- Email: [email protected]
Effect of β-adrenergic stimulation on the QRS duration of the signal-averaged electrocardiogram
Effect of 13-adrenergic stimulation on the QRS duration of the signal-averaged electrocardiogram David O. Arnar, MD, Kent J. Van Why, MD, Kent Gleed, MD, Blair Foreman, MD, James R. Hopson, MD, Hon-Chi Lee, MD, PhD, and James B. Martins, MD I o w a City, I o w a
Isoproterenol, a [3-adrenergic agonist, shortens ventricular effective refractory period and may facilitate the induction of ventricular tachyarrhythmias by programmed electrical stimulation. 1 Isoproterenol has also been shown to enhance the voltage-sensitive sodium current in rabbit cardiac myocytes. 2 In both dissociated rabbit cardiac myocytes and isolated rabbit hearts, isoproterenol reverses blockade of the sodium channel by lidocaine. 3 Because the sodium current is a major determinant of conduction Velocity, it stands to reason that [3-adrenergic stimulation could enhance conduction in t h e myocardium. This supposition may be important in helping to explain both the occurrence of ventricular arrhythmias and the variable effects of antiarrhythmic therapy in patients. The QRS duration may be used as an indicator of conduction in the ventricle. We used the signal-averaged electrocardiogram (SAECG) to measure QRS duration in this study to test the hypothesis that isoproterenol shortens QRS duration in human beings. Seven randomly selected patients who were undergoing an electrophysiology (EP) study for various clinical indications were included. The study was approved by the University of Iowa Committee on Human Subjects Research, and all patients gave written informed consent. At the time of the initial EP study, two quadripolar electrode catheters were percutaneously inserted into a femoral vein and advanced to the right ventricular apex and to the His bundle position under fluoroscopic guidFrom the Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. Dr. Arnar was supported by a Fellowship Award from the American Heart Association, Iowa Affiliate. Received for publication July 15, 1996: accepted April 7, 199Z Reprint requests: James B. Martins, MD, Cardiovascular Division, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242. E-mail: [email protected] Am Heart J 1997;134:395-8 Copyright © 1997 by Mosby- Year Book, Inc. 0002-8703/97/$5.00 + 0 4/I/82559
ance. Pacing was bipolar, at four times diastolic threshold, and performed at 400 msec cycle length. SAECGs were obtained from a commercially available computer and software (Predictor 5.0, Corazonix Corp.). Standard bipolar orthogonal X, Y, and Z leads were used to record signals that were amplified, digitized, and bidirectionally filtered (40 Hz). Complexes were gathered until a noise level of <0.5 btV was achieved, requiring approximately 400 complexes per patient. The filtered leads were combined into a vector magnitude that was stored on the computer for later measurement. An SAECG was obtained during right ventricular apex pacing at a cycle length of 400 msec, which was chosen to make certain that possible changes in the QRS duration by isoproterenol were not influenced by the heart rate increase. Ventricular effective refractory period (VERP) was determined by delivering extrastimuli after eight drive-paced complexes, with effective refractory period defined as the longest $1-$2 that did not capture the ventricle. Isoproterenol at a dose sufficient to increase the baseline sinus rate by at least 20% was then intravenously infused. The initial isoproterenol dose was 1 mcg/min and ff necessary was altered at 0.5 (gg/min increments every 5 minutes to obtain the desired heart rate response. Once the target heart rate had been achieved another SAECG and VERP were obtained during isoproterenol infusion. The duration of the QRS complex with and without isoproterenol was measured and compared (Fig. 1). The duration of the signal-averaged QRS was taken from the onset of the pacing spike to the end of QRS signal, defined as the end of the signal of an amplitude at least twice the level of noise. The QRS duration of the SAECG was manually measured in a blinded fashion. Surface (leads I, II, III, aVR, V1, and V6) a n d intracardiac electrograms were simultaneously recorded with the SAECG. All patients had catheters placed to record the bundle of His to exclude retrograde His bundle activation during pacing. In patients who demonstrated ventriculoatrial conduction, simultaneous atrial and ventricular pacing was used to exclude effects of retrograde
396
Arnaretal.
SAECG ANALYSIS
PREDICTOR Ver_sion 6.1
VECTOR
Date: 06/20/96
I00.0 uV
t3290740 [0/03/94 ~roto: type: 3and: 4i freq: 4i order:
90 0 80 0 70 0
ll:~2a BASIK2 Bidir Hipass 40 4
60 0 Total QRS
50.0 40.0
Terminal QRS
30.0 20.0 lO.O 0.0 0
40
80
120
i60
PREDICTOR Version B.1 uV 100.0
200
240
280
SAECG ANALYSIS
320
360
400
ms Scale:
Date: 06/20/95 J
VECTOR
73290740 10/03/94 Proto: iype: Band: Hi freq: Hi order:
90.0 80.0 70.0
10,0
ll:t2a BASIK2i Bidir Hipass 40 4
60.0 T o t a l QRS
50.0 40.0
Terminal QRS
30.0 20.0 10.0 0.0 0
i
i
40
80
ms 120
160
200
240
280
320
360
400
3cale:
iO.O
Signal-averaged electrocardiogram obtained during right ventricular pacing at cycle length 400 msec before (top) (QRS duration 186 msec) and during isoproterenol infusion (below) (QRS duration 178 msec).
AmericanHeartJournal September1997
Arnaretd.
P waves on the QRS duration of both the SAECG. A paired Student's t test was used to compare QRS duration, VERP, and heart rate before and during isoproterenol infusion. Data are expressed as mean + SEM. Significance was defined as a p value of <0.05. The mean age of the patients was 60 years (range 29 to 78 years). Table I shows the patients' clinical characteristics. None of the patients was taking antiarrhythmic medications, including ]3-blockers. The heart rate increased from 77.0 + 5 to 99.0 + 6 beats/min (28.5%) with an average isoproterenol dose of 1.2 btg/min (p < 0.00005). The VERP shortened from 253 + 26 msec to 232 + 27 msec (8.3o/o) (p < 0.001). The QRS duration measured by signal averaging shortened from 198 + 6 to 193 + 6 msec (2.5%) (p < 0.01) (Fig. 1). The pacing stimulus to electrogram interval did not change with isoproterenol, indicating that the effects of the drug were on the QRS duration. The results of heart rate increase, VERP and QRS shortening were consistent in all seven patients. A potential limitation to the SAECG technique is the inability to exclude paced P-wave duration interference with the QRS duration in patients with simultaneous atrioventricular pacing. However, in previous reports the signal averaged paced P-wave durations have been 20 to 25 msec shorter than the average QRS duration of our study. 4 Additionally, the effect of isoproterenol was consistent regardless of whether simultaneous atrial and ventricular or ventricular pacing alone was performed. To exclude the possibility that the QRS duration shortened because of time alone and not necessarily because of isoproterenol, in two patients protocol was reversed--isoproterenol was infused first and the "base'line" ~SAECG obtained after a washout period. The results were the same, supporting the fact that the QRS duration shortening seen was an effect of isoproterenol. The effects of [3-adrenergic stimulation on the sodium current have been the subject of controversy. Matsuda et al. 2 showed that isoproterenol enhanced the sodium current in isolated rabbit cardiac myocytes. Isoproterenol has also been reported to enhance the sodium, current in guinea pig cardiac myocytes. 5 However, contrasting those results, studies of adult guinea pig and neonatal rat cardiac myocytes showed that isoproterenol inhibited the sodium channel. 6-8 Others found no effect of isoproterenol on the sodium current in neonatal rat cardiac myocytes and rabbit atrial myocytes. 9-1° Thus the effects of isoproterenol on the sodium current seem to be dependent on both species and investigator. The reasons for this are not entirely
American Heart Journal Volume 134, Number 3
Age 62 43 68 73 68 78 29
Underlying cardiac disease CAD, HTN, MI, CHF CHF, HTN HTN, CAD, AF CAD, HTN, MR
-
Indication for EP VT Syncope Syncope Syncope Syncope Syncope Syncope
CAD, Coronary artery disease; HTN, hypeflensJon; ,M/, rnyecordial infarction; CHF, congestive heart failure; AF, history of alrial fibrillation; ,MR, mitral regurgitation; VT,yentricular tachycardia.
clear, although differences in voltage clamp techniques may possibly play a role. The effect of ~-adrenergic stimulation on the sodium channel in human cardiac myocytes is unknown. Although sympathetic stimulation shortens the effective refractory period in the myocardium it has traditionally been thought that conduction is not significantly affected. However, Markel et al. n recently demonstrated a shortening of the QRS duration and the ventricular effective refractory period with isoproterenol during ventricular pacing at 400 msec in human beings with scalar electrocardiogram. The changes of the QRS duration were similar in magnitude to those observed in this study. The results of this study, demonstrating shortening of QRS duration of the signal-averaged electrocardiogram with isoproterenol and indicating improved conduction, support the previously published results in isolated myocytes and hearts that show enhancement of the sodium current by [~-adrenergic stimulation. However, possible alternative mechanism for QRS shortening with isoproterenol could be an increase in conduction across gap junctions. The gap junction conductance is an important determinant of intercellular resistance, and alterations could have an effect on conduction velocity. 12 Isoproterenol has been shown to increase gap junction conductance in isolated rat ventricular cell pairs. 13 Sympathetic tone has previously been shown to influence both the occurrence 14 and inducibility 1 of ventricular arrhythmias and alter the effect of antiarrhythmic drugs. 11 This may be important for patients with ventricular tachycardia receiving antiarrhythmic medication. The findings of this study are supportive of prior studies, which have shown that adrenergic influences can reverse the electrophysiologic effects of some antiarrhythmic drags and may provide additional rationale for
397
398
Arnaretak
using ~-blocker medications in combination with membrane-active antiarrhythmic drugs.
References 1. Reddy CP, Gettes LS. Use af isoproterenol as a aid to electric conduction of chronic ventricular lachycardia. Am J Cardio11979;44:705-13. 2. Matsuda j J, Lee H, Shibata EF. Enhancement of rabbit cardiac sodium channels by beta adrenergic stimulation. Circ Res 1992;7:199-208. 3. Lee H, Matsuda Jj, Reynertson SJ, Martins JB, Shibata EF. Reversalof lidocaine effects on sodium currents by isoproterenol in rabbit hearts and heart cells. J Clin Invest 1993;91:693-701. 4. Keane D, Stafford P, Baker S, Lewis S, Jackson G, Vincent R. Signalaveraged electrocardiography of the sinus and paced P wave in sinus node disease. PACE ] 995;18 (7):1346-53. 5. Tytgat J, Vereecke J, Carmaliet E. A combined study of sodium current and T-type calcium current in isolated cardiac calls. Pflugers Arch 1990;417:142-78. 6. Ono K, Kiyosue T, Arita M. Jsoproterenor,dbcAMP and forskolin inhibit cardiac sodium current. Am J Physiol 1989;256:C 1131-7. Z Schubert B, Vandongen AN j, Kitsch GE, Brown AN. Beta adrenergic inhibition of cardiac sodium channels by dual G protein pathways. Science 1989;245-516.
8. Schubert B, Vandongen AN J, Kitsch GE, Brown AN. Inhibition of cardiac sodium currents by isoproterend. Am J PhysioF 1990;258:H97781. 9. Herzig jW, Kohlhardt M. Sodium channel blockade by cyclic AMP and other six aminopyrines in neonatal rat heart. J Mere Bid . ]991 ;119:163-70. ]0. Wendl DJ, Starmer CF, Grant AO. Perforated patch recording ofcardiac sodium channd currents without time dependent changes in kinetics: an approach to the study of hormonal channel regulation. Circulation 1992;80:1-Z 11. Markel ML, Miles WM, LuckJC, Klein LS, Prystowski EM. Differenlial effects of isoproterenol on sustained ventricular tachycardia before and during procainamide quinidine antiarrhythmic drug therapy. Circuration 1993;87:783-92. 12. Kieval RS, Spear JF, Moore EN. Mechanisms of arrhythmias and basis of antiarrhythmic drug action, in: Horovitz LN, editor. Current management of arrhythmias. BC Decker Inc. Philadelphia; 1991. p. 3. ]3. DeMello WC. Increase in functional conductance caused by isaprolerenol in heart cell pairs is suppressed by cAMP-dependent proteinkinase inhibitor. Biochem Biophys Res Commun ]988;154:509-]4. 14. Coumd P, Rosengarten MD, Leclercq JF, Attuel P. Role of sympathetic nervous system in non-ischaemic ventricular arrhythmias. Br HeartJ 1982; 47:137-4Z
American Heart Journal September 1997
Isoproterenol, a [3-adrenergic agonist, shortens ventricular effective refractory period and may facilitate the induction of ventricular tachyarrhythmias by programmed electrical stimulation. 1 Isoproterenol has also been shown to enhance the voltage-sensitive sodium current in rabbit cardiac myocytes. 2 In both dissociated rabbit cardiac myocytes and isolated rabbit hearts, isoproterenol reverses blockade of the sodium channel by lidocaine. 3 Because the sodium current is a major determinant of conduction Velocity, it stands to reason that [3-adrenergic stimulation could enhance conduction in t h e myocardium. This supposition may be important in helping to explain both the occurrence of ventricular arrhythmias and the variable effects of antiarrhythmic therapy in patients. The QRS duration may be used as an indicator of conduction in the ventricle. We used the signal-averaged electrocardiogram (SAECG) to measure QRS duration in this study to test the hypothesis that isoproterenol shortens QRS duration in human beings. Seven randomly selected patients who were undergoing an electrophysiology (EP) study for various clinical indications were included. The study was approved by the University of Iowa Committee on Human Subjects Research, and all patients gave written informed consent. At the time of the initial EP study, two quadripolar electrode catheters were percutaneously inserted into a femoral vein and advanced to the right ventricular apex and to the His bundle position under fluoroscopic guidFrom the Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. Dr. Arnar was supported by a Fellowship Award from the American Heart Association, Iowa Affiliate. Received for publication July 15, 1996: accepted April 7, 199Z Reprint requests: James B. Martins, MD, Cardiovascular Division, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242. E-mail: [email protected] Am Heart J 1997;134:395-8 Copyright © 1997 by Mosby- Year Book, Inc. 0002-8703/97/$5.00 + 0 4/I/82559
ance. Pacing was bipolar, at four times diastolic threshold, and performed at 400 msec cycle length. SAECGs were obtained from a commercially available computer and software (Predictor 5.0, Corazonix Corp.). Standard bipolar orthogonal X, Y, and Z leads were used to record signals that were amplified, digitized, and bidirectionally filtered (40 Hz). Complexes were gathered until a noise level of <0.5 btV was achieved, requiring approximately 400 complexes per patient. The filtered leads were combined into a vector magnitude that was stored on the computer for later measurement. An SAECG was obtained during right ventricular apex pacing at a cycle length of 400 msec, which was chosen to make certain that possible changes in the QRS duration by isoproterenol were not influenced by the heart rate increase. Ventricular effective refractory period (VERP) was determined by delivering extrastimuli after eight drive-paced complexes, with effective refractory period defined as the longest $1-$2 that did not capture the ventricle. Isoproterenol at a dose sufficient to increase the baseline sinus rate by at least 20% was then intravenously infused. The initial isoproterenol dose was 1 mcg/min and ff necessary was altered at 0.5 (gg/min increments every 5 minutes to obtain the desired heart rate response. Once the target heart rate had been achieved another SAECG and VERP were obtained during isoproterenol infusion. The duration of the QRS complex with and without isoproterenol was measured and compared (Fig. 1). The duration of the signal-averaged QRS was taken from the onset of the pacing spike to the end of QRS signal, defined as the end of the signal of an amplitude at least twice the level of noise. The QRS duration of the SAECG was manually measured in a blinded fashion. Surface (leads I, II, III, aVR, V1, and V6) a n d intracardiac electrograms were simultaneously recorded with the SAECG. All patients had catheters placed to record the bundle of His to exclude retrograde His bundle activation during pacing. In patients who demonstrated ventriculoatrial conduction, simultaneous atrial and ventricular pacing was used to exclude effects of retrograde
396
Arnaretal.
SAECG ANALYSIS
PREDICTOR Ver_sion 6.1
VECTOR
Date: 06/20/96
I00.0 uV
t3290740 [0/03/94 ~roto: type: 3and: 4i freq: 4i order:
90 0 80 0 70 0
ll:~2a BASIK2 Bidir Hipass 40 4
60 0 Total QRS
50.0 40.0
Terminal QRS
30.0 20.0 lO.O 0.0 0
40
80
120
i60
PREDICTOR Version B.1 uV 100.0
200
240
280
SAECG ANALYSIS
320
360
400
ms Scale:
Date: 06/20/95 J
VECTOR
73290740 10/03/94 Proto: iype: Band: Hi freq: Hi order:
90.0 80.0 70.0
10,0
ll:t2a BASIK2i Bidir Hipass 40 4
60.0 T o t a l QRS
50.0 40.0
Terminal QRS
30.0 20.0 10.0 0.0 0
i
i
40
80
ms 120
160
200
240
280
320
360
400
3cale:
iO.O
Signal-averaged electrocardiogram obtained during right ventricular pacing at cycle length 400 msec before (top) (QRS duration 186 msec) and during isoproterenol infusion (below) (QRS duration 178 msec).
AmericanHeartJournal September1997
Arnaretd.
P waves on the QRS duration of both the SAECG. A paired Student's t test was used to compare QRS duration, VERP, and heart rate before and during isoproterenol infusion. Data are expressed as mean + SEM. Significance was defined as a p value of <0.05. The mean age of the patients was 60 years (range 29 to 78 years). Table I shows the patients' clinical characteristics. None of the patients was taking antiarrhythmic medications, including ]3-blockers. The heart rate increased from 77.0 + 5 to 99.0 + 6 beats/min (28.5%) with an average isoproterenol dose of 1.2 btg/min (p < 0.00005). The VERP shortened from 253 + 26 msec to 232 + 27 msec (8.3o/o) (p < 0.001). The QRS duration measured by signal averaging shortened from 198 + 6 to 193 + 6 msec (2.5%) (p < 0.01) (Fig. 1). The pacing stimulus to electrogram interval did not change with isoproterenol, indicating that the effects of the drug were on the QRS duration. The results of heart rate increase, VERP and QRS shortening were consistent in all seven patients. A potential limitation to the SAECG technique is the inability to exclude paced P-wave duration interference with the QRS duration in patients with simultaneous atrioventricular pacing. However, in previous reports the signal averaged paced P-wave durations have been 20 to 25 msec shorter than the average QRS duration of our study. 4 Additionally, the effect of isoproterenol was consistent regardless of whether simultaneous atrial and ventricular or ventricular pacing alone was performed. To exclude the possibility that the QRS duration shortened because of time alone and not necessarily because of isoproterenol, in two patients protocol was reversed--isoproterenol was infused first and the "base'line" ~SAECG obtained after a washout period. The results were the same, supporting the fact that the QRS duration shortening seen was an effect of isoproterenol. The effects of [3-adrenergic stimulation on the sodium current have been the subject of controversy. Matsuda et al. 2 showed that isoproterenol enhanced the sodium current in isolated rabbit cardiac myocytes. Isoproterenol has also been reported to enhance the sodium, current in guinea pig cardiac myocytes. 5 However, contrasting those results, studies of adult guinea pig and neonatal rat cardiac myocytes showed that isoproterenol inhibited the sodium channel. 6-8 Others found no effect of isoproterenol on the sodium current in neonatal rat cardiac myocytes and rabbit atrial myocytes. 9-1° Thus the effects of isoproterenol on the sodium current seem to be dependent on both species and investigator. The reasons for this are not entirely
American Heart Journal Volume 134, Number 3
Age 62 43 68 73 68 78 29
Underlying cardiac disease CAD, HTN, MI, CHF CHF, HTN HTN, CAD, AF CAD, HTN, MR
-
Indication for EP VT Syncope Syncope Syncope Syncope Syncope Syncope
CAD, Coronary artery disease; HTN, hypeflensJon; ,M/, rnyecordial infarction; CHF, congestive heart failure; AF, history of alrial fibrillation; ,MR, mitral regurgitation; VT,yentricular tachycardia.
clear, although differences in voltage clamp techniques may possibly play a role. The effect of ~-adrenergic stimulation on the sodium channel in human cardiac myocytes is unknown. Although sympathetic stimulation shortens the effective refractory period in the myocardium it has traditionally been thought that conduction is not significantly affected. However, Markel et al. n recently demonstrated a shortening of the QRS duration and the ventricular effective refractory period with isoproterenol during ventricular pacing at 400 msec in human beings with scalar electrocardiogram. The changes of the QRS duration were similar in magnitude to those observed in this study. The results of this study, demonstrating shortening of QRS duration of the signal-averaged electrocardiogram with isoproterenol and indicating improved conduction, support the previously published results in isolated myocytes and hearts that show enhancement of the sodium current by [~-adrenergic stimulation. However, possible alternative mechanism for QRS shortening with isoproterenol could be an increase in conduction across gap junctions. The gap junction conductance is an important determinant of intercellular resistance, and alterations could have an effect on conduction velocity. 12 Isoproterenol has been shown to increase gap junction conductance in isolated rat ventricular cell pairs. 13 Sympathetic tone has previously been shown to influence both the occurrence 14 and inducibility 1 of ventricular arrhythmias and alter the effect of antiarrhythmic drugs. 11 This may be important for patients with ventricular tachycardia receiving antiarrhythmic medication. The findings of this study are supportive of prior studies, which have shown that adrenergic influences can reverse the electrophysiologic effects of some antiarrhythmic drags and may provide additional rationale for
397
398
Arnaretak
using ~-blocker medications in combination with membrane-active antiarrhythmic drugs.
References 1. Reddy CP, Gettes LS. Use af isoproterenol as a aid to electric conduction of chronic ventricular lachycardia. Am J Cardio11979;44:705-13. 2. Matsuda j J, Lee H, Shibata EF. Enhancement of rabbit cardiac sodium channels by beta adrenergic stimulation. Circ Res 1992;7:199-208. 3. Lee H, Matsuda Jj, Reynertson SJ, Martins JB, Shibata EF. Reversalof lidocaine effects on sodium currents by isoproterenol in rabbit hearts and heart cells. J Clin Invest 1993;91:693-701. 4. Keane D, Stafford P, Baker S, Lewis S, Jackson G, Vincent R. Signalaveraged electrocardiography of the sinus and paced P wave in sinus node disease. PACE ] 995;18 (7):1346-53. 5. Tytgat J, Vereecke J, Carmaliet E. A combined study of sodium current and T-type calcium current in isolated cardiac calls. Pflugers Arch 1990;417:142-78. 6. Ono K, Kiyosue T, Arita M. Jsoproterenor,dbcAMP and forskolin inhibit cardiac sodium current. Am J Physiol 1989;256:C 1131-7. Z Schubert B, Vandongen AN j, Kitsch GE, Brown AN. Beta adrenergic inhibition of cardiac sodium channels by dual G protein pathways. Science 1989;245-516.
8. Schubert B, Vandongen AN J, Kitsch GE, Brown AN. Inhibition of cardiac sodium currents by isoproterend. Am J PhysioF 1990;258:H97781. 9. Herzig jW, Kohlhardt M. Sodium channel blockade by cyclic AMP and other six aminopyrines in neonatal rat heart. J Mere Bid . ]991 ;119:163-70. ]0. Wendl DJ, Starmer CF, Grant AO. Perforated patch recording ofcardiac sodium channd currents without time dependent changes in kinetics: an approach to the study of hormonal channel regulation. Circulation 1992;80:1-Z 11. Markel ML, Miles WM, LuckJC, Klein LS, Prystowski EM. Differenlial effects of isoproterenol on sustained ventricular tachycardia before and during procainamide quinidine antiarrhythmic drug therapy. Circuration 1993;87:783-92. 12. Kieval RS, Spear JF, Moore EN. Mechanisms of arrhythmias and basis of antiarrhythmic drug action, in: Horovitz LN, editor. Current management of arrhythmias. BC Decker Inc. Philadelphia; 1991. p. 3. ]3. DeMello WC. Increase in functional conductance caused by isaprolerenol in heart cell pairs is suppressed by cAMP-dependent proteinkinase inhibitor. Biochem Biophys Res Commun ]988;154:509-]4. 14. Coumd P, Rosengarten MD, Leclercq JF, Attuel P. Role of sympathetic nervous system in non-ischaemic ventricular arrhythmias. Br HeartJ 1982; 47:137-4Z
American Heart Journal September 1997