Since their introduction in 1981, ventricular late potentials

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1 Sudden Cardiac Death After Coronary Artery Bypass Grafting Is Not Predicted by Signal- Averaged ECG Christoph Scharf, MD, Hermann Redecker, MD, Firat Duru, MD, Reto Candinas, MD, Hans Peter Brunner-La Rocca, MD, Andreas Gerber, MD, Osmund Bertel, MD, Marko I. Turina, MD, and Wolfgang Kiowski, MD Divisions of Cardiology and Cardiovascular Surgery, University Hospital, Zurich, and Division of Cardiology, Stadtspital Triemli, Zurich, Switzerland Background. Sudden cardiac death (SCD) is a major cause of death despite successful revascularization in patients with coronary artery disease. The signalaveraged ECG (SAECG) is a sensitive predictor of SCD and could be used in the screening strategy to select patients for prophylactic cardioverter implantation. Methods. The SAECG was recorded in 561 patients (mean age: years) within 10 days of coronary artery bypass grafting. Signal-averaged ECG was performed with a bandpass filtering of 40 to 250 Hz for more than 250 beats until a noise level of 0.6 V was achieved. All patients were followed for years after the procedure. Results. Preoperative angiographic ejection fraction was at least 60% in 393 patients (72%), 40% to 60% in 126 patients (23%), and 40% or less in 28 patients (5%). There were 34 deaths, 10 of which were SCD. Late potentials were found in a total of 150 patients (27%) and were equally frequent preoperatively and postoperatively and among patients with (30%) and without (27%) SCD. The only predictors for overall mortality were age and a reduced ejection fraction. Conclusions. Signal-averaged ECG did not predict prognosis in low-risk patients undergoing coronary artery bypass grafting. (Ann Thorac Surg 2001;72: ) 2001 by The Society of Thoracic Surgeons Accepted for publication July 30, Address reprint requests to Dr Scharf, Division of Cardiology, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland; christoph.scharf@dim.usz.ch. Since their introduction in 1981, ventricular late potentials (LPs), as registered from signal-averaged ECG (SAECG) recordings, have been used in risk stratification of patients at risk for sudden cardiac death (SCD) [1]. These potentials are low-amplitude, high-frequency signals at the terminal portion of the QRS complex and reflect delayed ventricular depolarizations, which can be visualized by signal averaging and bandpass filtering of the surface ECG [2]. Their presence may indicate an arrhythmic substrate for reentry, especially in patients with coronary artery disease (CAD) [3, 4]. Late potentials have been advocated as predictors of SCD after myocardial infarction, with a high sensitivity and high negative predictive values [3, 5]. Many reports, however, date from the prethrombolytic era, and the patency of the infarct artery may critically affect the genesis and prognostic value of LPs [6]. Thus, bypass grafting to the infarctrelated artery has been associated with a reduction of LPs in some patients [7]. In addition, LPs predict perioperative arrhythmic events, but their predictive value in long-term follow-up after coronary artery bypass grafting (CABG) has been studied only in small series without long-term follow-up [8, 9]. Implantable cardioverter defibrillators (ICD) have been shown to provide effective prevention of SCD. However, most cases of SCD occur in low-risk patients who have not been identified by such well-known factors as reduced ejection fraction or sustained ventricular tachycardia [10]. The SAECG, as a noninvasive test with high sensitivity and negative predictive value, could easily identify patients who would not profit from an ICD. A pathologic SAECG recording was used to include patients in a CABG Patch Trial, which demonstrated no benefit from a prophylactic ICD [11]. However, the prognostic value of SAECG in patients undergoing revascularization has not been evaluated either in a large number of patients or in unselected patients. Therefore, to define the sensitivity to be used in a screening strategy, the SAECG was routinely recorded preoperatively and postoperatively in patients undergoing CABG at our institution. End points of the study were SCD and all-cause mortality. Patients and Methods Signal averaging of real-time electrocardiograms was routinely performed in 561 patients (74 female, 487 male) within 10 days of CABG. Patients who died perioperatively were excluded from analysis. Further exclusion criteria were absence of sinus rhythm, intraventricular conduction delay (duration of the unfiltered QRS com by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (01)

2 Ann Thorac Surg SCHARF ET AL 2001;72: SIGNAL-AVERAGED ECG AS A PREDICTOR OF SCD 1547 Table 1. Characteristics of Survivors, Nonsurvivors and Patients With SCD Survivors (n 527) Dead (n 34) Difference (t-test) SCD (n 10) LPs preoperatively 96 5 a ns 3 a LPs postoperatively 80 4 a ( a one both) ns 1 a ( a one both) LPs neither pre- nor 385 (73%) 26 (76%) ns 7 (70%) postoperatively dqrs (ms) ns LAS40 (ms) ns RMS40 ( V) ns Age at operation (years) p Ejection fraction 40% 24 (5%) 4 (12%) ns 2 40% 60% 118 (23%) 8 (25%) ns 3 60% 372 (72%) 21 (65%) ns 4 No ventriculogram preoperatively RCA occluded 132 (25%) 11 (32%) p LAD occluded 97 (18%) 9 (26%) ns 2 LCX occluded 76 (14%) 6 (17%) p vessel disease 37 (7%) 4 (11%) ns 0 2-vessel disease 108 (20%) 5 (14%) ns 1 3-vessel disease 379 (72%) 25 (73%) ns 9 Number of grafts per patient ns 4 Arterial revascularization 462 (88%) 22 (64%) p Extracorporeal circulation (min) p Aortic cross-clamping time (min) ns Values are expressed as number of patients unless indicated otherwise. Age was the only predictor of overall survival, and a reduced ejection fraction was the only predictor of SCD on survival analysis (Cox regression). a One patient had both LPs preoperatively and postoperatively in the group of Dead and SCD Patients. dqrs QRS duration; LAD left anterior descending; LAS low amplitude signal; LCX left circumflex coronary artery; LPs late potentials; ns not significant; RMS40 root mean square of the terminal 40 ms of the QRS complex; SCD sudden cardiac death. plex of more than 120 milliseconds), and a noise level above 0.6 V during recording. According to the standards for time domain analysis [2], real-time recording was performed using a Marquette MAC 15 HiRes ECG recorder (Milwaukee, WI), as previously described [8]. The QRS signal in the three orthogonal Frank leads was filtered (40 to 250 Hz) and averaged for 250 beats or more, until a noise level of 0.6 V or less was achieved. Three parameters were calculated: filtered QRS duration (dqrs, ms), duration of the terminal low-amplitude signal lower than 40 V (LAS40, ms), and the root mean square of the terminal 40 ms of the QRS complex (RMS40, V). The presence of LPs was defined when two of the following three criteria were met: dqrs longer than 120 ms, LAS40 at least 38 msec, and RMS40 lower than 20 V. Medical records of all patients were reviewed for clinical and angiographic findings. Follow-up of patients was achieved by telephone calls to patients, their relatives, or family physicians. In the case of death, the exact circumstances for each case were obtained from relatives, family physicians, review of medical records in the case of hospitalization, or state death chart registry. The primary end point of the study was SCD, which was defined as witnessed instant death, death occurring after cardiac arrest due to ventricular fibrillation, or unwitnessed death without preceding symptoms of any underlying disease or specific etiology. Secondary end points were all-cause mortality and cardiac death including heart failure and myocardial infarction. Predictors for survival were assessed using Cox regression for continuous variables and Kaplan-Meier analysis for discontinuous variables. Differences in patient characteristics and SAECG were assessed using the paired t-test and the Wilcoxon rank-sum test as appropriate. Values are expressed as mean standard deviation. Calculations were made using a commercially available statistical package (SPSS 9.0 for Windows; SPSS, Inc, Chicago, IL). A p-value less than 0.05 was considered statistically significant. Results Baseline Characteristics Clinical and angiographic characteristics of 561 patients discharged after CABG are summarized in Tables 1 and 2. Of the 561 patients with SAECG recordings, 439 had a preoperative recording, 460 had a postoperative recording, and 338 had both. The remaining SAECG were missing or had to be exluded because of noise artifacts, duration of unfiltered QRS longer than 120 milliseconds,

3 1548 SCHARF ET AL Ann Thorac Surg SIGNAL-AVERAGED ECG AS A PREDICTOR OF SCD 2001;72: Table 2. Preoperatively and Postoperative Findings in Patients With and Without Late Potentials Patients With LPs Either Pre- or Postoperatively (n 150) Patients Without LPs (n 411) Difference (t-test) Age at operation yr yr Ejection fraction 40% 9 (6%) 19 (4.6%) ns 40% 60% 35 (23%) 91 (22.1%) ns 60% 102 (68%) 291 (70.8%) ns No major vessel occluded 63 (42%) 204 (49.6%) ns RCA occluded 48 (32%) 95 (23%) p 0.05 RAD occluded 19 (18%) 87 (21%) p 0.05 RCX occluded 31 (20%) 51 (12%) p vessel disease 8 (5.3%) 33 (8%) ns 2-vessel disease 30 (20%) 82 (20%) ns 3-vessel disease 111 (74%) 294 (72%) ns Arterial revascularization (LIMA used) 128 (85%) 356 (89%) ns Extracorporeal circulation time min 90 min 30.3 min ns Aortic cross-clamping time min min ns Years of follow-up yr yr ns Sudden cardiac death 3 (2%) 7 (1.7%) ns Cardiac death 3 (2%) 12 (2.9%) ns Noncardiac death 5 (3.3%) 14 (3.4%) ns Alive 142 (94.2%) 385 (93.7%) ns LIMA left internal mammary artery; LPs late potentials; ns not significant; RAD right anterior descending coronary artery; RCA right coronary artery; RCX right circumflex coronary artery. postoperative atrial fibrillation, or time delay in recording for more than 10 days after the operation. Late potentials were found in 150 patients (27%) either pre- or postoperatively. Of these, 35 patients had both preoperative and postoperative LPs, 38 had preoperatively positive and postoperatively negative LPs, 25 had only one preoperative SAECG available showing LPs, 22 had only one postoperative SAECG available showing LPs, and in 30 a previously normal SAECG showed LPs postoperatively (Table 3). Patients with LPs did not differ from patients without LPs with respect to most clinical and perioperative variables, except for type of vessel occluded (Table 2). Of note, the occurrence of LPs was not related to impaired left ventricular function, or to prolonged aortic cross-clamping or extracorporeal circulation time. The occurrence of LPs was not significantly influenced by the operation, but the minor changes of SAECG were statistically significant ( p Wilcoxon rank sum test) (Table 3). However, the shortening of dqrs ( ms) and LAS40 (1 11 ms), as well as the increase of RMS40 ( V) were too small to result in a change in the occurrence of LPs. Also, differences between preand postoperative recordings of SAECG parameters were not correlated with any clinical or perioperative parameters, including duration of aortic cross-clamping or extracorporeal circulation time. Nor were they related to outcome. Preoperative LPs were highly predictive of postoperative LPs (chi square 47, p 0.001). Long-Term Follow-up Follow-up was available for all 561 patients for a mean of years, resulting in a total of 3,085 patient-years of follow-up. Thirty-four patients (6.5%) died during Table 3. Preoperative and Postoperative Finding of SAECG SAECG (LPs) n SCD dqrs (ms) LAS40 (ms) RMS40 ( V) Pre Post Pre Post Pre Post All patients a a a Both negative Negative 3 positive Positive 3 negative Both positive a Statistically significant differences ( p Wilcoxon rank sum test) only for the first row with all patients. These differences were too small to account for any significant changes in the occurrence of LPs. dqrs QRS duration; LAS40 low amplitude signal 40; LPs late potentials; RMS40 root mean square of the terminal 40 ms of the QRS complex; SAECG signal-averaged ECG; SCD sudden cardiac death.

4 Ann Thorac Surg SCHARF ET AL 2001;72: SIGNAL-AVERAGED ECG AS A PREDICTOR OF SCD 1549 Table 4. SAECG in the Ten Patients With Sudden Cardiac Death Age/Sex Mode of Death Preoperative SAECG Postoperative SAECG dqrs LAS40 RMS40 dqrs LAS40 RMS40 65/Male SCD witnessed /Male SCD witnessed a a a 77/Male SCD, possible AMI /Male SCD witnessed /Male SCD witnessed /Male SCD witnessed b 58/Male SCD witnessed /Male SCD witnessed /Male SCD witnessed /Male VF documented in hospital a Censored because unfiltered QRS 123 ms. b Censored because atrial fibrillation occurred postoperatively. AMI acute myocardial infarction; dqrs QRS duration; LAS40 low amplitude signal 40; RMS40 root mean square of the terminal 40 ms of the QRS complex; SAECG signal-averaged ECG; SCD sudden cardiac death; VF ventricular fibrillation. follow-up, for an annual mortality of 1.2% after hospital discharge. Sudden cardiac death occurred in ten patients (29% of total mortality). The frequency of SCD was constant during follow-up, with two to three cases per year. The earliest SCD occurred 2 days after hospital discharge, after an uneventful postoperative course. Preoperatively, this patient (with LPs) had exercise-induced ventricular tachycardia lasting for 15 seconds, which means that ventricular arrhythmia was the likely cause of death. Clinical and angiographic characteristics of patients with SCD are summarized in Table 1. Perioperative myocardial infarction occurred in one patient. One patient underwent concurrent CABG and aortic valve replacement, and SCD occurred after 5 years. In three other patients not classified as SCD, ventricular arrhythmia could have been responsible for subsequent death: one patient died of worsening heart failure and pneumonia 3 months after documented ventricular fibrillation and successful cardiopulmonary resuscitation, and two other patients died in accidents. Acute myocardial infarction was responsible for five deaths (15%). Thus, fifteen of thirty-four patients died from cardiovascular causes (44%). Cancer accounted for ten deaths (29%), stroke for three, pneumonia for two, accidents for two, hepatic cirrhosis for one, and suicide for one. Predictors of SCD and Total Mortality The clinical, angiographic, perioperative, and electrocardiographic characteristics of survivors, nonsurvivors, and patients with SCD are outlined in Table 1. Individual values in SAECG of all patients with SCD are summarized in Table 4. Importantly, LPs were equally frequent in patients with and without SCD (30% vs 27%) and identified only three of ten patients with SCD (sensitivity 30%). Because the prevalence of SCD was low (1.8%), the negative predictive value of a normal SAECG was 98% (7 false-negative and 406 true-negative). However, 98% of LPs were false-positive (specificity 73%). Survival analysis did not show any significant relationship between LPs and SCD, cardiac death, or all-cause mortality. Neither preoperative nor postoperative LPs alone predicted SCD. There was an insignificant trend in the relationship of mean duration of filtered QRS complex to overall survival ( p 0.078), but not with SCD. Of 80 patients with postoperative LPs, only four died and only one of those died suddenly during follow-up. Although the presence and localization of an occluded vessel and the type of revascularization performed were statistically different (t-test) between survivors and nonsurvivors (Table 1), survival analysis using Cox regression identified only age (Wald 7.19, p 0.01) as a predictor of overall survival and a reduced ejection fraction (Wald 5.0, p 0.05) as a predictor of SCD. Aortic cross-clamping time and extracorporeal circulation duration did not correlate with survival or cardiac death, including SCD, in survival analysis. Comment In this study with over 3,000 patient-years of follow-up after CABG, overall mortality was low, ie, 1.2% per year. However, SCD was one of the most frequent causes of death, together with malignancy, and accounted for approximately 30% of total mortality. The incidence of SCD was stable during follow-up and occurred most often in patients without any risk factors. Most importantly, SAECG did not predict mortality or SCD after CABG. An abnormal SAECG with positive LPs was found in 26.7% of our patients, similar to previous results [6, 8] and was not related to such clinical or perioperative factors as left ventricular function, number of occluded coronary arteries, type of revascularization performed, or aortic crossclamping time. Only the type of occluded coronary was correlated with the frequency of LPs, which were more common in right coronary artery or right circumflex artery occlusion than in left anterior descending coronary artery occlusion. We studied unselected patients at low risk, only 5% of whom had an ejection fraction below 40%. Nevertheless, a reduced ejection fraction was the only predictor of SCD ( p 0.05), which agrees with other large-scale studies

5 1550 SCHARF ET AL Ann Thorac Surg SIGNAL-AVERAGED ECG AS A PREDICTOR OF SCD 2001;72: like MADIT [12], MUSTT [13], and CIDS [14], in which patients with a severely reduced ejection fraction profited most from ICD implantation. The effect of prophylactic ICD implantation in patients undergoing CABG was tested in a large multicenter CABG Patch Trial [11]. Patients with an abnormal SAECG and a reduced left ventricular ejection fraction less than 36% were randomly assigned to an ICD implantation group during CABG [11]. No benefit from ICD implantation was seen, and this was explained by the low incidence of arrhythmic death [15]. Our data suggest, however, that most patients with subsequent SCD presented with a normal SAECG and presumably were missed by the inclusion criteria. To date only one study including 100 patients with short follow-up assessed the prognostic role of SAECG in patients undergoing CABG, which confirms our results [9]. Our data appear to be in contrast to many previous reports demonstrating a prognostic role for SAECG in CAD patients. There is no ready explanation for this discrepancy. However, since the landmark study by Simson in 1981 [16] and numerous other studies [5, 17], remarkable progress in treatment of acute and chronic CAD has lowered cardiac mortality substantially. It is conceivable that thrombolysis and early revascularization after myocardial infarction, as well as widespread use of beta blockers, statins, and ACE inhibitors have changed patient characteristics and might render findings on SAECG less important for predicting survival and SCD, as compared in patients studied before such therapies became widespread. Although surgical revascularization did not influence the occurrence of LPs, there was a discrete but significant nonlinear effect on SAECG parameters. The clinical significance of these minor changes remains unknown. The changes in the occurrence of LPs between pre- and postoperative SAECG recordings are randomly occurring, without prognostic implication and the analysis of these subgroups should not lead to any conclusions in our opinion. To date, the effect of revascularization on SAECG has been demonstrated mainly in acute coronary occlusion, and reperfusion [18]. Results indicating abolition of LPs after CABG have been obtained in only a few selected patients and have not been replicated [7]. Another finding of our study is that the duration of extracorporeal circulation and aortic cross-clamping does not influence SAECG parameters or long-term prognosis. The longer extracorporeal circulation time in nonsurvivors was due to prolonged warming of a subgroup of significantly older patients; thus, it was not an independent predictor of prognosis. This finding may reassure thoracic surgeons and anesthesiologists in the current practice of extracorporeal circulation. Limitations of This Study A major limitation of clinical follow-up studies is the diagnosis of SCD. However, all but one of our SCD cases were witnessed, and no specific symptoms were noted before the event in any case. Acute myocardial infarction seems to be less frequent in survivors of out-of-hospital ventricular fibrillation [19, 20]. We did not include three patients, in whom death could be attributed to arrhythmia: two accidents and one death from pulmonary complications 3 months after initially successful cardiopulmonary resuscitation from ventricular fibrillation. Two of these patients had LPs. Even if these cases were included in the survival analysis, the presence or absence of LPs would not predict SCD ( p 0.78 on Cox regression), and the sensitivity would rise from 30% (3 of 10) to 38% (5 of 13) only. Another limitation of our study is the lack of information about concomitant medication during long term follow-up, which is known to influence prognosis. The definition of an abnormal SAECG was prospectively defined [2]. Even when applying the criteria of previous studies by Simson [16], Kuchar and associates [5], or Gomes and colleagues [17], only 4 of 10 patients would have positive LPs, increasing the sensitivity to 40% (Table 3). As we followed a low-risk population undergoing routine CABG, a low number of end points was reached which may lead to a type II error and could explain the discrepancy with other reports. Because most SCD cases occur in low-risk patients not identified by traditional risk factors, however, it was the aim of our study to assess the predictive value of SAECG in unselected patients undergoing revascularization at our institution. In conclusion, the SAECG was not useful to predict prognosis in unselected patients undergoing CABG, and it does not appear to be helpful in a screening strategy for ICD implantation. References 1. Breithardt G, Becker R, Seipel L, Abendroth RR, Ostermeyer J. 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