Discordant prolongation of the refractory period and repolarization time by a class III agent, E4031, in the healing phase of myocardial infarction.

Susceptibility to reentrant tachyarrhythmias and the antiarrhythmic efficacy of class III agents are related more to the duration of the refractory period (ERP) than to the repolarization time (RT). We measured both ERP and RT in a canine model of healing myocardial infarction, and evaluated the effect of a class III agent (E4031) on these parameters and on the inducibility of ventricular tachyarrhythmias. ERP and RT on the unipolar electrogram were measured at several cycle lengths in the normal (NZ) and infarct zones (IZ), respectively, in 10 canine myocardial infarction models and extrastimulation was used to induce ventricular arrhythmias. Measurements were repeated after E4031 administration. At baseline, both ERP and RT were significantly longer in IZ than in NZ with ERP/RT ratio also higher in IZ. This ratio tended to increase at longer cycle lengths. E4031 increased ERP and RT both in NZ and IZ at all cycle lengths, but increased the ERP/RT ratio predominantly in IZ. E4031 prevented induction of sustained VT or VF, which was inducible in 3 out of 10 dogs at baseline, although it facilitated induction of VF in 1 dog with no baseline arrhythmia. By increasing the ERP/RT ratio, class III drugs may shorten the relative refractory period in IZ at the expense of a greater ERP difference created between NZ and IZ.

Rate-dependent anisotropic conduction property in the epicardial border zone of canine myocardial infarcts and its modification by moricizine.

We evaluated anisotropic conduction properties, different conduction velocities depending on fiber orientation, in normal and infarcted myocardium and the effects of moricizine on anisotropic conduction. Various cycle lengths of stimulation were applied to 15 mongrel dogs, and epicardial mapping was performed using a 96-channel mapping electrode. Moricizine was then administered to seven dogs and the same procedure was performed. Conduction velocities were calculated from these maps. Programmed electrical stimulations were performed before and after moricizine administration to induce ventricular arrhythmias. Before moricizine administration, a rate-dependent decrease in longitudinal conduction velocity was observed in the infarcted zone. Moricizine suppressed longitudinal conduction in the normal zone significantly at 300 msec pacing, but not at slower rates. Moricizine at a dose of 4 mg/kg, on the other hand, suppressed longitudinal conduction in the infarcted zone significantly at all pacing cycle lengths. The effect of moricizine on transverse conduction was inconsistent. In three dogs, sustained ventricular tachycardia (VT) was induced either before or after moricizine administration. The mean cycle length of sustained VT was prolonged from 202 msec to 291 msec after 4 mg/kg of moricizine. Thus, the changes in cycle length of ventricular tachycardia observed were most likely the result of slowing of conduction velocity, especially in the longitudinal direction, in the infarcted myocardium. We conclude that the electrophysiologic nature of the subacute ischemic model was modified by moricizine, leading to depression of the conduction velocity of longitudinal conduction and the inducibility of ventricular arrhythmias.

Sympathetic denervation of the epicardial border zone in the genesis of dispersion of refractoriness and arrhythmogenesis in a 7-day-old canine myocardial infarction model.

BACKGROUND: The purpose of this study was to clarify whether sympathetic denervation occurs in the infarcted heart and contributes to the dispersion of the effective refractory period (ERP) and arrhythmogenesis. METHODS: ERP was measured at 47 epicardial sites in 13 dogs with 7-day-old infarctions after proximal ligation of the left anterior descending artery. To delineate the sympathetic innervation, the effects of ansae subclaviae stimulation (ASS), norepinephrine infusion, and prazosin infusion on ERP were tested. RESULTS: The per cent change in ERP (delta ERP) induced by ASS was significantly lower at test sites where the surviving epicardial myocardial thickness (Th) was 2 mm or less than at those with a Th of more than 2 mm and the normal zone. Eleven out of 179 sites (6.1%) overlying the infarct showed no ERP change after ASS. ASS paradoxically prolonged ERP at 29 sites (16.2%). In contrast, norepinephrine infusion produced a greater delta ERP in the infarct zone than in the normal zone. Prazosin shortened ERP at sites where ASS prolonged it, but had no effect at sites where ASS shortened ERP. ASS increased both the degree of ERP dispersion and inducibility of ventricular tachycardias or ventricular fibrillation (VT/VF), whereas norepinephrine increased VT/VF inducibility despite a reduction in ERP dispersion. CONCLUSIONS: We conclude that heterogeneous sympathetic denervation contributed to a prolongation and dispersion of ERP in the surviving epicardium overlying the infarct. Furthermore, a supersensitive response to norepinephrine with resultant ERP shortening and a paradoxical ERP prolongation during ASS caused by alpha-receptor mechanisms that may be related to increased electrical instability were observed.

Quantitative indices of dispersion of refractoriness for identification of propensity to re-entrant ventricular tachycardia in a canine model of myocardial infarction.

STUDY OBJECTIVE: To identify propensity to re-entry in a canine model of 7 day old myocardial infarction, the sensitivity and specificity of five indices of dispersion of refractoriness (ERP) were investigated. DESIGN: With an epicardial patch electrode containing 47 electrodes, ERP was measured by S1-S2 method at each site overlying the infarct. ERP range, maximum adjacent dispersion, difference between mean ERPS of the infarct and normal zones, standard deviation (sigma) of the mean ERP, and sigma/mean ERP X 100 were calculated. EXPERIMENTAL MATERIAL: 42 dogs were divided into three groups; 20 dogs with epicardial functional block on induction of sustained ventricular tachycardia or fibrillation, 10 dogs with inducible ventricular tachycardia or fibrillation but without epicardial functional block, and 12 control dogs without ventricular tachycardia, fibrillation or block. MEASUREMENTS AND MAIN RESULTS: All five indices were significantly greater in the 20 dogs with ventricular tachycardia or fibrillation than in control dogs. A receiver operating characteristic curve analysis of the five indices showed that sigma was the most sensitive and specific index for discriminating these 20 dogs. The sensitivity and specificity of a sigma value greater than 14 ms (the mean value plus two SD of the control dogs) were 70% and 100%, respectively.

Electrophysiologic effects of E-4031, a class III antiarrhythmic agent, on re-entrant ventricular arrhythmias in a canine 7-day-old myocardial infarction model.

Effects of E-4031, a class III antiarrhythmic agent, on re-entrant ventricular arrhythmias were studied in eight dogs with a 7-day-old myocardial infarction. Epicardial mapping and local refractory periods were obtained using 47-channel bipolar electrodes attached to the epicardium. The induction of sustained ventricular tachycardia by programmed electrical stimulation was not suppressed by i.v. infusion of E-4031 at 1 microgram/kg/min, but was suppressed markedly by infusion at 10 micrograms/kg/min in six of seven dogs. During the infusion of E-4031 at 10 micrograms/kg/min, epicardial conduction velocity in the normal ventricle did not change (0.7 +/- 0.12 to 0.71 +/- 0.13 m/sec, n = 6), whereas slowed conduction in the infarct zone improved (0.58 +/- 0.10 to 0.77 +/- 0.13 m/sec, n = 6). E-4031 at 10 micrograms/kg/min prolonged effective refractory periods (ERP) in the normal zone (139 +/- 8 to 164 +/- 18 msec, P less than .01, n = 8), nontransmural infarct zone (145 +/- 7 to 177 +/- 15 msec, P less than .01, n = 8) and transmural infarct zone (156 +/- 14 to 191 +/- 22 msec, P less than .01, n = 8). The degrees of ERP prolongation were almost equal in all zones. On epicardial mapping, the areas of longer ERP and delayed conduction were observed to become inexcitable after the administration of E-4031. These results demonstrated that E-4031 effectively prevented the induction of re-entrant ventricular tachycardia in canine myocardial infarction model, and suggested that E-4031 rendered re-entrant circuits inexcitable by marked ERP prolongation in both normal and infarct zones.

Electrophysiological and anatomical substrates for late potential recorded by signal averaging in seven-day-old myocardial infarction in dogs.

A filtered QRS (fQRS) was recorded by signal averaging in 7-day-old myocardial infarction (MI) in dogs to detect late potential (LP). The criteria for the LP included a duration of fQRS (D) greater than or equal to 60 msec and a voltage in the last 15 msec (V15) less than or equal to 10 microV. These parameters were determined from the control data from 15 dogs without infarction (D: 45 to 60 msec and V15: 12.0 to 83.6 microV). On the seventh day of infarction, the D had increased from 53.5 +/- 4.7 to 62.2 +/- 9.6 msec (P less than 0.05) and the V15 decreased from 38.6 +/- 19.5 to 18.4 +/- 16.0 microV (P less than 0.01). Of 23 dogs, 14 met the LP criteria (group A) and 9 did not (group B). Sustained ventricular tachycardia (SVT) was induced in 12 group A dogs and in none of the group B dogs. The delayed epicardial activation (DEA) was recorded after the end of QRS at 5.1 +/- 4.7 sites in group A dogs and 1.3 +/- 1.8 sites in group B dogs (P less than 0.05). The maximum value of epicardial activation time was more prolonged in group A than in group B (70.0 +/- 28.3 vs 44.4 +/- 9.8 msec, P less than 0.01). The area of MI was more extensive in dogs with DEA than those without (24.9 +/- 5.8% vs 10.3 +/- 9.0% of the total left ventricular weight, P less than 0.01). In 72 of 90 sites with DEA, the thickness of the surviving epicardial muscle was less than or equal to 1 mm. The sensitivity and specificity of the criteria for LP in detecting DEA were 71.4% and 55.6%, and 100% and 81.8% for predicting inducibility of SVT. It was thus concluded that LP, reflected the DEA, was identified from infarct areas of slow conduction within a reentry circuit of SVT.

Induction and repair of DNA strand breaks in cultured mammalian cells following fast neutron irradiation.

Induction and repair of DNA breaks following irradiation with NIRS cyclotron neutrons were studied in cultured mammalian cells (L5178Y) in comparison to those following gamma-rays. The yield of the total single-strand breaks, 3'OH terminals and sites susceptible to S1 endonuclease following fast neutrons was found to be approximately 50 per cent of that following gamma-irradiation. On the other hand, the yield of double-strand breaks was slightly higher after fast neutrons than after gamma-rays. The percentage of the total single-strand breaks remaining unrejoined at 3 hours after post-irradiation incubation was found to be distinctly higher after the fast neutrons than after gamma-rays. The neutron-induced damage appears to carry a higher proportion of alkali-labile lesions compared to gamma-rays. It was concluded that the increase in the yield of double-strand breaks and of unrejoinable breaks is responsible for a high r.b.e. of the cyclotron neutrons.

Induction and repair of strand breaks and 3'-hydroxy terminals in the DNA of mouse brain following gamma irradiation.

DNA was isolated from mouse brain after in vivo gamma-ray irradiation, treated with endonuclease S1 from Aspergillus oryzae if necessary, and analysed further by alkaline and neutral sucrose gradient centrifugation. In parallel, its template activity was determined by DNA polymerase (EC 2.7.7.7, enzyme A of Klenow from Escherichia coli) assay as described previously. Similar experiments were performed with cultured mouse leukaemia cells (L5178Y) irradiated in vitro at 0 degrees C. Irradiation induced single- and double-strand breaks in the DNA of the brain with a yield of 1.0 and 0.1 break per 10(12) dalton per rad (100 eV/break and 770 eV/break), respectively. The yield of single-strand breaks in the brain was lower than that found in the cultured cells, whereas the yield of double-strand breaks was found to be almost the same in both cases. Treatment of irradiated DNA with single-strand-specific S1 endonuclease gave rise to further breaks detected on neutral sucrose gradient analysis. The yield of these breaks was also higher in the brain compared to the cultured cells. The increase per unit dose in the template activity of the DNA from the brain was found to be five times as much as that found in the cultured cells. Then, the average number of deoxyribonucleotides incorporated per break was determined on DNA which had experienced different treatments. The value for the brain DNA irradiated in vivo was found to be five times as much as that found for DNA treated with pancreatic deoxyribonuclease and 10 times as much as those found for DNA from the cultured cells and isolated brain nuclei irradiated in vitro at 0 degrees C. Thus, in vivo irradiation seemed to induce gaps with 3'-OH terminals in addition to simple breaks with or without 3'-OH terminals found in the cultured cells. Radiation-induced single-strand breaks and 3'-OH terminals in the DNA of the brain were repaired following irradiation. Approx. 20--40% of the terminals or breaks induced were, however, remaining at 3 h or more after irradiation, depending on the dose administered.

Induction and repair of strand breaks and 3'-hydroxy terminals in the DNA of mammalian cells in culture following gamma-ray irradiation.

DNA was isolated in a fairly pure and intact state from cultured mouse leukaemia cells (L5178Y) after gamma-ray irradiation using a hydroxyapatite column chromatography method, and analysed further by sucrose gradient centrifugation or DNA polymerase (EC 2.7.7.7, enzyme A of Klenow from Escherichia coli) assay. Irradiation of the cells induced single- and double-strand breaks in the DNA with an efficiency of 100 eV/break and 1300 eV/break, respecitvely. Approximately 50% of the single-strand breaks were estimated to be those arising from allali-labile lesions. A linear, dose-dependent increase was found in the template activity of the DNA, indicating the induction of 3'-OH terminals by gamma-irradiation. Post-irradiation incubation of the cells in serum-free medium allowed the majority of the breaks to rejoin within a few hours. Repair of the alkali-labile lesions was, however, found to be much slower than that of "actual" single-strand breaks. A slight increase of the DNA template activity was found during the period of post-irradiation incubation. The reason for the increase is discussed.