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Immediate quantitation of antiarrhythmic drug effect by monophasic action potential recording in coronary artery disease
ImmediateQuantitationof AntiarrhythmicDrug Effect by MonophasicAction Potential Recordingin Coronary Artery Disease EDWARD V. PLATIA, MD, MYRON L. WEISFELDT, MD, and MICHAEL R. FRANZ, MD
A contact electrode catheter, which permits clinkal recording of cardiac monophask action potentials (MAPS), was used as a means of quantifying the electrophysklogic effect of 2 antiarrhythmic bugs, procalnamide and quinidine. ,MAP recordings were made in continuous fashion from the r&#tt ventricle in 16 patients, before and after the intravenous admintstration of procatnamide (11 patients) or qulnidine (5). Increases in the MAP duration at 90 % repolarlration (MAPDso) were used as indexes of drug effect and related to plasma drug level. Surface electrocardl raphic (QRS duration, corrected QT interval [QT,7 ) and eiectrophysiofogic (ventricular effective refractory period) measurements, in addition to MAPDgo, were made at the same time as blood sampling for plasma drug level determination.
P
lasma level determination of antiarrhythmic agents and their active metabolites often is useful in the management of cardiac arrhythmias. However, the analysis of blood samples is time consuming, precluding the use of drug levels during electrophysiologic drug testing or in intensive care situations, which require immediate level determination.lJ Electrocardiographic techniques, such as measurement of the QRS duration and QT interval, have been used as qualitative guides to drug dosage but have been shown to be too imprecise to be used quantitativelya Specific and quantifiable response to antiarrhythmic agents can be meaFrom the Cardiology Division, The Johns Hopkins Medical Institutions, Baltimore, Maryland, and the Cardiac Arrhythmia Center, Washington Hospital Center, Washington, DC. This study was supported in part by a grant from the Medlantic Research Foundation, Washington, DC. Manuscript received December 15, 1987; revised manuscript received February 16, 1988, and accepted February 17. Address for reprints: Edward V. Platia, MD, Cardiac Arrhythmia Center, Washington Hospital Center, 110 Irving Street, Washington, DC 20010.
Dose response curves, ptottkrg change in MAP&, versus plasma drug level, showed stron9 linear correlation for both procakamfde (p
sured in vitro by recording transmembrane action potentials4J However, it has not been possible to record such action potentials in the intact human heart. Recently, a new contact electrode catheter has been developed for continuous, stable recording of monophasic action potentials (MAPS) from the human endocardium.6 These MAPS have been shown to accurately reflect the time course of adjacent transmembrane action potentials7s8 and therefore should be useful in assessing electrophysiologic drug effects in patients. This study shows that procainamide and quinidine produce prolongation of MAP duration that correlates closely with the plasma drug level.
Methods Patient population: We studied 16 patients with a history of sustained ventricular tachycardia (9 patients), ventricular fibrillation (2 patients], or nonsustained ventricular tachycardia (5 patients]. There were 13 males and 3 females, whose ages ranged from 37 to 75 years (mean 54.5). All had coronary artery disease documented by cardiac angiography. All patients underwent electrophysiologic study with programmed
June 1, 1988
ventricular stimulation supplemented by simultaneous recordings made with the MAP catheter. Monophasic action potential recording: MAPS were recorded with a contact electrode catheter similar to that described previously.6 This catheter has 2 nonpolarizable electrodes, 1 forming the catheter tip and the other located 5 mm proximal to the tip. After percutaneous catheter insertion by way of the femoral vein and fluoroscopic positioning of the catheter at the right ventricular apex, MAPS were recorded from a single endocardial site throughout the investigational period. Catheter manipulation and positioning of the tip were carried out in a manner analogous to that of any pacing catheter, with roughly the same degree of ease. The MAPS were amplified by a differential, direct-current coupled amplifier (frequency response 0 to 5,000 Hz) and recorded simultaneously with standard electrocardiographic and filtered (30 to 300 Hz] intracardiac signals at a paper speed of 100 to 200 mm/s. Electropharmacologic study: After informed consent was obtained, all patients were studied in the fasting, nonsedated state, having received no drugs for at least 5 or more drug half-lives.g First, we performed a baseline electrophysiologic study for arrhythmia evaluation, using standard quadripolar catheters. We then determined the baseline effective refractory period at a basic drive cycle length of 500 or 600 ms at the right ventricular apex, near the MAP recording site. Extrastimuli of l-ms pulse duration and twice diastolic threshold strength were applied in diastole with coupling intervals decreasing by 10 ms. The effective refractory period, defined as the longest coupling interval at which the extrastimulus failed to capture the ventricle, was determined for each patient by averaging at least 4 measurements. MAPDSo and QT, were measured during right atria1 pacing within 5 minutes of determining the effective refractory period. Procainamide (20 to 25 mg/kg) or quinidine gluconate (5 mg/kg) was then infused over 20 to 30 minutes. Determinations of the effective refractory period were repeated at the same right ventricular apical site 30 minutes after infusion and then every 10 to 20 minutes for 1 hour. Blood samples were drawn for plasma drug level determination each time an effective refractory period determination was made. Plasma drug level determination: The procainamide plasma level was determined using the method of Carr et aLlo Quini d ine concentrations were measured in pg/ml plasma using fluorometric analysis after benzene extraction [a modification of the Cramer and Isaksson technique).‘l Data analysis: All surface electrocardiographic (surface leads I, aVF, and V,), intracardiac and MAP measurements were obtained by averaging measurements made from at least 5 consecutive complexes during constant right atria1 pacing at 500 or 600 ms. The duration of the MAP was measured, in ms, from the rapid upstroke to 90% repolarization (MAPDgO),as defined previously.6 QT, was measured using the Bazett formula.12 Measurements were made in blinded fashion with respect to intervention and time of recording.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 61
1285
All postdrug electrophysiologic changes were calculated as percent of predrug [baseline) values. Measurements before and after drug administration were compared using the paired Student t test. Data are reported as mean f standard deviation. A p value
Results Monophasic action potential recordings: After positioning the catheter, MAPS were recorded continuously from the same endocardial site throughout the investigational period [generally 2 hours]. Even during programmed stimulation and induction of sustained ventricular tachycardia, the stability of MAP recordings was maintained. Figure 1 shows a typical MAP recording from a right ventricular site near the apex-before and after procainamide infusion-with accompanying surface and intracardiac electrograms. In this example, the MAPDSo increased from 332 ms before to 380 ms after drug infusion. Dose response: Procainamide prolonged the mean MAP duration from a baseline of 233 f 28 ms to a maximum of 269 f 39 ms (p = 0.0051at a mean plasma A
v -
oVF VI RA
”
-r
His
MAPOg0’332mr.
FIGURE 1. Monophaslc action pote&al recordings, along with electrocardlographlc leads aVF and VI and lntracardlac slgnals, made before (Mf) and after (right) lnfuslon of procalnamlde 1 g. RA = right atria1 electrogram; His = HIS bundle electrogram; MAPRv = monophaslc actlon potentlal recorded at rlght ventricular apex; MAPDpo = monophaslc actlon potentlal duratlon measured at 90% repolarlzatlon.
1288
MAP RECOROINGS
TABLE I Correlation Between Plasma Drug Level and Electrophyslologlc/Electrocardloaraphlc Varlsblss Procainamlde
QT QRS ERP MAP&l
Qulnkiine
r
p Value
r
p Value
0.5 0.45 0.28 0.91
0.003 0.008 0.07 <0.0001
0.35 0.3 0.2 0.7
0.02 0.045 0.15
ERP = ventricular effective refractory period; MAPOw = monophasic action potential duration at 90% repolarizatlon: QRS = QRS duration; QT = QT interval; r = linear correlation coeff blent.
Figure 2A shows the relation of MAPDW to plasma drug level and Figure 2B that of QT to plasma drug level for patients receiving procainamide. Table I compares the correlation coefficients and significance levels for the correlation between the electrophysiologic variables QT, QRS, ERP and MAPDgoand plasma levels of procainamide and quinidine. The variance [error of estimation) of the predictive relation, MAP duration versus plasma drug level, was significantly lower than that of QT (p
level of 20.6 f 1.0 rg/ml. Quinidine prolonged the MAP duration from 242 f 17 to 266 f 21 ms (p = 0.015) at a mean plasma level of 2.5 f 6 pg/ml. The ventricular ERP increased from 242 f 35 to 276 f 44 ms (p = 0.014) with procainamide and from 232 f 21 to 259 f 26 ms (P = 0.035)with quinidine. MAPDW correlated closely with plasma drug level, both for procainamide (r = 0.91, p
June 1, 1988
MAPS from a single endocardial site, permitting a direct comparison before and after drug administration. There are several possible reasons why changes in MAP duration were the most accurate predictor of plasma drug concentration in our study. Measurement of electrocardiographic intervals is often imprecise, because the points of termination of the QRS complex and the T wave frequently are slurred and thus subject to inaccurate measurement.1g*20The QRS and QT intervals measured from a surface electrocardiogram reflect global electric activity from all parts of the heart,lgJO which means that dispersion of repolarization in different parts of the myocardium might mask changes in a summated signal. In contrast; MAP signals reflect local electrophysiologic events near the catheter tipU7J1Finally, although all hearts were diseased, the right ventricle from.which MAP recordings were taken may have relatively normal myocardium,22 whereas surface QRS and QT intervals are a summation of values recorded from both normal and diseased myocardium. The correlation between plasma drug level and MAP duration was high but not uniform. The relation between plasma drug level and electrophysiologic effect depends on such variables as serum protein and myocardial binding, receptor kinetics, activity of drug metabolites and drug-drug interactions. Further, diseased myocardium may respond to antiarrhythmic drugs in a different way than does normal myocardiurn. Direct measurement of the electrophysiologic effect, rather than of the plasma drug level assumed to produce it, may be a more meaningful index of therapy. This rationale may apply not only to the assessment of therapeutically,intended drug action but also to the detection of excessive electrophysiologic changes accompanying drug overdosage. This study has several limitations. We studied only the class IA antiarrhythmic agents procainamide and quinidine, and cannot assume that similarly close correlations can be obtained with other drugs. MAPS cannot be used to predict plasma drug levels of class II antiarrhythmic agents, such as propranolol, which have little effect on action potential duration. In contrast, class III antiarrhythmic drugs, such as amiodarone, markedly prolong repolarization and should be excellent candidates for direct and immediate assessment of drug effect as in the present study. Class IC agents, such as flecainide and encainide, would also be expected to prolong action potential duration, whereas class IB drugs, such as lidocaine, should shorten action potential duration. As we expected, although changes in MAPDgOindicated the presence and magnitude of an electrophysiologic drug effect, they did not predict the drug’s efficacy in suppressing inducibility of arrhythmias by programmed stimulation. The crucial effect of an antiarrhythmic drug in preventing serious arrhythmias
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 61
1207
may be its action on diseased tissue, which may not necessarily be measured by a technique dependent upon a recording from a single site in the right ventricle. Much additional research is required to increase our understanding of which type and magnitude of drug effect is needed to suppress a given type of arrhythmia.
Acknowledgment: We are grateful to Lisa Wade and Patti Anne Green for secretarial assistance, Lyn Dupre for editorial advice and Sharon Brooks-Robinson for statistical assistance.
References 1. Kates RE. Plasma level monitoring of antiarrhythmic drugs. Am J Cardiol 1983;52:8C-13c. 2. Brown ]E, Shand DG. Therapeutic drug monitoring of antiarrhythmic agents. Clin Pharmacokinet 1982;7:125-148. 3. Heissenbuttel RH. Bigger JT. The effect of oral quinidine or intraventricuJar conduction in man: correlation of plasma quinidine with changes in QRS duration Am Heart J 1970;60:453-462, 4. Mirro MJ. Watanabe AM, Bailey JC. Electrophysiological effects of the optical isomers of disopyramide and quinidine in the dog. Circ Res 1981; 4a:a67-874.
5. Rosen MR, Gelband H, Hoffman BF. Canine electrocardiographic and cardiac electrophysiologic changes induced by procainamide. Circulation 1972;46:52a-536. 6. Franz MR. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol 1963;51:1629’1634. 7. Franz MR, Spurgeon BH, Weisfeldt ML, Lakatta EG. In vitro validation of a new cardiac catheter technique for recording monophasic action potentials. Em Heart I 1986:7:34-4X 8. Levine JH, Spear JF, Guarnieri T. Weisfeldt ML, DeLangen CD], Becker LC. Moore EN. Cesium chloride induced long QT syndrome: demonstration of afterdepolarizations and triggered activity in vivo. Circulation 1985: 72:1092-1103. 9. Moe GK, Abildskov JA. Antiarrhythmic drugs. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 4th ed. New York: Macmillan, 1970:709-727.
10. Carr K, Woosley RL, Oates ]A. Simultaneous quantification of procainamide and N-acetylprocainamide with high performance liquid chromatogrophy. J Chromatogr 1976;129,363-366. 11. Cramer G, Isaksson B. Quantitative determination of quinidine in plasma. Stand J Clin Lab Invest 1963;15:553-556. 12. Bazett HC. An analysis of the time relations of electrocardiograms. Heart 1920;7:353-370. 13. Snedecor GW, Cochran WG. Statistical Methods, 7th ed. Ames, Iowa: Iowa State University Press, 1960:267. 14. Winer BJ. Statistical Principles in Experimental Design, 2nd ed. New York: McGraw-Hill, 1971:518. 15. Shabetai R, Surawicz B, Hamill W. Monophasic action potentials in man. Circulation 19fi8:38:341-352. 16. Harper RN, Olsson SB, Varnauskas E. Effect of mexiletine on monophasic action potentials recorded from the right ventricle in man. Cardiovasc Res 1974;13:303-310, 17. Olsson SB, Varnauskas E, Korsgren M. Further improved method for measuring monophasic action potentials of the intact human heart. J Electrocordial 1971;4:19-23. 18. Franz MR. Barnheer K. Rafflenbeul W. Haverich A. Lichtlen PR. Monophasic action poteitial mapping in human subjects with normal electrocardiograms: direct evidence for the genesis of the T wave. Circulation 1987;75:379-386, 19. Ahnve S. Errors in the visual determination of corrected QT (QT,) interval during acute myocardial infarction. JACC 1965;5:699-702. 20. Pudda PE, Jouve R, Torresani J. Prolonged electrical systole in acute myocardial infarction. J Electrocardiol 1960:13:337-340. 21. Franz MR. Flaherty JT, Platia EV, Bulkley BH, Weisfeldt ML. Localization of regional myocardial i&hernia by recording of monophosic action potentials. Circulation 1964; 69:593-604. 22. Alpert JS,Braunwald E. Acute myocardial infarction: pathological pathophysiological and clinical manifestations. In: Braunwald E, ed. Heart Disease-A Textbook of Cardiovascular Medicine. 2nd ed. Philadelphia: W.B. Sanders, 1984:1262-1300.
A contact electrode catheter, which permits clinkal recording of cardiac monophask action potentials (MAPS), was used as a means of quantifying the electrophysklogic effect of 2 antiarrhythmic bugs, procalnamide and quinidine. ,MAP recordings were made in continuous fashion from the r&#tt ventricle in 16 patients, before and after the intravenous admintstration of procatnamide (11 patients) or qulnidine (5). Increases in the MAP duration at 90 % repolarlration (MAPDso) were used as indexes of drug effect and related to plasma drug level. Surface electrocardl raphic (QRS duration, corrected QT interval [QT,7 ) and eiectrophysiofogic (ventricular effective refractory period) measurements, in addition to MAPDgo, were made at the same time as blood sampling for plasma drug level determination.
P
lasma level determination of antiarrhythmic agents and their active metabolites often is useful in the management of cardiac arrhythmias. However, the analysis of blood samples is time consuming, precluding the use of drug levels during electrophysiologic drug testing or in intensive care situations, which require immediate level determination.lJ Electrocardiographic techniques, such as measurement of the QRS duration and QT interval, have been used as qualitative guides to drug dosage but have been shown to be too imprecise to be used quantitativelya Specific and quantifiable response to antiarrhythmic agents can be meaFrom the Cardiology Division, The Johns Hopkins Medical Institutions, Baltimore, Maryland, and the Cardiac Arrhythmia Center, Washington Hospital Center, Washington, DC. This study was supported in part by a grant from the Medlantic Research Foundation, Washington, DC. Manuscript received December 15, 1987; revised manuscript received February 16, 1988, and accepted February 17. Address for reprints: Edward V. Platia, MD, Cardiac Arrhythmia Center, Washington Hospital Center, 110 Irving Street, Washington, DC 20010.
Dose response curves, ptottkrg change in MAP&, versus plasma drug level, showed stron9 linear correlation for both procakamfde (p
sured in vitro by recording transmembrane action potentials4J However, it has not been possible to record such action potentials in the intact human heart. Recently, a new contact electrode catheter has been developed for continuous, stable recording of monophasic action potentials (MAPS) from the human endocardium.6 These MAPS have been shown to accurately reflect the time course of adjacent transmembrane action potentials7s8 and therefore should be useful in assessing electrophysiologic drug effects in patients. This study shows that procainamide and quinidine produce prolongation of MAP duration that correlates closely with the plasma drug level.
Methods Patient population: We studied 16 patients with a history of sustained ventricular tachycardia (9 patients), ventricular fibrillation (2 patients], or nonsustained ventricular tachycardia (5 patients]. There were 13 males and 3 females, whose ages ranged from 37 to 75 years (mean 54.5). All had coronary artery disease documented by cardiac angiography. All patients underwent electrophysiologic study with programmed
June 1, 1988
ventricular stimulation supplemented by simultaneous recordings made with the MAP catheter. Monophasic action potential recording: MAPS were recorded with a contact electrode catheter similar to that described previously.6 This catheter has 2 nonpolarizable electrodes, 1 forming the catheter tip and the other located 5 mm proximal to the tip. After percutaneous catheter insertion by way of the femoral vein and fluoroscopic positioning of the catheter at the right ventricular apex, MAPS were recorded from a single endocardial site throughout the investigational period. Catheter manipulation and positioning of the tip were carried out in a manner analogous to that of any pacing catheter, with roughly the same degree of ease. The MAPS were amplified by a differential, direct-current coupled amplifier (frequency response 0 to 5,000 Hz) and recorded simultaneously with standard electrocardiographic and filtered (30 to 300 Hz] intracardiac signals at a paper speed of 100 to 200 mm/s. Electropharmacologic study: After informed consent was obtained, all patients were studied in the fasting, nonsedated state, having received no drugs for at least 5 or more drug half-lives.g First, we performed a baseline electrophysiologic study for arrhythmia evaluation, using standard quadripolar catheters. We then determined the baseline effective refractory period at a basic drive cycle length of 500 or 600 ms at the right ventricular apex, near the MAP recording site. Extrastimuli of l-ms pulse duration and twice diastolic threshold strength were applied in diastole with coupling intervals decreasing by 10 ms. The effective refractory period, defined as the longest coupling interval at which the extrastimulus failed to capture the ventricle, was determined for each patient by averaging at least 4 measurements. MAPDSo and QT, were measured during right atria1 pacing within 5 minutes of determining the effective refractory period. Procainamide (20 to 25 mg/kg) or quinidine gluconate (5 mg/kg) was then infused over 20 to 30 minutes. Determinations of the effective refractory period were repeated at the same right ventricular apical site 30 minutes after infusion and then every 10 to 20 minutes for 1 hour. Blood samples were drawn for plasma drug level determination each time an effective refractory period determination was made. Plasma drug level determination: The procainamide plasma level was determined using the method of Carr et aLlo Quini d ine concentrations were measured in pg/ml plasma using fluorometric analysis after benzene extraction [a modification of the Cramer and Isaksson technique).‘l Data analysis: All surface electrocardiographic (surface leads I, aVF, and V,), intracardiac and MAP measurements were obtained by averaging measurements made from at least 5 consecutive complexes during constant right atria1 pacing at 500 or 600 ms. The duration of the MAP was measured, in ms, from the rapid upstroke to 90% repolarization (MAPDgO),as defined previously.6 QT, was measured using the Bazett formula.12 Measurements were made in blinded fashion with respect to intervention and time of recording.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 61
1285
All postdrug electrophysiologic changes were calculated as percent of predrug [baseline) values. Measurements before and after drug administration were compared using the paired Student t test. Data are reported as mean f standard deviation. A p value
Results Monophasic action potential recordings: After positioning the catheter, MAPS were recorded continuously from the same endocardial site throughout the investigational period [generally 2 hours]. Even during programmed stimulation and induction of sustained ventricular tachycardia, the stability of MAP recordings was maintained. Figure 1 shows a typical MAP recording from a right ventricular site near the apex-before and after procainamide infusion-with accompanying surface and intracardiac electrograms. In this example, the MAPDSo increased from 332 ms before to 380 ms after drug infusion. Dose response: Procainamide prolonged the mean MAP duration from a baseline of 233 f 28 ms to a maximum of 269 f 39 ms (p = 0.0051at a mean plasma A
v -
oVF VI RA
”
-r
His
MAPOg0’332mr.
FIGURE 1. Monophaslc action pote&al recordings, along with electrocardlographlc leads aVF and VI and lntracardlac slgnals, made before (Mf) and after (right) lnfuslon of procalnamlde 1 g. RA = right atria1 electrogram; His = HIS bundle electrogram; MAPRv = monophaslc actlon potentlal recorded at rlght ventricular apex; MAPDpo = monophaslc actlon potentlal duratlon measured at 90% repolarlzatlon.
1288
MAP RECOROINGS
TABLE I Correlation Between Plasma Drug Level and Electrophyslologlc/Electrocardloaraphlc Varlsblss Procainamlde
QT QRS ERP MAP&l
Qulnkiine
r
p Value
r
p Value
0.5 0.45 0.28 0.91
0.003 0.008 0.07 <0.0001
0.35 0.3 0.2 0.7
0.02 0.045 0.15
ERP = ventricular effective refractory period; MAPOw = monophasic action potential duration at 90% repolarizatlon: QRS = QRS duration; QT = QT interval; r = linear correlation coeff blent.
Figure 2A shows the relation of MAPDW to plasma drug level and Figure 2B that of QT to plasma drug level for patients receiving procainamide. Table I compares the correlation coefficients and significance levels for the correlation between the electrophysiologic variables QT, QRS, ERP and MAPDgoand plasma levels of procainamide and quinidine. The variance [error of estimation) of the predictive relation, MAP duration versus plasma drug level, was significantly lower than that of QT (p
level of 20.6 f 1.0 rg/ml. Quinidine prolonged the MAP duration from 242 f 17 to 266 f 21 ms (p = 0.015) at a mean plasma level of 2.5 f 6 pg/ml. The ventricular ERP increased from 242 f 35 to 276 f 44 ms (p = 0.014) with procainamide and from 232 f 21 to 259 f 26 ms (P = 0.035)with quinidine. MAPDW correlated closely with plasma drug level, both for procainamide (r = 0.91, p
June 1, 1988
MAPS from a single endocardial site, permitting a direct comparison before and after drug administration. There are several possible reasons why changes in MAP duration were the most accurate predictor of plasma drug concentration in our study. Measurement of electrocardiographic intervals is often imprecise, because the points of termination of the QRS complex and the T wave frequently are slurred and thus subject to inaccurate measurement.1g*20The QRS and QT intervals measured from a surface electrocardiogram reflect global electric activity from all parts of the heart,lgJO which means that dispersion of repolarization in different parts of the myocardium might mask changes in a summated signal. In contrast; MAP signals reflect local electrophysiologic events near the catheter tipU7J1Finally, although all hearts were diseased, the right ventricle from.which MAP recordings were taken may have relatively normal myocardium,22 whereas surface QRS and QT intervals are a summation of values recorded from both normal and diseased myocardium. The correlation between plasma drug level and MAP duration was high but not uniform. The relation between plasma drug level and electrophysiologic effect depends on such variables as serum protein and myocardial binding, receptor kinetics, activity of drug metabolites and drug-drug interactions. Further, diseased myocardium may respond to antiarrhythmic drugs in a different way than does normal myocardiurn. Direct measurement of the electrophysiologic effect, rather than of the plasma drug level assumed to produce it, may be a more meaningful index of therapy. This rationale may apply not only to the assessment of therapeutically,intended drug action but also to the detection of excessive electrophysiologic changes accompanying drug overdosage. This study has several limitations. We studied only the class IA antiarrhythmic agents procainamide and quinidine, and cannot assume that similarly close correlations can be obtained with other drugs. MAPS cannot be used to predict plasma drug levels of class II antiarrhythmic agents, such as propranolol, which have little effect on action potential duration. In contrast, class III antiarrhythmic drugs, such as amiodarone, markedly prolong repolarization and should be excellent candidates for direct and immediate assessment of drug effect as in the present study. Class IC agents, such as flecainide and encainide, would also be expected to prolong action potential duration, whereas class IB drugs, such as lidocaine, should shorten action potential duration. As we expected, although changes in MAPDgOindicated the presence and magnitude of an electrophysiologic drug effect, they did not predict the drug’s efficacy in suppressing inducibility of arrhythmias by programmed stimulation. The crucial effect of an antiarrhythmic drug in preventing serious arrhythmias
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 61
1207
may be its action on diseased tissue, which may not necessarily be measured by a technique dependent upon a recording from a single site in the right ventricle. Much additional research is required to increase our understanding of which type and magnitude of drug effect is needed to suppress a given type of arrhythmia.
Acknowledgment: We are grateful to Lisa Wade and Patti Anne Green for secretarial assistance, Lyn Dupre for editorial advice and Sharon Brooks-Robinson for statistical assistance.
References 1. Kates RE. Plasma level monitoring of antiarrhythmic drugs. Am J Cardiol 1983;52:8C-13c. 2. Brown ]E, Shand DG. Therapeutic drug monitoring of antiarrhythmic agents. Clin Pharmacokinet 1982;7:125-148. 3. Heissenbuttel RH. Bigger JT. The effect of oral quinidine or intraventricuJar conduction in man: correlation of plasma quinidine with changes in QRS duration Am Heart J 1970;60:453-462, 4. Mirro MJ. Watanabe AM, Bailey JC. Electrophysiological effects of the optical isomers of disopyramide and quinidine in the dog. Circ Res 1981; 4a:a67-874.
5. Rosen MR, Gelband H, Hoffman BF. Canine electrocardiographic and cardiac electrophysiologic changes induced by procainamide. Circulation 1972;46:52a-536. 6. Franz MR. Long-term recording of monophasic action potentials from human endocardium. Am J Cardiol 1963;51:1629’1634. 7. Franz MR, Spurgeon BH, Weisfeldt ML, Lakatta EG. In vitro validation of a new cardiac catheter technique for recording monophasic action potentials. Em Heart I 1986:7:34-4X 8. Levine JH, Spear JF, Guarnieri T. Weisfeldt ML, DeLangen CD], Becker LC. Moore EN. Cesium chloride induced long QT syndrome: demonstration of afterdepolarizations and triggered activity in vivo. Circulation 1985: 72:1092-1103. 9. Moe GK, Abildskov JA. Antiarrhythmic drugs. In: Goodman LS, Gilman A, eds. The Pharmacologic Basis of Therapeutics. 4th ed. New York: Macmillan, 1970:709-727.
10. Carr K, Woosley RL, Oates ]A. Simultaneous quantification of procainamide and N-acetylprocainamide with high performance liquid chromatogrophy. J Chromatogr 1976;129,363-366. 11. Cramer G, Isaksson B. Quantitative determination of quinidine in plasma. Stand J Clin Lab Invest 1963;15:553-556. 12. Bazett HC. An analysis of the time relations of electrocardiograms. Heart 1920;7:353-370. 13. Snedecor GW, Cochran WG. Statistical Methods, 7th ed. Ames, Iowa: Iowa State University Press, 1960:267. 14. Winer BJ. Statistical Principles in Experimental Design, 2nd ed. New York: McGraw-Hill, 1971:518. 15. Shabetai R, Surawicz B, Hamill W. Monophasic action potentials in man. Circulation 19fi8:38:341-352. 16. Harper RN, Olsson SB, Varnauskas E. Effect of mexiletine on monophasic action potentials recorded from the right ventricle in man. Cardiovasc Res 1974;13:303-310, 17. Olsson SB, Varnauskas E, Korsgren M. Further improved method for measuring monophasic action potentials of the intact human heart. J Electrocordial 1971;4:19-23. 18. Franz MR. Barnheer K. Rafflenbeul W. Haverich A. Lichtlen PR. Monophasic action poteitial mapping in human subjects with normal electrocardiograms: direct evidence for the genesis of the T wave. Circulation 1987;75:379-386, 19. Ahnve S. Errors in the visual determination of corrected QT (QT,) interval during acute myocardial infarction. JACC 1965;5:699-702. 20. Pudda PE, Jouve R, Torresani J. Prolonged electrical systole in acute myocardial infarction. J Electrocardiol 1960:13:337-340. 21. Franz MR. Flaherty JT, Platia EV, Bulkley BH, Weisfeldt ML. Localization of regional myocardial i&hernia by recording of monophosic action potentials. Circulation 1964; 69:593-604. 22. Alpert JS,Braunwald E. Acute myocardial infarction: pathological pathophysiological and clinical manifestations. In: Braunwald E, ed. Heart Disease-A Textbook of Cardiovascular Medicine. 2nd ed. Philadelphia: W.B. Sanders, 1984:1262-1300.