541
JACC Vol. 19, No.3 March I, 1992:541-9
Late Potentials in a Bradycardia-Dependent Long QT Syndrome Associated With Sudden Death During Sleep TOM J. M. TORE, MD, eEES D. J. DE LANGEN, PHD, MARGREET TH.E. BINK-BOELKENS, MD, PIET H. MOOK, PHD, JAN-WILLEM VIERSMA, MD, KONG 1. LIE, MD, HARRY WESSELING, MD Groningen, The Netherlands
The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous family members without QT prolongation (n =13). Six (67%) of the 9family members with QT prolongation had late potentials on the signal-averaged electrocardiogram (ECG) compared with 1 of the 13 normal subjects (p < 0.007). Positive predictive accuracy of the signal-averaged ECG for the detection of subjects with QT prolongation was 86 %; negative predictive accuracy was 80%. During exercise testing, the QT interval normalized, whereas late potentials did not change significantly. Exercise testing did not reveal the presence of coronary artery disease as a possible cause of late potentials.
It is concluded that 1) compared with family members with a normal QT interval, patients with this type of bradycardiadependent QT prolongation have a high incidence of late potentials; 2) late potentials persist despite normalization of the QT interval at high heart rates, indicating that there is no direct relation between late potentials and QT prolongation; and 3) late potentials are not caused by coronary artery disease in these subjects. Therefore, the detection of late potentials might be a new aid in the detection and risk stratification of patients with the long QT syndrome. Late potentials possibly indicate a substrate for ventricular tachyarrhythmias in this type of bradycardia-dependent QT prolongation.
Life-threatening ventricular arrhythmias are frequently found in the congenital long QT syndromes (1). Among our outpatients, there is a family with a high rate of sudden death during sleep at a young age. In contrast to the QT prolongation during exercise in the Romano-Ward and JervellLange-Nielsen syndromes (2), in this family the QT interval is prolonged at rest and normalizes during exercise. The history taken from witnesses suggests that sudden death was due to cardiac arrhythmia. Because our previous efforts to detect ventricular arrhythmias that could clarify the cause of sudden death in this family were fruitless, we decided to look for factors like late potentials that indicate the presence of a possible substrate for ventricular arrhythmias. Late potentials are low amplitude signals at the end of the QRS complex that can be detected by signal-averaged electrocardiography (3). They are the body surface representation of fractionated local electrical activity detected by endocardial mapping in coronary artery disease (4,5). After
myocardial infarction, fractionated electrograms correlate, albeit not directly, with inducible ventricular tachycardia (6). In prospective studies (7,8) after myocardial infarction, late potentials were shown to be useful markers for sustained ventricular tachycardia and sudden death. The purpose of this study was to assess the presence of late potentials as markers for slow conduction and their relation to QT prolongation in this family with congenital bradycardia-dependent QT prolongation.
From the Departments of Pharmacology/Clinical Pharmacology, Paediatrics, Thoraxcentre and Cardiology, University of Groningen, Groningen, The Netherlands. This study was presented in part at the 63rd Scientific Sessions of the American Heart Association, Dallas, Texas, November 1990. This study was supported by Grant 86.061 of The Netherlands Heart Foundation, The Hague, The Netherlands. Manuscript received February 12, 1991; revised manuscript received July 29, 1991, accepted August 9, 1991. Address for reprints: Tom J. M. Tobe, MD, the Department of Medicine, Sophia Hospital, P.O. Box 10.400, 8000 GK Zwolle, The Netherlands. © 1992 by the American College of Cardiology
(J Am Coll CardioI1992;19:541-9)
Methods Study patients. Among our outpatients is a family in which 15 of 112 members died suddenly at a young age during sleep. A 12-lead electrocardiogram (ECG) from one of the patients who died suddenly showed marked QT interval prolongation and an abnormal T wave configuration. All patients who died suddenly were previously healthy, without a history of palpitation or syncope and with good exercise tolerance. In the surviving family members who have been studied in a standardized fashion since 1958 (9), no systolic murmur could be heard. Ventricular arrhythmias were not detected despite repeated 24-h ambulatory electrocardiographic (ECG) monitoring. Atrioventricular (AV) block was not observed. Previous echocardiography did not reveal abnormalities. None of the subjects was deaf and audiograms were normal. Twenty-eight consanguineous family members gave in0735-1097/92/$5.00
542
TORE ET AL. LATE POTENTIALS AND QT PROLONGATION
formed consent for the study. Six of the 28 were excluded: I with QT prolongation because the QRS duration on the 12-lead ECG was > 120 ms, 2 without QT prolongation, because of a ventricular pacemaker (implanted for treatment of sinus arrhythmia with pauses up to 7 s), 1 because of pre-excitation, 1 because the heart rate was not low enough for detection of bradycardia-dependent QT prolongation and 1 without QT prolongation because a low noise signalaveraged ECG could not be obtained at rest. None of the subjects received digitalis, antiarrhythmic drugs or other drugs with QT prolongation as a potential side effect. None had electrolyte disturbances. QT interval measurements. Measurement of the QT interval is difficult to standardize (10). We chose the method described by Cowan et al. (11), who showed that the maximal QT duration is predominantly measured in the right precordial leads. QT intervals were measured in lead V2 from the onset of the QRS complex to the end of the T wave. The end of the T wave was defined as a return to the TP baseline. When a U wave interrupted the T wave before return to baseline, the QT interval was measured to the nadir of the curve between T and U waves. Biphasic T waves were measured to the time of final return to baseline (11). The QT interval corrected for heart rate (QTc) was calculated with use of Bazett's equation (12) (QTc = QT/square root of RR). This interval was used only to compare the QT interval at different heart rates. RR.QT scattergrams. An RR-QT scattergram was plotted for each patient on the basis of the QT interval measurements (not corrected for heart rate) obtained from exercise testing and ambulatory ECG monitoring. The normal values described by Lepeschkin (13) were used to discriminate between subjects with normal or prolonged QT intervals. A patient was considered to have bradycardiadependent QT prolongation when the QT interval was consistently prolonged over a wide range of heart rates 20 ms (for an example Subject 4, Fig. 4: the QTc interval was prolonged 73 ms during sleep). Moreover, the configuration of the T wave became abnormal at low heart rates, whereas no such changes were observed in normal subjects. Furthermore, at night a clear difference developed between subjects with QT prolongation and the normal subjects, indicating again that the observed QT prolongation during sleep was pathologic and different from the physiologic nocturnal QT prolongation in normal humans. Because Lepeschkin's oval (13) clearly demonstrates the relation between measured QT
546
JACC Vol. 19, No.3 March I, 1992:541-9
TOBE ET AL. LATE POTENTIALS AND QT PROLONGATION
Table 2. Signal-Averaged Electrocardiography at Rest in 22 Subjects Subject No.
Age (yr)1 Gender
QRS a
QRS b
040
V40
Noise
HR
QT
QTc
QT prolongation 1 2 3 4 5 6 7 8 9 Mean SO
68/M 68/M 47/M 38/F 33/F 30/F 261M 17/F 7/F 37 21
100 80 100 100 110 110 120 110 80 101 14
III 100 102 III 133* 123* 130* 116* 91
14
27 31 26 53* 70* 48* 43* 21 42* 40 16
25 23 31 9* 10* 7* 16* 24 20* 18 8
0.9 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.4 0.6 0.1
86 86 72 69 86 73 60 70 70 75 9
395 380 445 415 380 430 460 445 420 419 29
472 456 489 445 452 471 462 480 453 464 15
33/F 281M 271M 271M 251F 251M 24/F 241M 191M 12/F 12/F 9/F
90 80 80 100 100 80 80 90 90 80 80 70 80 85 9 0.01
80 100 89 109 100 103 99 101 97 89 79 83 92 94 9 0.001
28 20 14 48* 32 17 34 24 II 19 8 18 24 23 II 0.007
49 38 40 17* 24 42 29 82 65 122 185 129 59 68 49 0.001
0.8 1 0.8 0.6 0.6 0.5 0.7 0.7 0.5 0.2 0.4 0.6 OJ 0.6 0.2 NS
55 41 100 77 81 69 75 53 50 48 90 72 94 70 20 NS
430 460 310 350 345 360 360 440 420 410 360 350 380 380 46 0.05
411 381 398 395 401 384 403 414 385 369 436 385 425 399 19 O.OOOlt
Normal subjects 10 II 12 13 14 15 16 17 18 19 20 21 22
Mean SO P value
6/M 21 8 0.03
113
*Abnormal signal-averaged variables. Note that the subjects were categorized on the basis of the scattergrams and not on the basis of QTc. 040 = duration of terminal activity
JACC Vol. 19, No.3 March I, 1992:541-9
Late Potentials in a Bradycardia-Dependent Long QT Syndrome Associated With Sudden Death During Sleep TOM J. M. TORE, MD, eEES D. J. DE LANGEN, PHD, MARGREET TH.E. BINK-BOELKENS, MD, PIET H. MOOK, PHD, JAN-WILLEM VIERSMA, MD, KONG 1. LIE, MD, HARRY WESSELING, MD Groningen, The Netherlands
The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous family members without QT prolongation (n =13). Six (67%) of the 9family members with QT prolongation had late potentials on the signal-averaged electrocardiogram (ECG) compared with 1 of the 13 normal subjects (p < 0.007). Positive predictive accuracy of the signal-averaged ECG for the detection of subjects with QT prolongation was 86 %; negative predictive accuracy was 80%. During exercise testing, the QT interval normalized, whereas late potentials did not change significantly. Exercise testing did not reveal the presence of coronary artery disease as a possible cause of late potentials.
It is concluded that 1) compared with family members with a normal QT interval, patients with this type of bradycardiadependent QT prolongation have a high incidence of late potentials; 2) late potentials persist despite normalization of the QT interval at high heart rates, indicating that there is no direct relation between late potentials and QT prolongation; and 3) late potentials are not caused by coronary artery disease in these subjects. Therefore, the detection of late potentials might be a new aid in the detection and risk stratification of patients with the long QT syndrome. Late potentials possibly indicate a substrate for ventricular tachyarrhythmias in this type of bradycardia-dependent QT prolongation.
Life-threatening ventricular arrhythmias are frequently found in the congenital long QT syndromes (1). Among our outpatients, there is a family with a high rate of sudden death during sleep at a young age. In contrast to the QT prolongation during exercise in the Romano-Ward and JervellLange-Nielsen syndromes (2), in this family the QT interval is prolonged at rest and normalizes during exercise. The history taken from witnesses suggests that sudden death was due to cardiac arrhythmia. Because our previous efforts to detect ventricular arrhythmias that could clarify the cause of sudden death in this family were fruitless, we decided to look for factors like late potentials that indicate the presence of a possible substrate for ventricular arrhythmias. Late potentials are low amplitude signals at the end of the QRS complex that can be detected by signal-averaged electrocardiography (3). They are the body surface representation of fractionated local electrical activity detected by endocardial mapping in coronary artery disease (4,5). After
myocardial infarction, fractionated electrograms correlate, albeit not directly, with inducible ventricular tachycardia (6). In prospective studies (7,8) after myocardial infarction, late potentials were shown to be useful markers for sustained ventricular tachycardia and sudden death. The purpose of this study was to assess the presence of late potentials as markers for slow conduction and their relation to QT prolongation in this family with congenital bradycardia-dependent QT prolongation.
From the Departments of Pharmacology/Clinical Pharmacology, Paediatrics, Thoraxcentre and Cardiology, University of Groningen, Groningen, The Netherlands. This study was presented in part at the 63rd Scientific Sessions of the American Heart Association, Dallas, Texas, November 1990. This study was supported by Grant 86.061 of The Netherlands Heart Foundation, The Hague, The Netherlands. Manuscript received February 12, 1991; revised manuscript received July 29, 1991, accepted August 9, 1991. Address for reprints: Tom J. M. Tobe, MD, the Department of Medicine, Sophia Hospital, P.O. Box 10.400, 8000 GK Zwolle, The Netherlands. © 1992 by the American College of Cardiology
(J Am Coll CardioI1992;19:541-9)
Methods Study patients. Among our outpatients is a family in which 15 of 112 members died suddenly at a young age during sleep. A 12-lead electrocardiogram (ECG) from one of the patients who died suddenly showed marked QT interval prolongation and an abnormal T wave configuration. All patients who died suddenly were previously healthy, without a history of palpitation or syncope and with good exercise tolerance. In the surviving family members who have been studied in a standardized fashion since 1958 (9), no systolic murmur could be heard. Ventricular arrhythmias were not detected despite repeated 24-h ambulatory electrocardiographic (ECG) monitoring. Atrioventricular (AV) block was not observed. Previous echocardiography did not reveal abnormalities. None of the subjects was deaf and audiograms were normal. Twenty-eight consanguineous family members gave in0735-1097/92/$5.00
542
TORE ET AL. LATE POTENTIALS AND QT PROLONGATION
formed consent for the study. Six of the 28 were excluded: I with QT prolongation because the QRS duration on the 12-lead ECG was > 120 ms, 2 without QT prolongation, because of a ventricular pacemaker (implanted for treatment of sinus arrhythmia with pauses up to 7 s), 1 because of pre-excitation, 1 because the heart rate was not low enough for detection of bradycardia-dependent QT prolongation and 1 without QT prolongation because a low noise signalaveraged ECG could not be obtained at rest. None of the subjects received digitalis, antiarrhythmic drugs or other drugs with QT prolongation as a potential side effect. None had electrolyte disturbances. QT interval measurements. Measurement of the QT interval is difficult to standardize (10). We chose the method described by Cowan et al. (11), who showed that the maximal QT duration is predominantly measured in the right precordial leads. QT intervals were measured in lead V2 from the onset of the QRS complex to the end of the T wave. The end of the T wave was defined as a return to the TP baseline. When a U wave interrupted the T wave before return to baseline, the QT interval was measured to the nadir of the curve between T and U waves. Biphasic T waves were measured to the time of final return to baseline (11). The QT interval corrected for heart rate (QTc) was calculated with use of Bazett's equation (12) (QTc = QT/square root of RR). This interval was used only to compare the QT interval at different heart rates. RR.QT scattergrams. An RR-QT scattergram was plotted for each patient on the basis of the QT interval measurements (not corrected for heart rate) obtained from exercise testing and ambulatory ECG monitoring. The normal values described by Lepeschkin (13) were used to discriminate between subjects with normal or prolonged QT intervals. A patient was considered to have bradycardiadependent QT prolongation when the QT interval was consistently prolonged over a wide range of heart rates 20 ms (for an example Subject 4, Fig. 4: the QTc interval was prolonged 73 ms during sleep). Moreover, the configuration of the T wave became abnormal at low heart rates, whereas no such changes were observed in normal subjects. Furthermore, at night a clear difference developed between subjects with QT prolongation and the normal subjects, indicating again that the observed QT prolongation during sleep was pathologic and different from the physiologic nocturnal QT prolongation in normal humans. Because Lepeschkin's oval (13) clearly demonstrates the relation between measured QT
546
JACC Vol. 19, No.3 March I, 1992:541-9
TOBE ET AL. LATE POTENTIALS AND QT PROLONGATION
Table 2. Signal-Averaged Electrocardiography at Rest in 22 Subjects Subject No.
Age (yr)1 Gender
QRS a
QRS b
040
V40
Noise
HR
QT
QTc
QT prolongation 1 2 3 4 5 6 7 8 9 Mean SO
68/M 68/M 47/M 38/F 33/F 30/F 261M 17/F 7/F 37 21
100 80 100 100 110 110 120 110 80 101 14
III 100 102 III 133* 123* 130* 116* 91
14
27 31 26 53* 70* 48* 43* 21 42* 40 16
25 23 31 9* 10* 7* 16* 24 20* 18 8
0.9 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.4 0.6 0.1
86 86 72 69 86 73 60 70 70 75 9
395 380 445 415 380 430 460 445 420 419 29
472 456 489 445 452 471 462 480 453 464 15
33/F 281M 271M 271M 251F 251M 24/F 241M 191M 12/F 12/F 9/F
90 80 80 100 100 80 80 90 90 80 80 70 80 85 9 0.01
80 100 89 109 100 103 99 101 97 89 79 83 92 94 9 0.001
28 20 14 48* 32 17 34 24 II 19 8 18 24 23 II 0.007
49 38 40 17* 24 42 29 82 65 122 185 129 59 68 49 0.001
0.8 1 0.8 0.6 0.6 0.5 0.7 0.7 0.5 0.2 0.4 0.6 OJ 0.6 0.2 NS
55 41 100 77 81 69 75 53 50 48 90 72 94 70 20 NS
430 460 310 350 345 360 360 440 420 410 360 350 380 380 46 0.05
411 381 398 395 401 384 403 414 385 369 436 385 425 399 19 O.OOOlt
Normal subjects 10 II 12 13 14 15 16 17 18 19 20 21 22
Mean SO P value
6/M 21 8 0.03
113
*Abnormal signal-averaged variables. Note that the subjects were categorized on the basis of the scattergrams and not on the basis of QTc. 040 = duration of terminal activity
