Association Between Parasympathetic Activity and Late Potentials at Low Noise Level Evald Hoj Christiansen, M.D., Ph.D., Lars Frost, M.D., Ph.D., Henning Molgaard, M.D., DMSci., Torsten Toftegaard Nielsen, M.D., DMSci., and Anders Kirstein Pedersen, M.D., DMSci, From the Department of Cardiology, Skjby Sygehus, University Hospital, Aarhus, Denmark Background: Late potentials (LP) in the signal-averaged ECC represent activation of myocardial areas with slow conduction and predicts re-entrant malignant ventricular arrhythmias in coronary artery disease. Low heart rate variability, which reflects low vagal and concomitantly elevated sympathetic activation also predicts ventricular arrhythmia. This autonomic profile is associated with the presence of LP (detected at noise level 0.4 pV) early after myocardial infarction. In contrast, sympathetic stimulation and diminution of vagal tone influence LP parameters (detected at noise level 0.2 pV) in the opposite direction in healthy subjects. The aim of this study was to estimate the possible association between measures of cardiac autonomic function and LP (detected at 0.4 and 0.2 pV) in patients with chronic coronary artery disease. Methods: ECGs of 174 consecutive patients with angiographically documented coronary artery disease and without myocardial infarction during the last 3 months were signal-averaged to noise level 0.2 and 0.4 pV. LP were considered to be present if any two of the following criteria were present: signal-averaged QRS duration > 120 ms, root-mean-square voltage of the terminal 40 ms of the averaged QRS complex < 25 pV, and late potential duration > 40 ms. Heart rate variability was measured at rest in 5-minute ECC recordings as: the standard deviation (SD) of all RR intervals, SD corrected for RR (SD/mean RR), and the power of high frequency (HF) component (0.15-0.40 Hz). Results: One hundred seven (61%) of the patients had LP at noise level 0.2 pV. LPs were more frequently observed in patients with slow heart rate, high heart rate variability, and high levels of vagal activity (mean RR = 1000 ms, SD 2 60 ms, and HF 2 100 ms2)than in patients with higher heart rate, low heart rate variability and attenuated vagal activity: 73% vs 54% (P = 0.02), 71% vs 53% (P = 0.02), 72% vs 51OO/ (P = 0.005) for mean RR, SD, and HF power, respectively. Adjustment for possible confounding from mean RR level, gender, previous acute myocardial infarction, treatment with betablocker, and left ventricular ejection fraction did not significantly alter these associations. At noise level 0.4 pV 26% (45/174) had LP and the diagnosis of LP was not significantly associated with heart rate variability. Conclusions: At low noise level (0.2 pV) higher parasympathetic activity is associated with the diagnosis of LP. The predictive power of presence of LP diagnosed at low noise level for development of sudden cardiac death may be reduced by this association. In order to increase the predictive accuracy of LP we recommend either the use of noise level 0.4 pV, or identification of high arrhythmia-risk patients by a combination of the presence LP and impaired heart rate variability. A.N.E. 1997;2(3):254-263 However, a prognostic study is needed to further clarify this. signal-averaged ECG; heart rate variability; parasympathetic activity; late potentials
The presence of late potentials (LP) in the signalaveraged electrocardiogram and impaired heart rate variability have independently shown to pre-
dict sudden cardiac death.'-13 The presence of LP is a marker of an electrophysiological substrate for ventricular tachyarrhythmias, whereas impaired
%is work was supported by the Danish Heart Foundation, the Laerdaf Foundation for Acute Medicine, Noway; the Institute of Experimental Clinical Research, Aarkus University, the Foundation for Clinical Electropkysiological Studies, Skejby University Hospital, Denmark. Address for reprints: Evald H+j Ckristiansen, Department of Cardiologv, Skejby Sygehus, University Hospital, DK-8200 Aarhus N, Denmark. Fax:(Ol I ) +45 89-496009. E-mail:
[email protected]
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heart rate variability reflects low vagal activity and concomitantly elevated sympathetic a~tivati0n.l~l6 Low indexes for vagal activity and high sympathetic activity are associated with the diagnosis of LP early after myocardial i n f a r ~ t i o n . ~In" ~healthy subjects, in contrast, the signal-averagedQRS duration and LP duration are prolonged in conditions with high vagal activity, whereas elevated sympathetic activity shortens signal-averaged electrocardiographic measures of late potentials. l8 This indicates that the autonomic balance may directly influence the depolarization process. The studies performed early after myocardial infarction used noise level 0.4 p V , while the study in healthy subjects used noise level 0.2 pV.8,'7,18 Considerable variations of the signal-averagedECG between noise level 0.4 and 0.2 p V have been found, and the demonstration of a relationship between autonomic activity and late potentials may depend on noise l e ~ e l . ' ~ - ~ ~ The aims of this study were first, to investigate in patients with chronic stable coronary artery disease the relationship between autonomic balance and late potentials, and second, to study whether a relation between autonomic activity and late potentials is dependent on noise level.
METHODS Patient Populations Consecutive patients with documented coronary artery disease scheduled for elective coronary artery bypass grafting (CABG)during a 9-month period were considered for the study. Exclusion criteria were myocardial infarction within the last 3 months (n = 14),unwilling patient (n = l ) ,bundle branch block (n = 5), atrial fibrillation (n = l ) ,or pacemaker treatment (n = 3). All patients gave informed consent and the study was approved by the regional Ethical Committee. Prior myocardial infarction was diagnosed according to the WHO criteria." Left ventricular ejection fraction (LVEF) was determined by contrast ventriculography in two orthogonal planes.
ECG Recording The ECG was recorded with patients lying quietly in the supine position. High quality Ag/AgCl adhesive electrodes (Blue Sensor, Medicotest NS, Denmark) were applied in the standard orthogonal X, Y, and Z lead system. Signals were analog-todigital converted at 1000 Hz (bandwidth at 0.05
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to 360 Hz, 1.25 p V precision) using a HIPEC 200 Analyzer, (Aerotel, Israel). Fifteen minutes of raw ECG were stored on optical discs for later analysis. The HIPEC 200 was driven by a rechargeable nicad battery to minimize electrical noise during data acquisition.
Signal-Averaged ECG QRS complexes in each raw ECG were accurately aligned (+- 1 ms) and averaged until the noise level was reduced to 0.4 and 0.2 p V , respectively. Noisy and abnormal complexes were rejected by a template recognition algorithm. The individual X, Y, and Z leads were filtered (bidirectional Butterworth filter) 40-250 Hz, and the filtered signalaveraged vector magnitude was calculated as square-root of (X2 + Y2 + Z'). The noise level was automatically measured as the minimum standard deviation (SD) of potentials over an interval of 40 ms in the ST segment of the filtered QRST complex. The start and end of the QRS complex were determined by a computer algorithm and defined as the midpoint of the 5-ms segment in which the mean voltage exceeded the mean noise level plus three times the SD of the noise sample. Standard timedomain parameters were measured by an automated algorithm: the signal-averaged QRS duration (SA-QRS),late potential duration (LPDJ measured as duration of terminal signals below 40 p V , and the root-mean-square voltage of the terminal 40 ms of the QRS complex (RMS,,). The presence of any two out of three abnormal parameters (SA-QRS> 120 ms, RMS4, < 25 p V , LPD > 40 ms) was used as the definition of LP. The computer calculations were reviewed by two investigators, and in case of inappropriate determination of QRS-onset or offset, the onset (19 of all cases) or offset (3 of all cases) was set manually. Figure 1 illustrates the filtered vector magnitude at the two noise levels for one of the patients.
Heart Rate Variability Information was measured in the initial 5 minutes of the recorded ECG. RR intervals related to artifacts, ventricular beats, and deviation more than & 25% from the preceding were excluded from analysis. Total variability was calculated as the SD of all RR intervals. Principally the SD is a measure of both the sympathetic and vagal influences. However, measured in short ECG segments at rest it mainly reflects vagal a~tivity.'~ An index normalized for mean RR level was also calculated
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SA-QRS = 108 rns LPD 41 ms RMS40 = 14.0 /./V Noise 0.2 /./V
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SA-QRS 93 ms LPD 26 ms RMS40 41 .O /./V Noise 0.4pV
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Mean RR (ms),SD of RR (ms),SD/mean RR, LF, and HF were dichotomized at levels near their median values. To determine the ability of the heart rate variability parameters to predict late potentials, odds ratios with 95% confidence interval were computed. Adjustment for possible confounding from gender, previous acute myocardial infarction, treatment with beta blocker, and LVEF (dichotomized at EF = 50%) was performed using logistic regression analysis. Discrimination was assessed using the area under the receiver operating characteristic (ROC)curve to evaluate how well the model (heart rate variability parameters combined with clinical data] distinguished patients with and without late potentials. In ROC curve analysis specificity values were associated with sensitivity values. The specificity was the proportion of patients with a negative test result in patients without late potentials, and the sensitivity was the proportion of patients with a positive test result in patients with late potentials. The BMDP (BMDP Statistical Software Inc., Los Angeles, CAIUSA)version 7.0 was
RESULTS
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Figure 1. Original signal-averaged ECG performed to noise level 0.2 and 0.4 p V in the same patient. The filtered signal-averaged QRS duration (SA-QRS), late potential duration (LPD] measured as duration of signals
