296 JACC Vol. 28, No. 2 August 1996:

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1 296 JACC Vl. 28, N. 2 August 1996: Distinctin Between Arrhythmic and Nnarrhythmic Death After Acute Mycardial Infarctin Based n Heart Rate Variability, Signal-Averaged Electrcardigram, Ventricular Arrhythmias and Left Ventricular Ejectin Fractin JUHA E. K. HARTIKAINEN, MD, PHD, MAREK MALIK, MD, PI-ID, FACC, ANNE STAUNTON, BSc, JAN POLONIECKI, PHD, A. JOHN CAMM, MD, FACC Lndn, England, United Kingdm Objectives. We investigated whether heart rate variability, the signal-averaged electrcardigram (ECG), ventricular arrhythmias and left ventricular ejectin fractin predict the mechanism f cardiac death after mycardial infarctin. Backgrund. Pstinfarctin risk stratificatin studies have almst exclusively fcused n predicting the risk f arrhythmic death. The factrs that identify and distinguish persns at risk fr arrhythmic and nnarrhythmic death are prly knwn. Methds. Heart rate variability, the signal-averaged ECG, ventricular arrhythmias and left ventricular ejectin fractin were assessed in 575 survivrs f acute mycardial infarctin. The patients were fllwed up fr 2 years; arrhythmic and nnarrhythmic cardiac deaths were used as clinical end pints. During the fllw-up perid, 47 cardiac deaths ccurred, 29 (62%) arrhythmic and 18 (38%) nnarrhythmic. Results. All risk factrs were assciated with cardiac mrtality in univariate analysis. With the exceptin f left ventricular ejectin fractin, they were als predictrs f arrhythmic death. Depressed heart rate variability (p < 0.001), ventricular ectpic beats (p < 0.001) and lw ejectin fractin (p < 0.001) were related t nnarrhythmic death. In multivariate analysis, depressed heart rate variability (p < 0.001) and runs f ventricular tachycardia (p < 0.05) predicted arrhythmic death. Nnarrhythmic death was assciated with depressed heart rate variability (p < 0.001), ventricular ectpic beats (p < 0.001) and lw ejectin fractin (p < 0.01). By selecting patients with depressed heart rate variability, lng filtered QRS duratin r ventricular arrhythmias and excluding patients with the lwest ejectin fractin, we identified a grup in which 75% f deaths were arrhythmic. Similarly, by selecting patients with a lw ejectin fractin and excluding patients with the lwest heart rate variability, we identified a grup in which 75% f deaths were nnarrhythmic. Cnclusins. Arrhythmic death was assciated predminantly with depressed heart rate variability and ventricular tachycardia runs, and nnarrhythmic death with lw ejectin fractin, yen. tricular ectpic beats and depressed heart rate variability. A cmbinatin f risk factrs identified patient grups in which a majrity f deaths were either arrhythmie r nnarrhythmic. (J Am Cll Cardi11996;28: ) In patients recvering frm acute mycardial infarctin, identificatin f thse at high risk f death is f great clinical imprtance. Great effrt has been made t identify high risk grups in which further investigatin and interventin are needed. Several methds such as determinatin f heart rate variability r barreflex sensitivity (1-5), the signal-averaged electrcardigram (ECG) (6-9), assessment f ventricular arrhythmias during 24-h ECG recrding (10-12) and evaluatin f left ventricular dysfunctin (12-14) have been shwn t predict pr utcme in patients recvering frm acute my- Frm the Department f Cardilgical Sciences, St. Gerge's Hspital, Medical Schl, Lndn, England, United Kingdm. This study was supprted in part by the British Heart Fundatin, Lndn and by a Fellwship f the Eurpean Sciety f Cardilgy, Rtterdam, The Netherlands. Manuscript received July 18, 1995; revised manuscript received March 26, 1996, accepted April 2, Address fr crrespndence: Dr. Marek Malik, Department f Cardilgical Sciences, St. Gerge's Hspital, Medical Schl, Lndn, England, United Kingdm. cardial infarctin. In particular, risk factrs determined with these techniques have been related t the risk f ventricular arrhythmias and f sudden death (15,16). In additin, patients at high risk ften have several risk factrs (2,3,17,18). Thus, the independent cntributin f varius risk factrs n cardiac mrtality are prly understd. Earlier studies almst exclusively investigated the predictin f cardiac r arrhythmic death. Only a very few studies have fcused n identifying patients with a high risk f specifically arrhythmic r nnarrhythmic death and n distinguishing between arrhythmic and nnarrhythmic death Althugh arrhythmic deaths accunt fr a great prprtin f cardiac deaths after mycardial infarctin, -40% f deaths are nnarrhythmic (14,19,20). Identificatin f patients at risk f death specifically by arrhythmic r nnarrhythmic mechanisms is f clinical imprtance, because these patients may benefit frm different mdes f treatment. Furthermre, when evaluating the effect f an interventin such as antiarrhythmic therapy in clinical trials, it wuld be useful t recruit patients

2 JACC Vl. 28, N. 2 HARTIKAINEN ET AL. 297 August 1996: ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH with a high risk f arrhythmic death and avid patients with a high likelihd f nnarrhythmic death. This study evaluated the relatin between data n heart rate variability, the signal-averaged ECG, ventricular arrhythmias during 24-h ECG recrding and left ventricular functin and the mechanism f cardiac death in survivrs f acute mycardial infarctin. Specifically, we investigated whether cmbinatins f such data culd be used t identify selectively patients with a high likelihd f arrhythmic r nnarrhythmic death. Methds Patients. The study grup cnsisted f 575 patients aged <75 years admitted t St. Gerge's Hspital because f acute mycardial infarctin. Acute mycardial infarctin was diagnsed as described previusly (21). Frm the cnsecutive patients, we excluded thse with valvular heart disease, a permanent pacemaker, diabetes mellitus, atrial fibrillatin r left bundle branch blck and thse wh were unable t be fllwed up. Study prtcl. Befre hspital discharge, patients underwent a standard investigatin prtcl including 24-h ECG recrding, assessment f cardiac systlic functin, signalaveraged ECG and exercise testing. Patients with a psitive exercise test respnse were referred fr cardiac catheterizatin and thse with a negative respnse underwent assessment f left ventricular systlic functin by radinuclide scanning. Patients gave written, infrmed cnsent t participate in the study and the prtcl was apprved by the lcal Ethics Cmmittee. Heart rate variability. The 24-h ambulatry ECG recrding was perfrmed by using a tw-channel recrder (either Reynlds Medical r Marquette Electrnics), recrding standard leads II and CM 5. Treatment with beta-adrenergic blcking agents was interrupted ->48 h befre the recrding. All recrdings were analyzed by using the Marquette Laser Hlter system 8000, and manual editing f RR intervals and QRS cnfiguratin was used. Heart rate variability was calculated by using the triangular index methd described elsewhere (4). Heart rate variability values were dichtmized at 20 U (21). Signal-averaged ECG. The signal-averaged ECG was analyzed with an ART 1200 EXP device (Arrhythmia Research Technlgy). The high pass filter was set at 40 Hz, and a mean f 234 cardiac betas were averaged t achieve a target standard deviatin nise level f <0.3 ~V as checked at the time f recrding. Results f the signal-averaged ECG were cnsidered psitive if tw f three f Simsn's criteria (22) were met: filtered QRS cmplex > 120 ms; rt-mean-square vltage <25 /~V during the last 40 ms f the filtered QRS cmplex; duratin f the filtered QRS cmplex >40 ms after the vltage decreased t <40 tzv. Ventricular arrhythmias during 24-h ambulatry ECG recrding. The 24-h ECG recrdings were visually checked fr arrhythmia recgnitin. The number f ventricular ectpic beats during each hur was assessed and the mean value calculated. A rate f ventricular ectpic beats >10/h was cnsidered abnrmal (12). The presence f nnsustained runs f ventricular tacbycardia was als examined. A run f ventricular tachycardia was defined as mre than three cnsecutive ventricular ectpic beats with a cycle length <600 ms. Left ventricular ejectin fractin. In patients wh had crnary angigraphy and left ventricular catheterizatin befre discharge, left ventricular ejectin fractin was calculated frm left ventricular ventriculgraphic silhuettes in the right anterir blique view (23). In patients wh did nt underg cardiac catheterizatin, ejectin fractin was determined frm radinuclide angigrams recrded in the supine psitin with use f a left anterir blique view. Ejectin fractin was then calculated by the multiple-gated methd (14). Values fr ejectin fractin were dichtmized at 40% (12). Fllw-up. Patients were fllwed up in ur utpatient clinic at 2, 6 and 12 mnths after infarctin and thereafter annually fr a minimal perid f 2 years (range 24 t 76 mnths). Ttal cardiac mrtality and arrhythmic and nnarrhythmic cardiac deaths were used as majr end pints. The mde f death was classified accrding t the criteria f the Cardiac Arrhythmia Suppressin Trial (CAST) (19,24). Arrhythmic death was defined as a sudden death, that is, 1) instantaneus death within 1 h f the nset f symptms in a patient withut evidence f the presence f ischemia r prgressive heart failure, r 2) death during sleep. An unwitnessed death in a patient wh had a dcumented histry f a sustained mnmrphic ventricular tachycardia after the index mycardial infarctin was als cnsidered an arrhythmic death. All ther cardiac deaths were cnsidered nnarrhythmic. Statistical analysis. Cmparisns between different grups were made by using the Student t test, and ne-way analysis f variance fr cntinuus variables and the chi-square test fr categric variables. The effect f heart rate variability, the signal-averaged ECG, ventricular ectpic beats, runs f ventricular tachycardia and left ventricular ejectin fractin n cardiac mrtality was studied with univariate and multivariate lgistic regressin analysis. A frward stepwise mdel with a PIN (p value fr entry) value f 0.05 was used. The remval f variables was based n the Wald statistics. T stratify 20% f the ttal patient grup with the highest prpensity fr arrhythmic death, we first excluded patients with the lwest 5th, 10th, 15th, 20th, 25th and 30th percentile f left ventricular ejectin fractin; frm the remaining patients we selected the grup with the lwest 20th percentile f heart rate variability. The analysis was repeated in a similar way but replacing heart rate variability in turns with the highest 20th percentile f the signal-averaged ECG, ventricular ectpic beats and runs f ventricular tachycardia. In these analyses, the signal-averaged ECG, ventricular ectpic beats and ventricular tachycardia were cnverted t cntinuus variables by means f duratin f the filtered QRS cmplex, average number f ventricular ectpic beats/h and the maximal number f cnsecutive ventricular ectpic beats during the 24-h ECG recrding, respectively. T identify patients at high risk f nnarrhythmic death we

3 298 HARTIKAINEN ET AL. JACC Vl. 28, N. 2 ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH August 1996: Table 1. Risk Factrs and Clinical Outcme During 2-Year Fllw-Up in Patients With Mycardial Infarctin Survivrs Arrhythmic Death Nnarrhythmic Death (n = 520) (n - 29) (n = 18) HRV (U) _+ 10.4" 19.0 _+ 14.4" SAECG (ps) 21.3% 42.9%]" 36.4% VE (>10/h) 14.5% 33.3%:~ 61.1%* VT (ps) 12.3% 29.6%~: 22.2% LVEF (%) 48.8 _ _+ 16.0:~ 33.8 _+ 16.4' *, ~, ~: - p < 0.001, p < 0.01 r p < 0.05, respectively, versus survivrs. Data presented are mean value _+ SD r percent f patients. HRV = heart rate variability index; LVEF = left ventricular ejectin fractin; ps = psitive findings; SAECG = signal-averaged electrcardigram; VE = ventricular ectpic beats; VT - runs f ventricular tachycardia during 24-b electrcardigraphic recrding. excluded first patients with the lwest 5th, 10th, 15th, 20th, 25th and 30th percentiles f heart rate variability, and frm the remaining patient grup we selected patients with the lwest 20th percentile f left ventricular ejectin fractin. The same analysis was repeated by replacing heart rate variability with the highest 5th, 10th, 15th, 20th, 25th and 30th percentiles f the signal-averaged ECG, ventricular ectpic beats and runs f ventricular tachycardia. Finally, we evaluated the distinctin between arrhythmic and nnarrhythmic mrtality when 10%, 15%, 20%, 25% and 30% f the ttal patient grup was stratified by means f cmbinatins f heart rate variability and left ventricular ejectin fractin. All data are expressed as mean value +_SD unless therwise indicated. A p value < 0.05 was cnsidered statistically significant. An SPSS package (versin 5.0.1) was used fr statistical analysis. Results Clinical characteristics f patients. The mean age f the patients n hspital admissin was years (range 25 t 75); 455 (79%) were men. A Q wave mycardial infarctin was present in 402 patients (70%), an anterir infarctin in 268 (47%); thrmblytie therapy was given t 311 patients (54%). A histry f previus mycardial infarctin was given by 91 patients (16%). At the time f discharge, beta-blcker therapy was prescribed in 228 patients (40%). Mrtality during fllw-up. Fifty-five patients (9.6%) died during the 2-year fllw-up perid. Eight deaths had nncardiac causes. Thus, there were 47 deaths (8.2%) f cardiac rigin; 29 (62%) classified as arrhythmic and 18 (38%) as nnarrhythmic. Univariate determinants f cardiac mrtality. Heart rate variability. The mean heart rate variability befre discharge averaged 27.5 _ U (range 2.3 t 71.5). Depressed heart rate variability was fund in 145 patients (25% f the ttal patient grup). Patients with arrhythmic r nnarrhythmic death had lwer heart rate variability than did survivrs (p < fr bth, Table 1). Heart rate variability did nt differ between patients with arrhythmic r nnarrhythmic death. Table 2. Univariate Predictrs f Cardiac Arrhythmic and Nnarrhythmic Mrtality After Mycardial Infarctin Mrtality Cardiac Arrhythmic Nnarrhythmic HRV >20 U 8.8 ( )* 7.5 ( )* 8.5 ( )* SAECG (ps) 2.4 ( )] 2.6 ( )t 2.0 ( ) VE (>10/h) 4.9 ( )* 2.5 ( )t 8.2 ( )* VT (ps) 2.6 ( ):~ 2.9 ( )t 1.9 ( ) LVEF <40% 3.0 ( )* 1.8 ( ) 6.1 ( )* *, t, ~, = P < 0.001, p < 0.01, p < 0.05 r p - NS, respectively. Data presented are relative risk (95% cnfidence interval). Abbreviatins as in Table 1. In univariate lgistic regressin analysis, heart rate variability was inversely assciated with ttal cardiac mrtality (p < 0.001) and arrhythmic (p < 0.001) and nnarrbythmic (p < 0.001) death. Crrespndingly, the rate f ttal cardiac mrtality (p < 0.001), arrhythmic death (p < 0.001) and nnarrhythmic death (p < 0.001) was higher in patients with lw than in thse with nrmal heart rate variability (Table 2). Signal-averaged ECG. A signal-averaged ECG recrding was available fr 358 patients and findings were psitive in 82 (23%). Table 1 demnstrates that signal-averaged ECG results were psitive in 43% f patients with an arrhythmic death but in nly 21% f survivrs (p < 0.05). The prprtin f psitive signal-averaged ECG results in patients with nnarrhythmic death (36%) did nt differ frm that in survivrs. In a univariate lgistic regressin analysis, psitive findings n the signal-averaged ECG were a predictr f ttal cardiac mrtality (p < 0.05) and arrhythmic death (p < 0.001) but nt f nnarrhythmic death. Finally, psitive signal-averaged ECG findings were assciated with an increased risk f bth ttal cardiac deaths (p < 0.05) and arrhythmic death (p < 0.05) (Table 2). Ventricular arrhythmias. Analysis f the 24-h ECG recrdings revealed frequent ventricular ectpic beats in 96 patients (17.6%) and nnsustained ventricular tachycardia runs in 74 (13.5%). Of patients wh had an arrhythmic death, 33% had ventricular ectpic beats and 30% had runs f ventricular tachycardia befre hspital discharge, in cntrast t 14.5% and 12.3% f survivrs, respectively (p < 0.01 fr bth, Table 1). In additin, a majrity (61%) f patients with nnarrhythmic death had ventricular ectpic beats during the ambulatry ECG recrding (Table 1). In a univariate regressin analysis the presence f frequent ventricular ectpic beats was related t ttal cardiac mrtality (p < 0.001) and arrhythmic (p < 0.05) and nnarrhythmic (p < 0.001) death. Crrespndingly, patients with ventricular ectpic beats had an increased risk f ttal cardiac (p < 0.001), arrhythmic (p < 0.05) and nnarrhythmic (p < 0.001) mrtality (Table 2). Runs f ventricular tachycardia als predicted the develpment f cardiac death (p < 0.01) and arrhythmic death (p < 0.05), but they did nt predict nnarrhythmic death.

4 JACC VL 28, N. 2 HARTIKAINEN ET AL. 299 August 1996: ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH Table 3. Distributin f Risk Factrs in Patients at the Time f Hspital Discharge After Acute Mycardial Infarctin HRV SAECG VE VT LVEF (<20U) (ps) (>10/11) (ps) (<40%) HRV (<20 U) (n = 145) 33% 25% 13% 50% SAECG (ps) (n = 82) 37% 28% 17% 39% VE (>10/h) (n = 96) 35% 39% 40% 51% VT (ps) (n = 74) 23% 31% 51% 46% LVEF (<40%) (n = 181) 40% 25% 28% 19% Abbreviatins as in Table 1. Left ventricular ejectin fractin. The mean left ventricular ejectin fractin was 47.8 _+ 14.9% (range 9.0% t 87.0%) befre hspital discharge. Depressed left ventricular functin was fund in 181 patients (31%). Ejectin fractin was lwer in patients with arrhythmic r nnarrhythmic death than in survivrs (p < 0.01 and p < 0.001, respectively) but did nt differ between patients with arrhythmic r nnarrhythmic death (Table 1). In the univariate lgistic regressin analysis, depressed left ventricular ejectin fractin predicted ttal cardiac (p < 0.001), arrhythmic (p < 0.05) and nnarrhythmic (p < 0.001) mrtality. Crrespndingly, patients with a lw ejectin fractin had a higher rate f ttal cardiac mrtality (p < 0.001) and nnarrhythmic death (p < 0.001) than did patients with a nrmal ejectin fractin. They als tended t have a higher rate f arrhythmic death than patients with nrmal ejectin fractin, (p = NS) (Table 2). Multivariate determinants f cardiac mrtality. Table 3 shws the distributin f risk factrs in ur patient grup. A ttal f 242 patients (42%) had n risk factrs, 177 (31%) had ne risk factr and 160 (28%) had tw r mre risk factrs. By using the multivariate lgistic regressin analysis, we fund that depressed heart rate variability (p < 0.001), lw left ventricular ejectin fractin (p < 0.05), ventricular ectpic beats (p < 0.05) and age (p < 0.05) were determinants f ttal cardiac mrtality. Depressed heart rate variability (p < 0.001) and the presence f runs f ventricular tachycardia (p < 0.05) were the nly predictrs f arrhythmic death. Finally, depressed heart rate variability (p < 0.001), ventricular ectpic beats (p < 0.001), lw left ventricular ejectin fractin (p < 0.01), female gender (p < 0.05) and previus mycardial infarctin (p < 0.05) were related t nnarrhythmic death. Cmbinatin f risk factrs and the mechanism f cardiac death. We studied the use f a cmbinatin f tw risk factrs in predicting the mechanism f death. On the basis f univariate and multivariate analyses, the ther risk factr represented prpensity f ventricular arrhythmias: depressed heart rate variability (trigger f arrhythmias), signal-averaged ECG (substrate f arrhythmias), presence f ventricular ectpic beats r ventricular tachycardia runs (dcumentatin f arrhythmias). The secnd risk factr was left ventricular ejectin fractin, that is, a risk factr describing left ventricular dysfunctin. Finally, we analyzed cmbinatins f heart rate variability with ventricular ectpic beats and runs f ventricular tachycardia. Figure la illustrates that depressed heart rate variability was related t ttal cardiac and arrhythmic mrtality in patients with a nrmal (p < fr bth) r lw (p < fr bth) left ventricular ejectin fractin. In additin, in Figure 1. Cmbinatin f tw risk factrs and cardiac mrtality during 2-year fllw-up after mycardial infarctin. The slid bars illustrate arrhythmic mrtality and the pen bars nnarrhythmic mrtality; the cumulative height f the bars illustrates ttal cardiac mrtality. Symbls abve the slid bars indicate significance related t 50 4O 3O "C 20 arrhythmic mrtality and symbls abve the pen bars significance related t nnarrhythmic mrtality. *p < 0.05, **p < 0.01, ***p < versus the grup with n risk factrs (Nne). #p < 0.05, ##p < 0.01, ###p < versus the grup with 50 lw left ventricular ejectin fractin (LVEF) (a t d), versus the grup with frequent ventricular 40 ectpic beats (VE) (e) and versus the grup with ~" runs fventricular tachycardia (VT) (f). +p < 0.05, ~ p < versus the grup with depressed heart rate variability (HRV) (e and f). SAECG = 20 psitive findings n the signal-averaged electrcar- = digram (a) *** 1 I(d) Nne LVEF HRV Bth Risk factrs ** (b) Nne LVEFSAECGBth (e) Risk factrs ~f (c) Nne LVEF VE Bth Risk factrs (fl Nne LVEF VT Bth Nne VE HRV Bth Nne VT HRV Bth Risk factrs Risk factrs Risk factrs

5 300 HARTIKAINEN ET AL. JACC Vl. 28, N. 2 ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH August 1996: v Q 80 '~ 60._~ 40 (3_ 20 0 E 10 >, 20 E a c~ b/ 40 g, 5O I I I I I I I , LVEF percentiles excluded LVEF percentiles excluded LVEF percentiles excluded I I I I i I I LVEF percentiles excluded Figure 2. Identificatin f patients with arrhythmic death (AD). First, patients in the lwest 5th, 10th, 15th, 20th, 25th and 30th percentiles fr left ventricular ejectin fractin (LVEF) were excluded (X axis). Then, frm the remaining grup, patients in the lwest 20th percentile f heart rate variability (HRV) (a), highest 20th percentile f filtered QRS cmplex duratin (TQRS) (b), ventricular ectpic beats (VE) (c) and ventricular tachycardia (VT) (d) were selected. The prprtin f arrhythmic deaths is indicated n the Y axis f the upper panel (slid bars) and the crrespnding ttal cardiac mrtality n the Y axis f the lwer panel (pen bars). patients with a nrmal ejectin fractin, depressed heart rate variability was assciated with nnarrhythmic death (p < 0.001). A lw ejectin fractin had a significant impact n ttal cardiac (p < 0.05) and nnarrhythmic mrtality (p < 0.001) but nly in patients with nrmal heart rate variability. Ejectin fractin was nt a significant determinant f any mde f cardiac death in patients with depressed heart rate variability. The signal-averaged ECG was related t ttal cardiac (p < 0.05) and nnarrhythmic mrtality (p < 0.05) in patients with a nrmal left ventricular ejectin fractin (Fig. lb). The cmbinatin f a psitive signal-averaged ECG and a lw ejectin fractin was a predictr f arrhythmic death (p < 0.05). A lw ejectin fractin was assciated with ttal cardiac (p < 0.01) and nnarrhythmic mrtality (p < 0.01) in patients with negative signal-averaged ECG findings. Frequent ventricular ectpic beats increased the risk f ttal cardiac mrtality in patients with a nrmal (p < 0.01) r lw (p < 0.001) left ventricular ejectin fractin. This increased risk was predminantly due t an increased risk f nnarrhythmic death (p < 0.01 fr patients with a nrmal r lw ejectin fractin, Fig. lc). The cmbinatin f frequent ventricular ectpic beats and a lw ejectin fractin greatly increased the risk f nnarrhythmic death. Tgether with a lw left ventricular ejectin fractin, ventricular ectpic beats als were assciated with arrhythmic death (p < 0.01). The presence f runs f ventricular tachycardia was a predictr f ttal cardiac mrtality in patients with a nrmal left ventricular ejectin fractin (p < 0.05). Their presence was related t arrhythmic death in patients with a lw ejectin fractin (p < 0.05) but nt in patients with a nrmal ejectin fractin (Fig. ld). Als in this analysis, a lw ejectin fractin was assciated with nnarrhythmic death (p < 0.001). When evaluating the cmbinatin f ventricular ectpic beats and heart rate variability, we fund that depressed heart rate variability was assciated with arrhythmic death in patients with (p < 0.001) and withut (p < 0.05) frequent ventricular ectpic beats (Fig. le). Ventricular ectpic beats were related t nnarrhythmic death in patients with a nrmal (p < 0.01) r depressed (p < 0.01) heart rate variability. Particularly, the cmbinatin f depressed heart rate variability and frequent ventricular ectpic beats resulted in a very marked increase in ttal cardiac (41%, p < 0.001) and nnarrhythmic (24%, p < 0.01) mrtality. Figure if demnstrates that depressed heart rate variability was related t arrhythmic but als t nnarrhythmic death. In patients with depressed heart rate variability, runs f ventricular tachycardia were assciated with arrhythmic death (p < 0.05). The cmbinatin f runs f ventricular tachycardia and depressed heart rate variability was the mst pwerful predictr f cardiac death (ttal cardiac mrtality 47%). This pwer was predminantly due t an increased risk f arrhythmic death (arrhythmic mrtality 29%, p < 0.001) but als f nnarrhythmic death (nnarrhythmic mrtality 18%, p < 0.001). Identificatin f patients with arrhythmic r nnarrhythmic death. We attempted t stratify 20% f the ttal patient grup with a high prpensity fr either arrhythmic r nnarrhythmic death. When excluding patients with the lwest ejectin fractin (i. e., patients at risk f nnarrhythmic death) and selecting patients with the lwest 20th percentile f heart rate variability, highest 20th percentile f filtered QRS cmplex duratin, ventricular ectpic beats r ventricular tachycardias, the prprtin f patients with arrhythmic death increased. In all cmbinatins, the highest prprtin f patients with arrhythmic death (71% t 75%) was stratified when we mitted patients belnging t the lwest 20th t 30th percentiles f ejectin fractin (Fig. 2, a t d, upper panel). At

6 JACC Vl. 28, N. 2 HARTIKAINEN ET AL. 301 August 1996: ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH 100 ~ 8 z 6O ~, 4 ~_ 20 0 >, 10 e 20 ~ 3 ~ 40 5() i I I I I I I I [ I I I I I I I I I I I I I I ~ I [ I I , HRV percentiles excluded TQRS percent;les excluded VE percentiles excluded VT percentiles excluded the peak prprtin f arrhythmic deaths, the ttal cardiac mrtality rates were 17%, 9%, 9% and 9%, respectively, fr heart rate variability, filtered QRS-cmplex duratin, ventricular ectpic beats and ventricular tachycardia runs (Fig. 2, a t d, lwer panel). Crrespndingly, by selecting patients with the lwest 20th percentile f left ventricular ejectin fractin and excluding patients with the lwest heart rate variability, the prprtin f patients with nnarrbythmic death increased, whereas the prprtin f patients with an arrhythmic death decreased. The peak prprtin f patients with nnarrhythmic death (75%) was achieved when patients with the lwest 20th percentile f heart rate variability were excluded (Fig. 3a, upper panel). Hwever, mitting patients with depressed heart rate variability decreased ttal cardiac mrtality. Thus, with the peak stratificatin f nnarrhythmic death, ttal cardiac mrtality was 7% (Fig. 3a, lwer panel). In cntrast, exclusin f patients with the highest ttal duratin f QRS cmplex, a high number f ventricular ectpic beats and lng runs f nnsustained ventricular tachycardia did nt imprve the identificatin f risk f nnarrhythmic death ver that btained with left ventricular ejectin fractin alne (Fig. 3, b t d, upper panel). Finally, we studied further the distinctin between arrhythmic and nnarrhythmic death. Because in the preceding analyses the cmbinatins f heart rate variability and left ventricular ejectin fractin prvided the best distinctin between arrhythmic and nnarrhythmic death, we repeated the stratificatin using these variables t select 10%, 15%, 20%, 25% and 30% f the patient grup. We fund that irrespective f the selected prprtin f patients, the peak f arrhythmic mrtality (up t 75% f cardiac deaths) was reached when the lwest 20th t 25th percentiles f left ventricular ejectin fractin were excluded (Fig. 4a). Excluding patients with a lw ejectin fractin reduces ttal cardiac mrtality. Nevertheless, excluding patients with the lwest 20th percentile f ejectin fractin and selecting patients in the lwest 10th and 15th Figure 3. Identificatin f patients with nnarrhythmic death (NAD). First, patients in the lwest 5th, 10th, 15th, 20th, 25th and 30th percentiles fr heart rate variability (HRV) were excluded (a). Then, frm the remaining grup, patients in the lwest 20th percentile fr left ventricular ejectin fractin (LVEF) were selected. The same stratificatin was repeated but excluding the highest 5th, 10th, 15th, 20th, 25th and 30th percentiles f filtered QRS cmplex duratin (TQRS) (b), ventricular ectpic beats (VE) (c) and runs f ventricular tachycardia (VT) (d) and then selecting frm the remaining patients a grup in the lwest 20th percentile fr left ventricular ejectin fractin. The prprtin f nnarrhythmic deaths is indicated n the Y axis f the upper panel (slid bars) and crrespnding ttal cardiac mrtality n the Y axis f the lwer panel (pen bars). percentile heart rate variability grups, ttal cardiac mrtality remained >20% and arrhythmic mrtality >17% (Fig. 4b). Crrespndingly, the peak f nnarrhythmic mrtality (up t 75% f cardiac deaths) was bserved when the lwest 20th percentile f heart rate variability was excluded, and the grups with the lwest 15th r 20th percentile f ejectin fractin were selected frm the remaining patients (Fig. 5a). Hwever, mitting patients with depressed heart rate variability significantly decreased cardiac mrtality. Thus, at the peak stratificatin f nnarrhythmic death, the ttal cardiac mrtality rate was 9% and nnarrhythmic mrtality rate 6.9% (Fig. 5b). Discussin Predictin f the mechanism f cardiac death. Increasing attentin has been fcused n risk stratificatin studies t identify patients at high risk after acute mycardial infarctin. Almst exclusively these studies have attempted t identify patients wh are at high risk fr sudden r arrhythmic death. Althugh sudden death and arrhythmias are respnsible fr a large prprtin f deaths after mycardial infarctin, identificatin f patients at risk f nnarrhythmic death wuld be f clinical imprtance. In this study we demnstrated that estab-

7 302 HARTIKAINEN ET AL. JACC Vl. 28, N. 2 ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH August 1996: / P, i 45- _ 35-5 ~R V _VEF percentiles 5 tiles selected g,21 H 5 ii : b Figure 4. Identificatin f patients with a high risk fr arrhythmic death. First, patients in the lwest 5th, 10th, 15th, 20th, 25th and 30th percentiles fr left ventricular ejectin fractin (LVEF) (X axis) were excluded. Frm the remaining grup, patients in the lwest 10th, 15th, 20th, 25th and 30th percentiles fr heart rate variability (HRV) were selected, a, The Y axis illustrates the prprtin f arrhythmic deaths (AD). b, The Y axis dentes abslute arrhythmic mrtality using the same stratificatin as in panel a. R g22gt s,5 20 LVEF percentiles 25 selected b HRV percentiles 30 excluded Figure 5. Identificatin f patients with a high risk fr nnarrhythmic deaths (NAD). First, patients in the lwest 5th, 10th, 15th, 20th, 25th and 30th percentiles fr heart rate variability (HRV) (X axis) were excluded. Frm the remaining grup, patients in the lwest 10th, 15th, 20th, 25th and 30th percentiles fr left ventricular ejectin fractin (LVEF) were selected, a, The Y axis illustrates the prprtin f nnarrhythmic deaths, b, The Y axis dentes abslute nnarrhythmic mrtality using the same stratificatin as in panel a. lished risk factrs, such as depressed heart rate variability, psitive signal-averaged ECG findings, ventricular arrhythmias during ambulatry ECG recrding and lw left ventricular ejectin fractin, can prvide different and supplementary infrmatin abut the mechanism f death after mycardial infarctin and that these risk factrs can be cmbined t differentiate patients at risk f either arrhythmic r nnarrhythmic death. In the univariate analysis, all the analyzed risk factrs were significant predictrs f cardiac mrtality. With the exceptin f lw left ventricular ejectin fractin, all the ther risk factrs were assciated with arrhythmic death. In fact, analyzed as a cntinuus variable, ejectin fractin als was a significant predictr f arrhythmic death. In this respect ur results are in agreement with thse f previus studies (1-8,10-14). Accrding t previus studies (2,3,6,11,17,18), a great prprtin f patients have mre than ne risk factr after infarctin. In ur study, 28% f patients had at least tw risk factrs at the time f hspital discharge. Thus, the risk related t ne risk factr is influenced by the cncmitant presence f ther risk factrs. Cnsequently, the independent cntributin f the risk factrs t the mechanisms f death cannt be assessed withut a multivariate apprach. Arrhythmic death. The multivariate analysis clearly revealed that depressed lw heart rate variability was an independent predictr f arrhythmic death. This was true fr patients with either a lw r a nrmal ejectin fractin. This finding is in accrd with previus studies, in which depressed heart rate variability predicted inducibility f ventricular tachycardia during prgrammed ventricular stimulatin (17) and

8 JACC Vl. 28, N. 2 HARTIKA1NEN ET AL. 303 August 1996: ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH arrhythmic death during fllw-up (1,2,17,19). In additin, runs f ventricular tachycardia during the 24-h ECG recrding were related t arrhythmic death, a finding als in accrd with earlier studies (10-12). In fact, the risk fr arrhythmic death was highest (29%) in patients with bth depressed heart rate variability and runs f ventricular tachycardia. Althugh there was a tendency t an increased prpensity fr arrhythmic death in patients with psitive findings n the signal-averaged ECG, frequent ventricular ectpic beats and lw left ventricular ejectin fractin, in multivariate analysis these did nt reach the level f statistical significance. In this respect ur results may seem t cntradict earlier studies (8,10-12). In a large multicenter study (14), lw left ventricular ejectin fractin was related t bth ttal cardiac and arrhythmic mrtality. In anther study (13), lw ejectin fractin was the best nninvasive predictr f ventricular tachycardia and sudden death in pstinfarctin patients. In thse studies, hwever, the impact f heart rate variability was nt analyzed. As we demnstrated, a great prprtin f pstinfarctin patients with psitive findings n the signal-averaged ECG, ventricular ectpic beats r lw ejectin fractin als have depressed heart rate variability. Thus, the independent cntributin f risk cannt be assessed withut evaluating all factrs simultaneusly. Indeed, als in ur study when using the univariate apprach, the signal-averaged ECG, ventricular ectpic beats and ejectin fractin were related t arrhythmic death. This finding clearly highlights a significant interactin amng different risk factrs, a cnditin that cmplicates risk stratificatin in pstinfarctin patients. Nnarrhythmic death. Lw left ventricular ejectin fractin, depressed heart rate variability and ventricular ectpic beats were the nly predictrs f nnarrhythmic death. Figure 1 shws that lw ejectin fractin was assciated with nnarrhythmic death, particularly in patients withut depressed heart rate variability. Ventricular ectpic beats and, particularly, the cmbinatin f lw ejectin fractin and frequent ventricular ectpic beats turned ut t be very pwerful predictrs f nnarrhythmic death. Lw ejectin fractin was fund in 72% and frequent ventricular ectpic beats in 61% f patients wh had a nnarrhythmic death. In cntrast t sme earlier studies (10-12), the presence f frequent ventricular ectpic beats was nt assciated with risk f arrhythmias but was indicative f left ventricular dysfunctin. Hwever, in the earlier studies multivariate analysis including heart rate variability was nt applied. Thus, it seems that ventricular ectpic beats and runs f ventricular tachycardia prvide different infrmatin abut the mechanism f death. Nnarrhythmic death was als related t depressed heart rate variability, which was identified in 72% f patients with nnarrhythmic death. Patients with the cmbinatin f depressed heart rate variability and frequent ventricular ectpic beats had the highest risk (24%) fr nnarrhythmic death. It seems that sme patients at risk f nnarrhythmic death can be identified by a lw left ventricular ejectin fractin. Hwever, sme patients with subsequent nnarrhythmic death present with abnrmal cardivascular regulatin that cannt be detected by means f impaired cardiac systlic functin but becmes manifest as depressed heart rate variability r frequent ventricular ectpic beats. Distinctin between arrhythmic and nnarrhythmic death. Frm a clinical pint f view it is imprtant t identify pstinfarctin patients wh are at high risk f death. In additin, it wuld be f imprtance t predict the mechanism f death, because this might influence the treatment strategy. Patients with a high prpensity fr arrhythmic death may benefit frm antiarrhythmic therapy r interventin, whereas such treatment may prvide n benefit r even increase the risk f mrtality in patients wh are likely t die f a nnarrhythmic mechanism. An imprtant implicatin f ur study is that cmbined infrmatin f risk factrs can be used t identify patient grups with a substantially high ttal cardiac mrtality rate and a high prprtin f either arrhythmic r nnarrhythmic deaths. By selecting patients with a high risk f arrhythmic death (depressed heart rate variability) and deselecting patients with a high risk f nnarrhythmic death (lw ejectin fractin), we were able t identify a patient grup in which 75% f deaths were arrbythmic. Similarly, by selecting patients with the lwest ejectin fractin and mitting patients with the lwest heart rate variability we were able t define a patient grup having 75% f deaths due t nnarrhythmic mechanism. Methdlgic cnsideratins. The classificatin f deaths as arrhythmic r nnarrhythmic is f crucial imprtance in ur study. The Cardiac Arrhythmia Pilt Study (CAPS) investigatrs (19) have clearly shwn the difficulties related t the classificatin f the primary mechanism f death after mycardial infarctin. Mst imprtant, they cncluded that sudden death is nt necessarily equivalent t arrhythmic death. In the CAPS study, 55% f deaths were classified as arrhythmic, a prprtin in clse agreement with the 62% f arrhythmic deaths in ur study. Our results als agree well with the rate f ->50% reprted in several earlier studies (19,20). Previus studies (3,4,17) have suggested that depressed barreflex sensitivity bears the strngest assciatin with inductin f sustained mnmrphic ventricular tachycardia and risk f arrhythmic death in patients recvering frm an acute mycardial infarctin. In ur study, nly a small number f patients underwent assessment f barreflex sensitivity; therefre, this imprtant risk factr culd nt be included in ur analysis. In previus risk stratificatin studies, the time dmain standard deviatin f nrmal RR intervals (SDNN) is perhaps mst cmmnly used t assess heart rate variability. Hwever, the heart rate variability index used in this study has been shwn (25) t crrelate highly with SDNN, and bth indexes prvide equivalent results fr risk stratificatin. Cnclusins. In this study we fund a significant interactin amng different risk factrs used in risk stratificatin after mycardial infarctin. We demnstrated that established risk factrs prvide supplementary infrmatin fr risk stratificatin after mycardial infarctin. In particular, we fund that arrhythmic mrtality was assciated with depressed heart rate

9 304 HARTIKAINEN ET AL JACC Vl. 28, N. 2 ARRHYTHMIC AND NONARRHYTHMIC POSTINFARCTION DEATH August 1996: variability and presence f runs f ventricular tachycardia during 24-h ECG recrding. Lw left ventricular ejectin fractin, frequent ventrieular ectpic beats and depressed heart rate variability were related t risk f nnarrhythmic death. In additin, by using cmbined risk factrs infrmatin we were able t identify patient grups in which up t 75% f deaths were either arrhythmic r nnarrhythmic. References 1. Farrell TG, Odemuyiwa O, Bashir Y, Malik M, Ward DE, Camm AJ. Prgnstic value f barreflex sensitivity testing after acute mycardial infarctin. Br Heart J 1992;67: Kleiger RE, Miller JP, Bigger JT, Mss AJ, and the Multicenter Pst- Infarctin Research Grup. Decreased heart rate variability and its assciatin with increased mrtality after acute mycardial infarctin. Am J Cardil 1987;59: La Rvere MT, Specchia G, Mrtara A, Schwartz PJ. 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Cmparisn f the predictive characteristics f heart rate variability index and left ventricular ejectin fractin fr all-cause mrtality, arrhythmic events and sudden death after acute mycardial infarctin. Am J Cardil 1991;68: Simsn MB. The use f signals in the terminal QRS cmplex t identify patients with ventricular tachycardia after mycardial infarctin. Circulatin 1981;64: Sandler H, Ddge H. The use f single plane angigrams fr the calculatin f left ventricular vlume in man. Am Heart J 1968;75: Cardiac Arrhythmia Suppressin Trial (CAST) Investigatrs. Preliminary reprt: effect f encainide and flecainide n mrtality in a randmized trial f arrhythmic suppressin after mycardial infarctin. N Engl J Med 1989;321: Task Frce f ESC and NASPE. Heart rate variability--standards f measurement, physilgical interpretatin, and clinical use. Circulatin 1996;93: