei programmierter rechtsventrikullrer Stimulation (abstr). Z Kardiol 69:211, 1980. Breithardt G, Seipel L, Meyer T, Abendroth R-R: Prognostic significance of the repetitive ventricular response (abstr) PACE 4%5, 1981. Borggrefe M, Breithardt G, Seipel L, Abendroth R-R Yeh HL: Klinisch-elektrophysiologische Befunde bei Patienten nach Kammerflimmern (abstr). Z Kardiol 70:326, 1981. Farshidi A. Michelson EL. Greensnan AM. Saielman SR. Horowitz LN, Josephson ME: Repetitive responses to ven: tricular extrastimuli: Independence, mechanism, and significance. AM HEART J 100:59, 1980. Fleischmann DW. Pop T, Marschall HU, DeBakker JMT:
American
42.
43.
44.
45. 46.
47.
48.
49.
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Rate and rhythm dependent vulnerability of the human ventricular myocardium. Basic Res Cardiol 74:203, 1979. Meinertz T, Treese N, Kasper W, Pop T: Kammervulnerabilitat bei normalem Herzbefund, koronarer Herzkrankheit (KHK) und kongestiver Kardiomyopathie (COCM). Z Kardiol 70:298, 1981. Probst P, Schwarzer C, Pachinger 0: Repetitive Kammerant wort IRK) und koronare Herzkrankheit (KHK). Z Kardiol 69:724, 1980. VandePol CJ, Farshidi A, Spielman RS, Greenspan AM, Horowitz LN, Kastor JA, Josephson ME: Sensitivity and specificity of programmed ventricular stimulation in patients with ventricular tachycardia. Am J Cardiol 45:407, 1980. Kent KM: Assessing the electrical stability of the heart in human beings. Am J Cardiol451305, 1980. Lyons CJ, Burgess MJ: Demonstration of re-entry within the canine specialized conduction system. AM HEART J 97:595. 1980. Vismara LA, Miller PR, Price JE, Karem R, De Maria AN, Mason DT: Improved longevity due to reduction of sudden death by coronary bypass in aortocoronary atherosclerosis. Prospective evaluation of medical versus surgical therapy in matched patients with multivessel disease. Am d Cardiol 39:919, 1977. Graboys TB, Lown B, Collins JJ, Cohn LH: Does coronary revascularization reduce the prevalence of ventricular ectopic activity? Am J Cardiol 41:401, 1978. Garan H, Ruskin JN, DiMarco J: Electrophysiologic studies before and after aortocoronary bypass in patients with outof-hospital ventricular fibrillation (abstr). Am J Cardiol 47:497, 1981.
G. Breithardt,
R.-R. Abendroth,
M. Borggrefe, H. L. Yeh, K. Haerten,
and L. Seipel
Diisseldorf, West Germany
Ventricular echo beats, or the so-called repetitive ventricular response, are occasionaNy observed if programmed right ventricular stimulation is performed during either sinus rhythm or a driven atrial rhythm.‘-” In spite of several studies, the prevalence and the clinical significance of the repetitive ventricular response (RVR) for various groups of patients are still a matter of controversy. Recently, Greene et a1.2s3 reported a high prevalence of the RVR in patients with a history of recurrent ventricular
From the Medical Hospital B (Cardiology), The University of Diisseldorf. Supported by the Sonderforschungsbereich Kardiologie (SFB 30) of the Deutsche Forschungsgemeinschaft and the Minister fiir Wissenschaft und Forschung. Nordrhein-W&f&n, and a research fellowship (Dr. Yeh) of the Alexander van Humboldt-Stiftung. Received for publication Dec. 10, 1981; revision received Aug. 26, 1982; accepted Oct. 8, 1982. Reprint requests: Gunter Breithardt, M.D., Medizinische Klinik B, Universitgt Diisseldorf, Moorenstrasse 5, D-4000 Dtiseldorf, West Germany.
tachycardia and noted that the initiation of the RVR is of clinical significance for the identification of patients after recent acute myocardial infarction who are prone to sudden death. Further studies*-13 were not able to corroborate these data and to provide definite conclusions about the clinical significance of the RVR. Therefore, the purpose of the present study was to evaluate the prevalence of the RVR in different groups of cardiac patients with the use of the stimulation protocol suggested by Greene et al.* and extending it to the additional application of two premature stimuli. Furthermore, in a subgroup of patients the prognostic significance of the RVR was assessed prospectively. METHODS Patients. Electrophysiologic studies were carried out in three groups of patients (n = 343). Group 1 included 237 patients (mean age 50 -t 7.6 years) who were referred for coronary angiography and ventriculography to our hospi229
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I. Prevalence of RVR in the three groups of patients -___ No. of Table
Patients
Group 1 (n = 237) Group1A (n = 63) Group 1B (n = 174) Group2 (n = 44) Group3 (n = 61)
right oentricular sites tested 2
After 6)
S,
21.9
9.5
After
S,-S, 67) 63.2 60.3
26.4
64.3
1
25
34.1
1
14.8
41
tal and who were included in a prospective protocol after having given informed consent. The protocol was approved by the Ethical Committee of the Medical Faculty of this university. One hundred sixty patients had coronary heart disease(51 with one-vesseldisease,68 with two-vesseldisease,and 41 with three-vesseldisease).With regard to coronary angiography, coronary artery disease wasdefined ascoronary arterial narrowing of greater than 50% of vesseldiameter. One hundred thirty patients had a history of previous myocardial infarction with a mean interval between the infarction and the study of 31 months (range 2 to 171 months). The patients were subdivided according to their left ventricular function. Normal left ventricular function was defined as ejection fraction greater than 59%) end-diastolic volume index less than or equal to 100ml/m2 body surface area,and absence of regional contraction abnormalities (group 1A). However, if one or more of these parameterswere abnormal, the patients were categorized ashaving abnormal left ventricular function (group 1B). GFOU~ 2 included 44 consecutive patients (meanage55 years) after recent acute myocardial infarction (median day of study 25.5 days, range 16 to 81 days). Twenty-one patients had had anterior wall infarction and 23 had inferior wall infarction. The diagnosisof acute myocardial infarction was based on conventional ECG and enzymatic criteria, aswell ason history. GFOU~ 3 included 61 patients (mean age 54.3 f 12.3 years) with ECG-documented sustainedventricular tachycardia and/ or fibrillation. Eighteen patients had had one previous episodeof ventricular tachycardia, nine patients had had one episode of ventricular fibrillation, and 34 patients presented with chronic recurrent ventricular tachycardia without (n = 28) or with (n = 6) ventricular fibrillation. None of these latter patients had evidence of acute myocardial infarction associatedwith their arrhythmias. Programmed electrical stlmulation. All patients were informed about the nature of the study and had given their written consent. They were studied in the postabsorptive and nonsedated state. All ant&rhythmic drugs were withheld for at least four to five half-lives. Digitalis
1984
Heart Journal
wasdiscontinued 5 days before the study. In most group 1 and 2 patients, only one 4F (Cordis) bipolar electrode catheter (interelectrode distance 10 mm) was inserted percutaneously and positioned in the heart under fluoroscopy. In all group 3 patients, one additional quadripolar catheter was introduced into the high right atrium with the tip in the right auricular appendagefor stimulating and recording. Another bipolar electrode catheter (4F, Cordis, interelectrode distance 5 mm) was used to record His bundle activity. All signals were recorded simultaneously on an eight-channel, ink-writing recorder (modified Mingograph, Siemens-Elema)taking care to ensure appropriate isolation and grounding. In groups 1 and 2, lead, I, II, and V, were recorded, whereas in group 3, bipolar electrogramsfrom the bundle of His and from the high right atrium were recorded in addition. Programmed electrical stimulation was performed by means of the Conduction System Analyzer (Medtronic, 5325). The stimuli were 2 msec in duration and twice the diastolic threshold (always lessthan 2 mA). The stimulation protocol included the introduction of single and double ventricular extrastimuli during sinus rhythm or, in caseof sinusbradycardia (lessthan 60 bpm), during a paced supraventricular rhythm (rate 85 bpm). After every eighth supraventricular beat, one premature stimulus was introduced beginning in late diastole and moving progressively earlier until ventricular refractoriness was reached. Then, the coupling interval of the premature stimulus (S,) was prolonged again until effective capture of the ventricles was achieved. The second premature stimulus (SJ wasthen introduced beginning at a coupling interval that was about 150 mseclonger than S,-S, and decreasedin decrementsof 10 msec.In group 1 patients, the same stimulation procedure was also performed in the right ventricular outflow tract if the electrode catheter could be placed there in a stable position (which was possible in 217 patients, 92%). In group 3 patients, programmed ventricular stimulation with single and double premature stimuli was performed during both supraventricular rhythm and basic ventricular drive. at cycle lengths of 500,430, 370, and 330 msecuntil ventricular tachycardia (defined as 10 or more consecutive echo beats) was induced or the end of the stimulation protocol was reached. The ventricular responseto the introduction of premature stimuli was categorized as follows. A RVR was present if one or more nonstimulated premature ventricular depolarizations occurred. In the presenceof His bundle recordings, ventricular echo beats were considered to represent intraventricular or nonbundle branch reentry, if they met the criteria recently suggested.3,8In case of nonbundle branch reentry, the QRS complex is not preceded by a His potential and has a morphologic pattern different from the one of the paced QRS complex. Bundle branch reentry was consideredto be the mechanismof a RVR if it occurred after a critical V, H, delay and had an HZV, interval greater than or equal to the H-V interval of the conducted supraventricular complexes.In the absence of His bundle recordings (groups 1 and 2), a RVR was
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II. Crosstable relating the prevalence of the RVR during programmed premature stimulation with single and double stimuli introduced during a supraventricular rhythm (vertical columns) to a paced ventricular drive at cycle lengths of 500,430,370, and 330 msec(horizontal columns) in 61 patients with documented ventricular tachycardia or fibrillation (group 3)
Table
Stimulation protocol
Supraventricular Type
of response
Paced ventricular
0 VE 1 VE 2-3VE r4 VE
drive
(AT$RS)
VF All
0 VE
1 VE
2-3 VE
rhythm r4
VE
VT (r
10 QRS)
All
0 2 0
2 9
1
2
2
1
15
23 1 35
6
3
3
8
7
5
5
9
43 1 61 patients
Numbers indicate the number of patients with the specific response observed with each of the stimulation techniques. For instance, seven patients had one ventricular echo beat during a supraventricular rhythm; six of these seven patients had inducible VT and one had four ventricular echo beats during a paced ventricular drive. Abbrevations: VE = ventricular echo beats; VF = ventricular fibrillation.
classified as possible bundle branch reentry if it was present after early coupling intervals of the premature stimulus and the contour wassimilar to the QRS complex induced by right apical pacing. All other RVRs were interpreted as nonbundle branch reentry. Follow-up. Patients in group 1 were prospectively followed up after discharge from the hospital. Part of the protocol was that the results of programmed ventricular stimulation should not influence the treatment of the patients who participated in the prospective study. Therefore, the results of programmed ventricular stimulation were not communicated to the physician in charge of the patient. Follow-up data were obtained either by a questionnaire sent to the patients and their referring physicians or from the data of the outpatient clinic. Follow-up was done after a mean follow-up time of 27.2 f 10.7 months ( t-SD; II maximum 40 months). The end point of the study was to assessthe incidence of ventricular tachycardia or of sudden death during follow-up. The following causesof death were defined: sudden cardiac death (lessthan 1 hour from onsetof symptomsto death), nonsuddencardiac death, and noncardiac death. RESULTS Prevalence of RVR. The prevalence of the RVR in the various groups of patients is listed in Table I. Group 1. In 21.9% (52 of 237) patients, ventricular echo beats were induced during programmed
premature single stimulation during sinus rhythm.
After double premature stimulation, 63.2% (150 of 237) of patients exhibited ventricular echo beats. There was no significant difference in the prevalence of the RVR when the right ventricular apex (n = 237) or the outflow tract (n = 190) was stimulated. The maximal number of ventricular echo beats was two (mean + SD, 1.2 f 0.51) after single and seven (1.39 k 0.83) after double premature
stimulation. These echo beats were identical to the stimulated premature beat in four and 44 casesafter one and two premature stimuli, respectively, which
was considered as possible bundle branch reentry.3*8 In no patient was sustained ventricular tachycardia initiated. In patients with normal left ventricular function (group lA, n = 63), 9.5% had inducible ventricular echo beats after single premature stimuli which increased to 26.4% in patients with abnormal left ventricular function (group lB, n = 174; p < 0.01). After double premature stimulation, the prevalence of ventricular echo beats in patients with normal and abnormal left ventricular function was 60.3% and 64.3 % , respectively. There was no statistically significant correlation between the initiation
RVR and the age and sex of the patients, frequency of previous myocardial infarctions,
of the
the the
time interval between the study and the previous
myocardial infarction, the frequency and severity of angina pectoris, or exertional dyspnea. Group 2. Forty-four patients were studied after recent acute myocardial infarction. The overall incidence of the RVR during sinus rhythm after a single premature stimulus was 25 % (11 of 44 patients) and after two premature stimuli, 34.1% (15 of 44 patients). There was no significant difference in the prevalence of the RVR in patients with previous anterior versus inferior wall infarction. In 6 and 10 patients, respectively, only single echo beats were induced after one or two premature stimuli. In another four patients each, two ventricular echo beats were induced by single or double premature stimuli. Another patient exhibited three ventricular echo beats after double premature stimuli. In only
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one patient, sustained ventricular tachycardia was elicited by one premature stimulus. Group 3. Sixty-one patients with previously documented ventricular tachycardia and/or ventricular fibrillation were studied. As there were no significant differences in the response of the individual subgroups, these patients are considered together. During supraventricular rhythm, nine patients (14.8% ) demonstrated ventricular echo beats or ventricular tachycardia after one premature stimulus. Four patients had one and one patient each had three and six ventricular echo beats, respectively, whereas in another three patients, sustained ventricular tachycardia was initiated. After two premature stimuli, 25 patients (41%) had ventricular echo beats. Seventeen patients had between one and seven ventricular echo beats (one ventricular echo beat in nine patients, two to three in four patients, and four to seven echo beats in another four patients). In eight patients, ventricular tachycardia was induced being sustained (greater than 30 seconds) or requiring premature overdrive suppression in almost all patients. However, if an extended stimulation protocol was applied by using a basic ventricular drive at different cycle lengths (Table II), ventricular tachycardia was induced in 43 of 61 patients (70.5 % ) and four or more consecutive ventricular echo beats in another 15 of 61 patients (24.6%). In one patient, ventricular fibrillation was initiated. In two patients only, one ventricular echo beat was observed. Thus, the sensitivity of the extended stimulation protocol for the initiation of four or more ventricular echo beats was 96.7 % compared to 23 % during sinus rhythm. In all those patients in whom two or more ventricular echo beats were induced, these responses met the criteria for intraventricular reentry, whereas single echo beats of both types were often observed in the same patient. Prognostic significance. In 233 patients of group 1, sufficient follow-up data were obtained. In only four patients, no information was available. The mean follow-up period was 27.2 +- 10.7 months (range 1 to 40 months). During follow-up, seven patients died suddenly. All these patients had had abnormal left ventricular function. In three of these patients, no ventricular echo beats were induced, whereas in another three patients, one ventricular echo beat supervened. In only one patient were three consecutive ventricular echo beats initiated. Another seven patients died from heart failure or reinfarction. Two patients died from noncardiac death (one from carcinoma of the rectum and one during an accident). In 57 patients (24%), aortocoronary
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1984 Journal
bypass grafting was performed during the follow-up time. In these patients, the follow-up period terminated at the time of surgery. During the follow-up period, 33 % of patients were on beta blockers, 9% on antiarrhythmic drugs, and 31% on digitalis. In 4% of patients, antiarrhythmic drugs were combined with beta blockers. The distribution of drugs in patients without and with ventricular echo beats was: beta blockers 29% and 35%) respectively; antiarrhythmic drugs 10% and 9% ; and digitalis 33 % and 27 % . These differences were not significant. Follow-up duration in patients without echo beats was 27.8 f 11.5 months and in patients with echo beats, 27.1 f 10.3 months. The duration of followup was shorter in those patients who were operated upon (6 + 8.8 months). However, the incidence of echo beats was not different in surgically and medically treated patients. No echo beats were induced in 32.8% of surgical and 31.8% of medical patients; one echo beat occurred in 44.8% and 48.9 % , respectively. More than one echo beat was observed in the remaining surgically and medically treated patients. DISCUSSION
The experimental initiation of a RVR after a single ventricular stimulus has been used as an index of ventricular electrical stability.5-7, 14-17Also, in the clinical electrophysiologic laboratory, programmed ventricular stimulation has gained increasing importance during recent years.18-26 It has mainly been used in patients with suspected or documented ventricular tachycardia to establish the diagnosis and the inducibility of this arrhythmia, and for control of the efficacy of antiarrhythmic drug therapy in patients with chronic recurrent ventricular tachycardia in whom these arrhythmias could be reproducibly initiated. 27-35The prognostic significance of this technique has remained controversial since Greene et a1.2 reported a positive correlation between the repetitive ventricular response (induced by one premature stimulus during sinus rhythm) and prognosis in patients with recent acute myocardial infarction. Several subsequent studies have addressed the problem of assessing ventricular vulnerability by using programmed ventricular stimulation. 1*8.13,20,22-24.3644 These studies have not yielded unequivocal results. Some confusion has arisen as the type of electrophysiologic testing has not been identical in all studies. This, however, seems to be important as experimental studies have shown that the prevalence of inducible arrhythmias during programmed
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ventricular stimulation depends on several factors, including the number of premature stimuli and the no ventricular type of basic rhythm. 5,7 Normally, echo beat can be induced by premature single stimuli of less than double diastolic threshold during sinus rhythm.‘, 5,41 However, in the presence of abnormally contracting myocardium, ventricular echo beats can be induced with different frequenCY.~,7 The prevalence of RVR is greatly increased if programmed ventricular stimulation is performed during a basic ventricular drive.‘, “9 l3
and abnormal left ventricular function (Table I). The patient population in the present study was comparable to those patients studied by Greene et al2 at a mean interval of 24 ? 19 days (*SD) after recent myocardial infarction. Nevertheless, the incidence of the RVR was higher in the latter study (39.6 % ) which cannot be explained. Introduction of two premature stimuli during sinus rhythm did not increase the prevalence of the RVR in contrast to the findings in patients without a history of ventricular tachycardia (group 1).
Prevalence of RVR in patients without history of ventricular tachycardia (group 1). In a recent retrO-
Prevalence of RVR in patients with history of ventrlcular tachycardia (group 3). A low prevalence of RVR
spective analysis of patients in whom electrophysiologic studies had been performed, Naccarelli et al.9 observed a RVR response in 2 of 21 patients (9.5% ) without a history of ventricular tachycardia after a single premature stimulus during sinus rhythm. In contrast, Fleischmann et al.4’ did not observe any RVR after single premature stimuli during sinus rhythm. This is similar to the results of Greene et al2 in 12 patients with normal coronary and left ventricular angiograms. The lack of RVRs during sinus rhythm probably is due to the fact that measurably prolonged intraventricular conduction times during a supraventricular rhythm can rarely be demonstrated never reaching the critical delay to exhibit reentry.41 In the present study, which is the only one to correlate the presence of the RVR to left ventricular angiographic findings in a large group of patients, a similarly low prevalence of the RVR was observed after one single stimulus in patients with normal left ventricular function (9.5%), whereas in patients with abnormal left ventricular function, the prevalence of the RVR increased to 26.4% (Table I). In those patients with previous myocardial infarction, the event was remote (range 2 to 171 months; mean interval 31 months). Introduction of two premature stimuli led to a marked increase in the prevalence of the RVR to 60.3% and 64.3%) respectively, in patients with either normal or abnormal left ventricular function. This had not yet been examined consistently in previous studies.
induced by single premature ventricular depolarizations during sinus rhythm in patients with a history of recurrent ventricular tachycardia has already been described by Josephson et al.23 They observed that ventricular tachycardia could be induced in only 3 of 21 patients during sinus rhythm. The relatively low prevalence of the RVR in these patients was later confirmed by other reports, mostly published in abstract form,8* 11-13although the prevalence of the RVR varied between 0% ,11 37 % , and a maximum of 47% .12In another study, Mason8 examined 59 patients with recurrent ventricular tachycardia in whom the RVR was initiated in only nine patients (15 % ). Ruskin et al.‘O studied 85 patients with serious ventricular arrhythmias. They observed a prevalence of the RVR of 16% in patients with recurrent sustained ventricular tachycardia, 6% in those with recurrent nonsustained ventricular tachycardia, and 12% in patients with recent ventricular fibrillation. Our own results of a 15% prevalence of the RVR in patients with a history of ventricular tachycardia are between these extremes. Introduction of two premature stimuli during sinus rhythm led to an increase in the prevalence of the repetitive ventricular response from 15% to 41% (Table I). This has not been studied consistently in other studies.
Prevalence of RVR after recent myocardial infarction (group 2). None of these previous studies, except for
the original study by Greene et al.2 and the present one, has addressed the prevalence of RVR in patients after recent acute myocardial infarction (AMI). In this group, which was studied at a median interval after AM1 of 25.5 days, the prevalence of the RVR (25% ) after one premature stimulus during sinus rhythm was not different from the one in patients without a history of ventricular tachycardia
Reasons
for differences
between
different
studies.
The reason for the differences in results of the various studies reported after the initial one by Greene et al.’ remains obscure. Several possible reasons that have been discussed elsewhere2ov45exist but they are not able to explain all differences. It has been argued20 that one possible reason for the greater incidence of the RVR in the study by Greene et al2 might be that these authors not only stimulated the right ventricle from the apex but also from the right ventricular outflow tract. This site might be more prone to the mechanical induction of echo beats as it is usually more difficult to obtain a stable position of the catheter. In our study, the same
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experience was obtained as far as the difficulties in obtaining a stable position are concerned. However, in those patients in whom the catheter was in a stable position during spontaneous rhythm, the overall incidence of subsequent induction of the RVR was not greater than from the right ventricular apex, thus excluding the argument of mechanical irritation. Nevertheless, in some patients a RVR was initiated at only one site and not at the other. Furthermore, patients were largely identical with regard to age, onset of myocardial infarction, and prevalence of anterior and inferior wall myocardial infarction. One difference, the importance of which remains debatable, was the shorter pulse duration used in the study by Greene et al2 (0.9 msec) and the higher maximum thresholds resulting (less than 4 mA). The greater incidence of a RVR in our patients without a history of ventricular tachycardia (group 1) compared to those after recent myocardial infarction (group 2) may possibly be explained by two sites of stimulation being tested in group 1 patients. The application of single or double premature stimuli is further limited by the fact that, at least during a supraventricular rhythm, the reproducibility is low.37 Mechanisms of RVR. Another question concerns the type of inducible reentrant beats. It has been accepted that echo beats probably caused by intraventricular reentrFs can be considered as a pathologic finding, whereas echo beats of the bundle branch reentrant type almost certainly represent a physiologic phenomenon. ~3,I3846In the present study, a clear definition of the type of RVR could only be made in patients with documented ventricular tachycardia or flbrillation.3*8 All those patients of this group who had two or more ventricular echo beats had those of the intraventricular reentrant type (besides some additional ventricular echo beats of the bundle branch reentrant type). Greene et a1.3 reported the results of 30 patients exhibiting a RVR after one premature stimulus during sinus rhythm. His bundle or right bundle branch deflections did not precede the repetitive complex in 29 of the 30 patients, which was regarded as evidence that the proximal His-Purkinje system was not involved in the reentry circuit. In 24 of 30 patients, the QRS axis of the repetitive complex was divergent 45 degrees or more from the stimulated complex. In 22 of 30 patients, the repetitive complex had a right bundle branch block configuration. Mason and Winkle32 observed a repetitive ventricular response in 9 to 59 patients with recurrent ventricular tachycardia after one premature stimulus. The repetitive ventricular response seemed to
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February, 1984 Heart Journal
be the result of bundle branch reentry in four patients and possibly a result of other mechanisms in five. In the present study, which included a large cohort of patients, the protocol was designed to be as feasible as possible for routine application. In view of available reports that had suggested a very low incidence of bundle branch reentry after single premature stimuli during sinus rhythm,3’41 it was decided not to record His bundle potentials as this would have required the introduction of another catheter. This restriction was demanded by the Ethical Committee as the study was done in patients without symptoms caused by tachyarrhythmias. Prognostic significance. In 1978 Greene et al2 reported that within 1 year of follow-up, 15 of 19 patients with a positive RVR experienced ventricular tachycardia or sudden death, whereas only 4 of 29 patients without RVR developed ventricular tachycardia or sudden death. This study has been the only one that demonstrated a predictive value of the RVR for subsequent ventricular tachycardia or sudden death in patients after recent acute myocardial infarction. Later studies, in which a comparable stimulation protocol was used, could not substantiate these results.** ‘* Troup et a1.12studied 32 patients with documented ventricular tachycardia or fibrillation. The prevalence of the RVR in those surviving was 47 % and in those with sudden death 63% (NS). Mason,8 who studied 59 patients with recurrent ventricular tachycardia, was also not able to find a significant difference in the prevalence of sudden death in patients with and without repetitive beating. Similarly, in the present study, which yielded a mean follow-up duration of more than 2 years in 237 patients without previously documented ventricular tachycardia who were studied prospectively, there was no prognostic significance of the test. Although some patients received beta blockers or antiarrhythmic drugs, the distribution of these drugs among patients with and without a RVR was identical. Thus, it seems unlikely that a possible untoward prognostic significance of the RVR might have been obscured by these medications. Furthermore, the lack of predictive value cannot be explained by the fact that, in about one third of those patients with left ventricular contraction abnormalities (group lB), aortocoronary bypass grafting was performed during the follow-up period, which might have prevented sudden death as has been suggested previ0us1y.~~ However, aortocoronary bypass does not seem to have a salutary effect on ventricular arrhythmias.48*4p Furthermore, the low prevalence of the RVR in patients who previously had had malig-
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Evaluation
nant ventricular arrhythmias is noteworthy (Table I). Especially in this group of patients, one should be able tc elicit a RVR if it indeed could detect the risk of serious ventricular arrhythmias. However, the low prevalence of the RVR in this group of patients, which is in contrast to that of Greene et al.,’ is in accordance with the data of Mason et aLa Clinical implications. There is now considerable evidence that the RVR induced by single premature stimuli during a supraventricular rhythm is not able to differentiate between patients with or without documented ventricular tachycardia or patients with recent acute myocardial infarction. However, this study and others g*l*, 13,3*,3g have provided evidence that by a more extended stimulation protocol, which includes the application of single, and double premature stimuli during a basic ventricular drive at various cycle lengths, the sensitivity of the test can be greatly increased in patients with documented ventricular tachyarrhythmias. The only useful differentiation which was possible on the basis of single premature stimuli was between patients with normal or abnormal left ventricular function (Table I). However, this seems to be of minor clinical value. Introduction of two instead of one premature stimuli did not increase the differentiating potency of the test. Furthermore, this test does not have any prognostic significance as far as patients with chronic coronary artery disease are concerned. REFERENCES
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