Masahiro Usui

ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: insight into the mechanism of Brugada syndrome.

ST Segment Elevation by Class IC Drugs. We evaluated two patients without previous episodes of syncope who showed characteristic ECG changes similar to Brugada syndrome following administration of Class IC drugs, flecainide and pilsicainide, but not following Class IA drugs. Patient 1 had frequent episodes of paroxysmal atrial fibrillation resistant to Class IA drugs. After treatment with flecainide, the ECG showed a marked ST elevation in leads V2, and V3, and the coved‐type configuration of ST segment in lead V2. A signal‐averaged ECG showed late potentials that became more prominent after flecainide. Pilsicainide, a Class IC drug, induced the same ST segment elevation as flecainide, but procainamide did not. Patient 2 also had frequent episodes of paroxysmal atrial fibrillation. Pilsicainide changed atrial flbrillation to atrial flutter with 2:1 ventricular response, and the ECG showed right bundle branch block and a marked coved‐type ST elevation in leads V1 and V2. After termination of atrial flutter, ST segment elevation in leads V1 and V2/ continued. In this patient, procainamide and quinidine did not induce this type of ECG change. In conclusion, strong Na channel blocking drugs induce ST segment elevation similar to Brugada syndrome even in patients without any history of syncope or ventricular fibrillation.

Autonomic Nervous System Activity in Idiopathic Dilated Cardiomyopathy and in Hypertrophic Cardiomyopathy

To assess autonomic nervous activity in patients with cardiomyopathies, analysis of heart rate variability was performed using 24-hour ambulatory electrocardiograms in 14 patients with idiopathic dilated cardiomyopathy (IDC), 15 with hypertrophic cardiomyopathy (HC) and 18 healthy subjects. Heart rate variability during the night and daytime was calculated using fast-Fourier transform, and power spectra were quantified in 2 frequency bandwidths: 0.00 to 0.15 Hz (low-frequency power [LF]) and 0.15 to 0.50 Hz (high-frequency power [HF]). Log(HF) was used as an index of parasympathetic nervous activity, and log(LF/HF), of sympathetic nervous activity. Log(HF) was significantly lower and log(LF/HF) was significantly higher in IDC. These changes were related to ejection fraction. In HC, lower log(HF) and higher log(LF/HF) were recognized only during the night, and these changes were independent of the degree of myocardial hypertrophy. Our results indicated attenuation of parasympathetic activity and enhanced sympathetic activity in HC during the night, and also in IDC. Assessment of autonomic imbalance by analysis of heart rate variability may be useful for understanding the pathophysiology of cardiomyopathies.

Circadian variation of idiopathic ventricular tachycardia originating from right ventricular outflow tract

We determined circadian variation of isolated ventricular premature complexes (VPCs), 2 to 4 consecutive VPCs, and ventricular tachycardia (5 consecutive VPCs) originating from the right ventricular outflow tract in patients without apparent structural heart diseases. There was apparent circadian variation with 2 prominent peaks for these ventricular arrhythmias, and blockade abolished ventricular tachycardia and attenuated the circadian variation of consecutive VPCs.

Parasympathetic activity is a major modulator of the circadian variability of heart rate in healthy subjects and in patients with coronary artery disease or diabetes mellitus

Autonomic heart rate control was assessed by power spectral analysis of heart rate variability in 24-hour ambulatory electrocardiographic recordings from 23 healthy subjects, 14 patients with coronary artery disease without cardiac dysfunction, and 14 patients with diabetes mellitus. The log value of the ratio of the low-frequency component (LF = 0.04 to 0.15 Hz) to the high-frequency component (HF = 0.15 to 0.5 Hz) and logHF were employed as indexes of sympathetic and parasympathetic activity, respectively. Diurnal and nocturnal logLF, logHF, and log(LF/HF) values were calculated for heart rates of 60, 70, and 80 beats/min. Intergroup differences among these three variables were not significant at any heart rate. Although a heart rate-related decrease in logHF was generally observed, the relationship between log(LF/HF) and heart rate was not consistent. The correlation between diurnal and nocturnal logHF values was significant at all three heart rates (r = 0.63, 0.87, and 0.59), whereas the diurnal log(LF/HF) was correlated with the nocturnal value only at 70 beats/min (r = 0.77). These results suggest that the heart rate during normal daily activities is a reliable indicator of parasympathetic tone, if not sympathetic tone, in healthy subjects and patients with coronary artery disease or diabetes mellitus.

Relationship between distribution of hypertrophy and electrocardiographic changes in hypertrophic cardiomyopathy

To assess the relationship between the distribution of hypertrophy and electrocardiographic changes in patients with hypertrophic cardiomyopathy, magnetic resonance imaging and ECG findings were correlated in 25 patients with apical hypertrophy (group I), 15 patients with both apical and basal hypertrophy (group II), and 11 patients with hypertrophy localized to the basal left ventricle (group III). The number of precordial leads with negative T waves (-0.5 mV or more) was greater in group I than in groups II and III (I = 3.0 +/- 1.5, II = 1.7 +/- 1.5, III = 0.3 +/- 0.6; p < 0.01). Giant negative T waves (-1.0 mV or more) in precordial leads were found in 13 patients (52%) in group I and five patients (33%) in group II but were not found in group III. In contrast, tall positive T waves (> or = 1.0 mV) in precordial leads were found in two patients (13%) in group II and five (45%) in group III but were not found in group I. These results suggest that the distribution of hypertrophy in patients with hypertrophic cardiomyopathy produces a particular T wave polarity in precordial leads.

Shock-induced refractory period extension and pharmacologic modulation of defibrillation threshold.

Summary: Shock-induced refractory period extension (RPE) has been suggested as a mechanism of electrical defibrillation. We measured RPE caused by localized field stimulation measured before and during infusion of disopyramide (n = 5), flecainide (n = 5), or E-4031 (n = 5) in anesthetized dogs and determined the effect of the drugs on the internal defibrillation threshold (DFT). In the baseline state (n = 15), 16 V/cm S2 field stimulation prolonged the effective RP by 36 ± 15 ms (22 ± 12% of RP without S2), whereas 4 and 8 V/cm S2 stimuli did not cause marked RPE. The RPE normalized by the RP without S2 was not significantly influenced by any drug (16 V/cm: disopyramide 30 ± 11 vs. 27 ± 11, flecainide 25 ± 5 vs. 19 ± 12, and E-4031 18 ± 13 vs. 22 ± 14%). Disopyramide did not alter the defibrillation threshold (4.2 ± 0.6–4.4 ± 0.6 J). In 2 dogs given flecainide, ventricular fibrillation became refractory to defibrillation. In contrast, E-4031 lowered the threshold from 4.5 ± 2.4 to 2.2 ± 1.2 J (p < 0.01). The results suggest that flecainide and E-4031 do not modulate defibrillation efficiency through their effects on RPE.

Prolongation of intraventricular conduction time associated with fetal impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents

Summary To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 ± 1.5 to 4.4 ± 1.6 J (3.1 ± 1.2 μg/ml)]. Mexiletine tended to increase DFT [from 4.6 ± 1.2 to 6.1 ± 2.0 J (1.8 ± 0.6 μg/ml): p < 0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 ± 3%). Flecainide increased DFT from 4.2 ± 1.3 to 6.1 ± 1.5 J at a plasma level of 1.04 ± 0.37 μg/ml (p < 0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 ± 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.

Slow abnormal conduction in the low right atrium : its anatomic basis and relevance to atrial reentry

To characterize slow abnormal conduction in the low right atrium, which is known to be responsible for atrial flutter, electrophysiologic findings were correlated with anatomic features in a canine model of atrial flutter with ligation of the crista terminalis in the midright atrium. Activation in the low right atrium was mapped with a patch electrode containing 52 bipolar electrodes and a multiplexing system. A particular region in the low right atrium showed atrioventricular node-like electrophysiologic properties, a rate-dependent conduction delay, and Wenckebach periodicity. This area coincided with an area responsible for slow conduction during atrial flutter and unidirectional block at its initiation. Both pilsicainide and E-4031 preferentially blocked conduction in the specific area, leading to the termination of atrial flutter. Although refractoriness could not explain the abnormal conduction, anatomic studies consistently found the specific region to be in or around a thick muscle bundle, that is, the crista terminalis, or a thick pectinate muscle branching from the crista, located perpendicular to the wavefront of the pacing impulse and atrial flutter. These electrophysiologic and anatomic findings suggest that slow abnormal and atrioventricular node-like conduction over a thick muscle bundle, which is a normal anatomic feature of the low right atrium, plays a role in the initiation, maintenance, and termination of atrial reentry.

Effects of pentisomide and E-4031 on canine atrial flutter due to reentry: a comparative study with disopyramide and propafenone.

Effects of new antiarrhythmic drugs, pentisomide [3.5 ± 0.5 mg/kg intravenously (i.v.) n = 8], and E-4031 (5.6 ± 1.0 μg/kg, n = 8), a class III drug, on atrial flutter (AF) caused by reentry were compared with those of disopyramide (1.6 ± 0.2 mg/kg, n = 8) and propafenone (2.2 ± 0.2 mg/kg, n = 8). AF was induced with burst atrial pacing after we made an intercaval crush in anesthetized, open-chest dogs. Termination of AF did not differ among test drugs (8 of 8 with disopyramide, 7 of 8 with propafenone, 6 of 8 with pentisomide, and 8 of 8 with E-4031). Cycle length (CL) of AF was prolonged more with propafenone (57 ± 10%) and pentisomide (41 ± 5%) than with E-4031 < 12 ± 3%, p < 0.05). This was also true for increase in interatrial conduction time determined at a pacing CL of 150 ms. Increase in atrial effective refractory period (ERP) determined at a basic pacing CL of 300 ms did not differ among test drugs. Changes in CL of AF correlated significantly with those in interatrial conduction time (r = 0.84, p < 0.001), but not with those of ERP (r = 0.10, NS). Reinitiation of AF was significantly greater in propafenone (7 of 7) and pentisomide (5 of 6) groups than in disopyramide (1 of 8) and E-4031 (0 of 8) groups (p < 0.001). Pentisomide and E-4031 were effective in terminating canine AF due to reentry, as were disopyramide and propafenone. Reinitiation of AF was greater in dogs treated with antiarrhythmic drugs that had more prominent effects on conduction time than on ERP.

Antifibrillatory effects of class III antiarrhythmic drugs: comparative study with flecainide.

The antifibrillatory effects of flecainide 1 mg/ kg + 0.05 mg/kg/min intravenously (i.v.), bretylium 6 mg/kg i.v., D-sotalol 2 mg/kg + 0.1 mg/kg/min i.v., and E-4031, a new class III drug, 50 μ/kg + 5 μg/kg/min i.v. were compared with three different methods of determining ventricular fibrillation threshold (VFT) in anesthetized open-chest dogs. In protocol 1, VFT was determined with 2-S, 50-Hz continuous pulses. Flecainide (n = 7) prolonged intraventricular conduction time (CT) and ventricular effective refractory period (ERP) and increased VFT significantly. Bretylium (n = 6) prolonged ERP slightly, but did not increase VFT significantly. Both D-sotalol (n = 6) and E-4031 (n = 6) prolonged ERP and increased VFT. In protocol 2, VFT was determined with the extrastimulus technique in dogs, with localized ventricular necrosis produced with protease. Flecainide (n = 10), D-sotalol (n = 8), and E-4031 (n = 8) restored VFT, which had been decreased by protease injection, to the baseline level, whereas bretylium (n = 8) did not. In protocol 3, the train pulse method with 100-Hz train pulses covering the vulnerable period was used in the same dogs used for protocol 2. Flecainide, bretylium, and D-sotalol increased VFT, but E-4031 did not. The antifibrillatory effects of class III drugs differ depending on the method of VFT determination. The present data suggest that the antifibrillatory effects of antiarrhythmic drugs should be assessed by different methods of VFT determination.