Yasuo Nagamoto

Relationship of alternans of monophasic action potential and conduction delay inside the ischemic border zone to serious ventricular arrhythmia during acute myocardial ischemia in dogs

We studied the relationship of conduction delay and monophasic action potential (MAP) at an ischemic border zone to serious ventricular arrhythmia (VA). Measurements were made in 36 adult mongrel dogs 15 minutes after occlusion of the left anterior descending coronary artery. We recorded MAPs and bipolar electrograms simultaneously inside and outside the ischemic border zone in the dog hearts. Of the 36 dogs, 24 that had favorable MAP recordings were chosen and were divided into two groups according to an occurrence of VA. In group A (n = 12), an onset time of VA was 5.1 +/- 0.8 minutes after ischemia, while in group B (n = 12) VA did not occur during ischemia. The conduction delay at the ischemic border zone was significantly greater from 3 minutes after ischemia in group A than in group B. MAP alternans, defined as the difference in duration of two consecutive MAPs inside the ischemic border, was marked in group A but mild in group B. Duration of a small MAP of alternans was markedly shorter than that of a corresponding MAP outside the ischemic border in both groups, but was followed by VA in group A. Duration of a large MAP was markedly prolonged compared with that of a corresponding MAP outside the ischemic border in seven dogs of group A and in only one dog of group B (p less than 0.01), and was followed by VA in seven dogs of group A. Our results suggest that the mechanism of VA is due not only to reentry but also to an injury current flowing from ischemic to nonischemic tissues, because VA was preceded by conduction delay and by a difference in MAP durations when comparing regions inside and outside the ischemic border.

ELECTROPHYSIOLOGICAL ACTIONS OF MEXILETINE (Kö1173) ON CANINE PURKINJE FIBRES AND VENTRICULAR MUSCLE

1 The effects of mexiletine (Kö1173) were investigated in canine isolated cardiac Purkinje fibres and ventricular muscle with microelectrodes. Some Purkinje fibres were depolarized by mechanical stretch to induce spontaneous activity with slow upstroke velocity. The preparations were stimulated at rates of 1, 2, 3 and 4 Hz. The drug concentrations tested were 0.4, 2 and 10 μg/ml in Tyrode solution (KCl = 5.4 mm). 2 The ‘therapeutic’ drug concentration (2 μg/ml) shortened action potential duration and effective refractory period of Purkinje fibres, the effect being pronounced at lower stimulation rates. In ventricular fibres, action potential duration changes were not consistent while the effective refractory period was prolonged. 3 In depolarized Purkinje fibres showing automatic activity, the drug (0.4 or 2 μg/ml) depressed phase 4 depolarization and reduced the firing rate without changing maximum diastolic potential. However, when depolarized Purkinje fibres were electrically driven at a constant rate, the maximum diastolic potential became more negative with a concomitant decrease of pacemaker slope and increase of maximum rate of rise (V̇max) of action potentials. 4 Moderate (2 μg/ml) to high (10 μg/ml) concentrations of the drug depressed V̇max in Purkinje fibres stimulated at 2 Hz by 12 and 42% respectively and depressed ‘membrane responsiveness’. The decrease in V̇max depended upon the stimulation rate, being minimum at the lowest (1 Hz) and maximum at the highest (4 Hz) stimulation rate. 5 The drug (2 μg/ml) improved V̇max of the earliest propagated premature action potentials by shifting the takeoff potential to more negative levels in both Purkinje and ventricular fibres. 6 Membrane conductance in fibres mounted in a single sucrose gap chamber was increased by the drug (2 μg/ml) in both fibre types in normal and in Na+ ‐deficient solutions. This increase was attributed to an increase in membrane K+ permeability produced by the drug. 7 All these effects are similar to those of lignocaine, diphenylhydantoin or aprindine, and can explain the antiarrhythmic action of mexiletine.

Ventricular fibrillation during partial reperfusion following severe myocardial ischemia in the canine model

The authors examined whether partial reperfusion protects against reperfusion ventricular fibrillation (VF) following severe acute myocardial ischemia. Fifty-seven dogs were divided into two groups. In group A (n = 21), the left anterior descending coronary artery was occluded for 10 minutes, followed by full reperfusion. In the remaining 36 dogs (group B), myocardial ischemia was induced by retrograde blood flow (RBF) for 10 minutes. Thereafter, these dogs were divided into three subgroups: in group B1 (n = 10), full reperfusion was made by a carotid-left anterior descending coronary artery bypass; in group B2 (n = 13), partial reperfusion was achieved by collateral flow into the ischemic zone due to stopping RBF; in group B3 (n = 13), RBF was continued for an additional 5 minutes. During 10 minute ischemia, the myocardial blood flow at the ischemic zone measured by the H2 gas-clearance method was 12.3 +/- 2.0 ml/min/100 g in A, 3.4 +/- 0.9 ml/min/100 g in B1, 4.7 +/- 0.6 ml/min/100 g in B2, and 4.7 +/- 0.6 ml/min/100 g in B3 (A vs B1, p less than 0.02; A vs B2 and B3, p less than 0.01). Maximal ST-segment elevation was 11.4 +/- 1.8 mV in A, 28.2 +/- 2.7 mV in B1, 25.1 +/- 3.0 mV in B2, and 27.0 +/- 1.9 mV in B3 (A vs B1, B2, and B3, p less than 0.001). Maximal conduction delay was 48.6 +/- 9.4 ms in A, 106.4 +/- 5.2 ms in B1, 101.6 +/- 9.9 ms in B2, and 91.2 +/- 5.1 ms in B3 (A vs B1, B2, and B3, p less than 0.001). The incidence of reperfusion VF was 14% (3/21) in A, 80% (8/10) in B1, and 69% (9/13) in B2 (A vs B1, p less than 0.001; A vs B2, p less than 0.005). In group B3, VF occurred in only 1 of 13 dogs for the additional 5 minutes. It is concluded that reperfusion VF occurred frequently when ischemia was severe even though the duration of ischemia was short (B1), and that reperfusion VF was not prevented by partial reperfusion when the ischemia was severe (B2).

Effects of lidocaine and diltiazem on recovery of electrophysiologic activity during partial reperfusion following severe myocardial ischemia in canine hearts

The effects of lidocaine and diltiazem on recovery of electrophysiologic activity during partial reperfusion following severe myocardial ischemia were investigated in 28 dogs. The left anterior descending artery was ligated, and the distal end was connected to the carotid artery. Myocardial ischemia was induced by retrograde blood flow for 10 minutes, after which flow-limited reperfusion (30-60% of the coronary flow before ischemia) was performed. The dogs were divided according to the agent administered before ischemia into the following three groups: saline (group S, n = 11); lidocaine (group L, n = 8, 0.07 mg/kg/min by intravenous drip infusion following 2 mg/kg intravenous injection); and diltiazem (group D, n = 9, 0.02 mg/kg/min by intravenous drip infusion. There were no significant differences among the three groups in the incidence of ventricular tachyarrhythmia, which occurred as ventricular tachycardia (VT) or ventricular fibrillation (VF). In each group, the occurrence of VT was frequently preceded by delayed potential which was initiated after reperfusion, with depressed conduction in the epicardium, suggesting reentry (82%, 96%, and 87%, not significant). The determining factors for VT with degeneration into VF were long duration of VT in groups S and L (VT with degeneration into VF vs VT without, 1.2 +/- 0.2 seconds vs 0.6 +/- 0.1 seconds, P < .05, in group S and 11.6 +/- 2.5 seconds vs 2.2 +/- 0.4 seconds, P < .05, in group L), and decrease in average R-R interval during VT in groups L and D (195 +/- 8 ms vs 313 +/- 17 ms, P< .01, in group L and 201 +/- 11 ms vs 327 +/- 28 ms, P< 0.01, in group D). In addition, occurrence of epicardial electrophysiologic activity with reduced time from onset of the QRS complex in the surface electrocardiogram to the onset of the activity during VT preceded VF in group L (VT with degeneration into VF vs VT without, 130.0 +/- 15.1 ms vs 185.8 +/- 21.4 ms, P < .05), while that with prolongation of the time had this effect in group D (116.0 +/- 15.7 ms vs 69.0 +/- 10.7 ms, P < .05). It is concluded that, even when partial reperfusion is applied, neither lidocaine nor diltiazem suppresses VT because neither drug decreases delayed potential acting as a triggering factor or suppresses VF, since the alteration of the epicardial conductivity during VT can change the VT circuit to a smaller one.