Effect of mexiletine on monophasic action potentials recorded from the right ventricle in man.

The effect of mexiletine, a new antiarrhythmic agent, on ventricular refractoriness and monophasic action potentials recorded from the right ventricle was studied in nine subjects. The effective refractory period of the right ventricle was determined by the extra stimulus technique using a pacing electrode situated at the right ventricular apex. Following this determination the right ventricular apex was paced at a constant cycle length and premature stimuli were introduced starting at a coupling interval of 2 ms greater than the ventricular refractory period and then at progressively increasing coupling intervals of 5 ms increments. Simultaneous recordings of monophasic action potentials of both the regular paced beats and the induced premature beats were made using a specially designed suction electrode catheter. The monophasic action potential durations were measured at 50% and 90% repolarisation. All these control measurements were repeated after an intravenous dose of 2 mg.kg-1 body wt. of mexiletine. The results showed that mexiletine did not significantly change the effective ventricular refractory period nor did it alter the monophasic action potential duration of the regular paced beat. The drug did, however, significantly prolong the monophasic action potential duration of the early induced premature beats and it is possible that this property of the drug may be related to its antiarrhythmic activity.     

Endocardial monophasic action potential recordings for the detection of myocardial ischemia in man: a study using atrial pacing stress and myocardial perfusion scintigraphy

In a study designed to appraise the use of monophasic action potentials (MAPs) to detect myocardial ischemia in endocardial recordings, changes in steady-state MAP duration were compared in recordings between normal and ischemic areas of myocardium identified by the use of a radionuclide tracer simultaneously with the MAP recording procedure. Single-site recordings were made from the left or right ventricular endocardium or both in 26 patients (32 recording sites) during atrial pacing up to angina threshold. Pacing was maintained for 2 minutes at each increment in heart rate and MAPs were recorded at the end of each 2-minute period. Perfusion defects produced by atrial pacing stress were detected using technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile injected at peak pacing stress. In 18 recordings from normally perfused areas of endocardium, MAP duration at 70% and 90% repolarization shortened by a mean (+/- SD) of 20.9 (3.7) msec and 22.0 (4.8 msec, respectively, for every 100 msec change in cycle length. This is in keeping with the effect of cycle length changes on the action potential duration. The extent of shortening was significantly greater (p less than 0.01) for 14 recordings from ischemic areas, being 32.0 (8.6) and 33.8 (9.7) msec, respectively, indicating the additional effect of localized myocardial ischemia. These results validate the applicability of the endocardially recorded MAPs for the detection of ischemia. Such methodology may provide a means of assessing therapeutic interventions aimed at the early phase of ischemia.     

体表心电图、腔内单极电图与单相动作电位测定心室复极离散度相关分析

目的探讨心室复极离散度测定方法的可靠性.方法对19例无器质性心脏病者,应用左、右心室内膜单相动作电位(MAP)标测、腔内单极电图(UECG)和体表12导联同步心电图(ECG)3种方法研究心室复极离散度.结果UECG测值(UQ-Td,33±7ms)大于MAP测值(RTd,27±6ms,P＜0.01),而小于体表心电图测值(Q-Td,38±7m,P＜0.01),即Q-Td＞UQ-Td＞R-Td,但UQ-Td与R-Td、UQ-Td与Q-Td、R-Td与Q-Td均呈显著线性相关(r=0.75、0.87,0.78,P均＜0.01).结论体表心电图Q-Td可以代表心室复极离散.     

The monophasic action potential upstroke: a means of characterizing local conduction

The upstrokes of monophasic action potentials (MAPs) recorded with an extracellular pressure electrode were characterized in isolated canine tissue preparations in vitro. The characteristics of the MAP upstroke were compared with those of the local action potential foot as well as with the characteristics of approaching electrical activation during uniform and asynchronous conduction. The upstroke of the MAP was exponential during uniform conduction. The time constant of rise of the MAP upstroke (TMAP) correlated with that of the action potential foot (Tfoot): TMAP + 1.01 Tfoot + 0.50; r2 = .80. Furthermore, changes in Tfoot with alterations in cycle length were associated with similar changes in TMAP: Tfoot = 1.06 TMAP - 0.11; r2 = .78. In addition, TMAP and Tfoot both deviated from exponential during asynchronous activation; the inflections that developed in the MAP upstroke correlated in time with intracellular action potential upstrokes that were asynchronous in onset in these tissues. Finally, the field of view of the MAP was determined and was found to be dependent in part on tissue architecture and the space constant. Specifically, the field of view of the MAP was found to be greater parallel compared with transverse to fiber orientation (6.02 +/- 1.74 vs 3.03 +/- 1.10 mm; p less than .01). These data suggest that the MAP upstroke may be used to define and characterize local electrical activation. The relatively large field of view of the MAP suggests that this technique may be a sensitive means to record focal membrane phenomena in vivo.     

Initial vectors of ventricular premature beats and anterior fascicular conduction defects.

Vectorcardiographic studies on ventricular premature beats (VPB'S), occurring in records wherein the sinus beats were associated with an intraventricular conduction defect attributed to anterior fascicular delay or block, did not identify the exact site of a presumed reentry mechanism.The hypothesis that the orientation of the initial vectors of the VPB might reveal either anterograde or retrograde emergence from the anterior fasciulus iwth a reentry PVB was not strongly supported, although one or the other mechanism was compatible with the early vectors of certain VPBs. The VPBs revealed greater angular change on the spatial orientation of sequential early vectors (5--10--15 milliseconds) than occurred in sinus beats. Recurring VPBs, which appeared to casual visual inspection steriotyped in form, showed considerable variation in the orientation of the early vectors, indicating, in the cases studied, that VPBs, in the strictest sense, may be associated with differing initial entrance pathways to the myocardium and thus may be 'multiform'.     

Recording of monophasic action potentials of the right ventricle in long QT syndromes complicated by severe ventricular arrhythmias

Monophasic action potentials (MAPs) were recorded with intracardiacsuction electrodes in several areas of the right ventricle in10 patients with long QT syndromes (with ‘torsades depointe’) of different etiology. In all cases two characteristic electrophysiological featureswere observed: (1) a marked difference in MAP duration in thedifferent areas of the right ventricle (asynchronous repolarization);(2) an alteration in the shape of the longest MAPs consistingin humps which occurred on the repolarization phase of MAP. Humps may be interpreted as delayed repolarization phenomenaprobably due to a decrease in potassium conductance of someventricular cells. These may lead to focal re-excitation asa result of partial membrane depolarization. Focal re-excitationseems to play a key role in the genesis of severe arrhythmiasoccurring in the above mentioned syndromes.     

The epicardial electrogram: a quantitative assessment during balloon angioplasty incorporating monophasic action potential recordings.

An electrogram was recorded from the angioplasty catheter guide wire when coronary blood flow was interrupted in 20 patients undergoing percutaneous transluminal coronary angioplasty. Monophasic action potentials were recorded from the right ventricular septum together with the routine electrocardiogram. The patients were studied during angioplasty for lesions in the left anterior descending (12), circumflex (3), and right coronary arteries (6). ST elevation in the electrogram recorded in the left anterior descending and circumflex systems was usually more obvious than that in the electrocardiogram. Signals obtained from the right coronary artery were of very low amplitude and registered only minimal ST changes. The ST elevation developed in the electrogram during insertion of the catheter before inflation of the balloon in 11 of the 15 patients undergoing angioplasty of the left system. In eight of the patients showing pre-inflation ST elevation the ST shift lessened after successive inflations. Monophasic action potential recordings were obtained during 45 balloon inflations in 19 patients. In those patients undergoing angioplasty for lesions of the circumflex coronary artery the monophasic action potential showed no change during balloon inflation. In patients undergoing angioplasty for the right coronary artery the mean normalised duration at 60 seconds' occlusion was 99.6 (1.5)% of control. Of a total of 25 occlusions in the patients undergoing angioplasty for the left anterior descending coronary artery 19 showed shortening of less than 5%, five showed shortening between 5 and 10%, and one showed a shortening of 16.4% in the monophasic action potential. The QT interval was satisfactorily measured in the electrogram during 36 balloon inflations, and in 24 of these it was also measured in the electrocardiogram. QT changes in the electrogram tended to be the opposite of those in the electrocardiogram. When changes in RR interval were minimal (less than 20 ms) during the balloon inflation 14 of 17 electrograms showed QT prolongation but only one of 12 electrocardiograms showed prolongation. Conversely one of 17 electrograms showed shortening compared with eight of 12 electrocardiograms. There was angiographic evidence of the development of collaterals in six of 15 patients undergoing angioplasty of the left system. ST segment elevation in both the electrogram and electrocardiogram was less pronounced in these patients than in those without evidence of the development of collaterals. ST segment changes recorded from the angioplasty guide wire provide a more sensitive index of ischaemia than the surface 12 lead electrocardiogram, and fall in ST segments on balloon deflation is a prognostic index of a good angiographic result in the left anterior descending and circumflex arteries, but not in the right coronary artery.     

Effects of lidocaine, procainamide, metoprolol, digoxin and atropine on the conduction of premature ventricular beats in man

The acute electrophysiologic effects of clinical doses of procainamide, lidocaine, metoprolol, digoxin and atropine upon the conduction of ventricular premature beats, were studied in 48 healthy volunteers. The conduction time of the first premature beat, induced 1 ms after the ventricular effective refractory period (VERP) was longer than that of the basic paced beats in 41 of the 48 subjects (85%); in 31 (65%) the delay was greater than 5 ms, indicating subnormal conduction. Digoxin decreased the delay so that it became insignificant, while, after procainamide, the delay increased significantly. The other agents did not significantly affect the subnormal conduction. The mean conduction times of premature beats, induced 30-50 ms after the VERP, were shorter than the basic conduction time in 43 of the 48 subjects (90%), and in 25 (52%) the decrease was greater than 5 ms, showing supernormal conduction. Lidocaine abolished the supernormal conduction. The other agents did not significantly alter the supernormal conduction. In the healthy heart, sub- and supernormal conduction of premature beats seem to be common phenomena, and seem, with few exceptions, to be largely unaffected by clinical doses of procainamide, lidocaine, metoprolol, digoxin and atropine.     

Clinical electrophysiologic study of antiarrhythmic properties of flecainide: Acute intraventricular delayed conduction and prolonged repolarization in regular paced and premature beats using intracardiac monophasic action potentials with programmed stimulation

Flecainide acetate is one of the few antiarrhythmic drugs that substantially delay myocardial repolarization in tissue preparations. The potential clinical benefit of this mechanism stimulated our study of the acute effects of this agent on intraventricular conduction and repolarization in man. Thus three normals and six patients were studied before and after an intravenous dose of 2 mg of flecainide/kg. We determined ventricular effective refractory period (VERP) and recorded monophasic action potentials (MAP) from the right ventricle during induction of ventricular ectopic beats with coupling intervals of VERP +1, +30, +40, and +50 msec. Flecainide induced significant prolongations of MAP (+9.6%, p < 0.01) and VERP (+9.8%, p < 0.05) during regular pacing, as well as delayed intraventricular conduction time (+16.8%, p < 0.05). The MAP of the earliest inducible ventricular ectopic beat was even more markedly prolonged (+19.0%, p < 0.001) and at coupling intervals 30 to 50 msec longer than VERP such considerable prolongation remained (+14.2%, p < 0.001). In addition, this study illustrates the utility of the MAP ventricular recording method, combined with programmed ventricular stimulation, in demonstrating clinical electrophyslologic properties directly comparable with those of microelectrode investigations.     

Dispersion of monophasic action potential duration: demonstrable in humans after premature ventricular extrastimulation but not in steady state.

Abnormal dispersion of repolarization may contribute to the arrhythmogenic physiologic substrate of ventricular arrhythmia. Geographic dispersion of monophasic action potential duration was determined in steady state (drive cycle lengths 600 and 430 ms) between widely spaced right ventricular endocardial sites (geographic dispersion) in 10 control patients with right ventricular disease and complicating ventricular tachycardia (n = 9), 6 patients with right and left ventricular disease and complicating ventricular tachycardia and 7 patients with ischemic heart disease and complicating ventricular tachycardia. No significant difference in geographic dispersion could be demonstrated among the groups. Difference of monophasic action potential duration at adjacent right ventricular endocardial sites (adjacent dispersion) was determined after ventricular extrastimulation during construction of simultaneous electrical restitution curves in the same patient groups. Maximal adjacent dispersion over the electrical restitution curve was compared between disease and control groups. There was a significant difference in observations of maximal adjacent dispersion in patients with right ventricular disease and complicating ventricular tachycardia (range 5 to 85 ms, median 22.5; 14 pairs of sites; p less than 0.05) and patients with right and left ventricular disease and complicating ventricular tachycardia (range 5 to 50 ms, median 17.5; 14 pairs of sites; p less than 0.05) compared with control patients (range 5 to 20 ms, median 10; 15 pairs of sites). This difference was not evident when patients with ischemic heart disease and complicating ventricular tachycardia (range 5 to 25 ms, median 12.5; 12 pairs of sites) were compared with control patients. Maximal percent monophasic action potential shortening from steady state was significantly greater (p less than 0.001) in both groups with greater adjacent dispersions, and prolongation of activation time at monophasic action potential recording sites after premature extrastimulation tended to be greater in patients with right or right and left ventricular disease and complicating ventricular tachycardia. It is concluded that in disease, exaggeration of monophasic action potential shortening after premature ventricular extrastimulation may contribute to the electrophysiologic arrhythmogenic substrate.     

Efficacy of disopyramide and mexiletine used alone or in combination in the treatment of ventricular premature beats

The efficacy of oral disopyramide and mexiletine used alone or in combination was studied in 75 patients with frequent ventricular premature beats (VPBs). The efficacy was evaluated with 24-hour ambulatory ECG and 75% reduction in the number of VPBs was defined as effective. When disopyramide or mexiletine were ineffective or not tolerated, the alternative drug was administered and the efficacy was again evaluated. If the single administration of neither drug was effective, the combination of disopyramide and mexiletine was then given. Either disopyramide or mexiletine was effective in 48 patients, and neither drug was effective in 19 patients. In 19 patients unresponsive to both drugs, combination therapy was effective in six patients (32%). Both drugs caused side effects or one drug caused side effects and another drug was ineffective in eight patients. In five out of those patients, we attempted combined therapy with a reduced dosage of those drugs that caused side effects. This therapy was effective in two patients without intolerable side effects. Thus, when the single use of neither disopyramide nor mexiletine single-drug therapy is effective, it is worth-while to try combination therapy. Also, combination therapy with a reduced dosage of the drugs that caused side effects might be the therapy of choice in patients who have developed dose-dependent side effects.     

Effect of ventricular premature beats on idioventricular pacemaker activity

The effect of ventricular premature beats on idioventricular pacemaker activity was studied in open-chest dog hearts with a surgically induced block in the His bundle. While the ventricle was paced by basic stimuli at a given rate, the pacing was interrupted for about 2.5 seconds following every twelfth basic beat (V₁) in order to obtain the interval between V₁ and the first escape beat (V_e) or the basic escape interval (V₁V_e). Ventricular premature beats (V₂) were then introduced at various coupling intervals (V₁V₂) and the effect of these premature beats on the postextrasystolic escape interval (V₁V_e) was observed. The plot of V₂V_e against V₁V₂ intervals showed that the V₂V_e interval was shortest at shorter V₁V₂ intervals, and it increased gradually with the increase in V₁V₂ intervals. The V₂V_e intervals at shorter coupling intervals were much shorter than the basic escape interval (V₁V_e), indicating enhanced automaticity after early premature beats. The V₂V_e at longer coupling intervals were much longer than the basic escape intervals, indicating suppressed automaticity after late premature beats. The similar response to ventricular premature beats was noted during spontaneous idioventricular rhythm. The suppression was more pronounced at faster pacing rates and following two successive premature beats, probably due to the phenomenon of overdrive suppression. The same phenomena of altered automaticity after premature beats could be observed under the influence of ouabain, epinephrine, lidocaine, and propranolol, although these agents either decreased or increased the average escape intervals. The results may explain the clinically observed alteration of the idioventricular pacemaker rate following ventricular premature beats.     

The epicardial electrogram: a quantitative assessment during balloon angioplasty incorporating monophasic action potential recordings

An electrogram was recorded from the angioplasty catheter guide wire when coronary blood flow was interrupted in 20 patients undergoing percutaneous transluminal coronary angioplasty. Monophasic action potentials were recorded from the right ventricular septum together with the routine electrocardiogram. The patients were studied during angioplasty for lesions in the left anterior descending (12), circumflex (3), and right coronary arteries (6). ST elevation in the electrogram recorded in the left anterior descending and circumflex systems was usually more obvious than that in the electrocardiogram. Signals obtained from the right coronary artery were of very low amplitude and registered only minimal ST changes. The ST elevation developed in the electrogram during insertion of the catheter before inflation of the balloon in 11 of the 15 patients undergoing angioplasty of the left system. In eight of the patients showing pre-inflation ST elevation the ST shift lessened after successive inflations. Monophasic action potential recordings were obtained during 45 balloon inflations in 19 patients. In those patients undergoing angioplasty for lesions of the circumflex coronary artery the monophasic action potential showed no change during balloon inflation. In patients undergoing angioplasty for the right coronary artery the mean normalised duration at 60 seconds' occlusion was 99.6 (1.5)% of control. Of a total of 25 occlusions in the patients undergoing angioplasty for the left anterior descending coronary artery 19 showed shortening of less than 5%, five showed shortening between 5 and 10%, and one showed a shortening of 16.4% in the monophasic action potential. The QT interval was satisfactorily measured in the electrogram during 36 balloon inflations, and in 24 of these it was also measured in the electrocardiogram. QT changes in the electrogram tended to be the opposite of those in the electrocardiogram. When changes in RR interval were minimal (less than 20 ms) during the balloon inflation 14 of 17 electrograms showed QT prolongation but only one of 12 electrocardiograms showed prolongation. Conversely one of 17 electrograms showed shortening compared with eight of 12 electrocardiograms. There was angiographic evidence of the development of collaterals in six of 15 patients undergoing angioplasty of the left system. ST segment elevation in both the electrogram and electrocardiogram was less pronounced in these patients than in those without evidence of the development of collaterals. ST segment changes recorded from the angioplasty guide wire provide a more sensitive index of ischaemia than the surface 12 lead electrocardiogram, and fall in ST segments on balloon deflation is a prognostic index of a good angiographic result in the left anterior descending and circumflex arteries, but not in the right coronary artery.