Yuji Murakawa

Regional Differences in Transient Outward Current Density and Inhomogeneities of Repolarization in Rabbit Right Atrium

BACKGROUNDnRecent experimental and clinical studies on atrial flutter have demonstrated that the crista terminalis (CT) plays an important role in the genesis of atrial reentry. To elucidate the underlying mechanism of its role, we characterized the electrophysiological repolarization properties of CT cells by comparing them with those of the pectinate muscles (PM).nnnMETHODS AND RESULTSnAfter action potential properties of both regions were compared by conventional microelectrode technique in multicellular atrial tissues, the whole-cell clamp experiments were applied in atrial cells isolated from both regions. Action potential duration (APD) was more prolonged in CT than in PM in multicellular preparations (APD90 77 +/- 5 ms versus 52 +/- 8 ms at 1 Hz, P < .01), though the other properties did not differ significantly. Similarly, in isolated atrial cells, APD was more prolonged in CT cells than in PM cells (APD90 63 +/- 7 ms versus 41 +/- 6 ms at 0.1 Hz, P < .01). Isolated single cells were larger in CT than in PM. The whole-cell clamp recordings showed no definite distinctions in the density of the voltage-dependent L-type Ca2+ current and the inwardly rectifying K+ current between these cells but revealed a significant reduction of the density of the 4-aminopyridine-sensitive transient outward current (Ito) in CT cells compared with that in PM cells (6.3 +/- 0.7 pA/pF versus 10.3 +/- 0.8 pA/pF at +20 mV, P < .05). However, no differences in the kinetics or the voltage dependence of Ito were observed between the cells. The time course of recovery from inactivation of Ito was also similar in both types of cells.nnnCONCLUSIONSnThese results suggest that the preferential reduction in the density of Ito in the CT cells could contribute to prolong their APD, which may be related to the genesis of atrial reentry.

The Defibrillation Success Rate Versus Energy Relationship: Part I‐Curve Fitting and the Most Efficient Defibrillation Energy

The effect of applying an energy pulse to the heart during ventricular fibrillation is described by the probability of successful defibrillation or success rate. Seven to ten (8.60 ± 0.84: mean ± standard deviation) defibrillation trials per energy were randomly attempted at energies which span the defibrillation success rate versus energy curve. We obtained 70.0 ± 8.4 episodes per dog. We fit the defibrillation success rate versus energy relationship from ten dogs (20.5 y1.5 kg) to four types of curves: linear, exponential, profit transformed linear, and logic transformed linear. The correlation coefficients for each fit are 0.957 ± 0.057,0.944 ±0.014, 0.926± 0.051, and 0.889 ± 0.098. respectively. We therefore conclude that the exponential curve best describes the DSRE relationship. This suggests the existence of an energy below which defibrillation does not occur. At higher energies, the exponential curve asymptotically approaches a 100% success rate, which indicates that increasing the energy produces a diminishing benefit to defibrillation success rate. The estimated energies with a 0% defibrillation success rate are surprisingly consistent among dogs, with 2.072 ± 0.553 J. The estimated energy with an 80% defibrillation success rate is 5.217 ± 1.091 J. The estimated defibrillation success rate corresponding to the defibrillation threshold of 3.59 ± 3.06 J is consistent with 0.516 ± 0.144. The estimated energies with a 0% success rate correlate well with the defibrillation thresholds with R = 0.772; P = 0.0088. Since implant able defibrillators have a limited energy supply, we determined energy efficiency by dividing defibrillation success rate by the applied energy and energy consumption by dividing the applied energy by the defibrillation success rate. The most efficient defibrillation energy occurs at the maximum energy efficiency and the minimum energy consumption. The most efficient defibrillation energy of 4.34 ± 0.97 J determined from the exponential fit has a success rate of 0.70 ± 0.06. The most efficient defibrillation energy can be predicted from the defibrillation threshold. Clinically, a 70% success rate may not be adequate. We, therefore, compared the energy efficiency and consumption of energies with 90% and 95% success rates to the most efficient defibrillation energy. About a 50% increase in energy from the most efficient defibrillation energy is necessary for a 90% success rate which results in about a 33% loss in energy efficiency and about a 16% increase in energy consumption. About an 84% energy increase is necessary for a 95% success rate which results in about a 24% loss in energy efficiency and about a 33% increase in energy consumption. For these energies, the benefit to success rate may outweigh the decrease in energy efficiency and may be more appropriate clinically. A prudent choice of energy setting for the AICD must include careful consideration of energy efficiency and consumption.

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.

Ostensible day-night difference of QT prolongation during long-term treatment with antiarrhythmic drugs : Reappraisal of the law of regression to the mean

This study was designed to test whether the law of regression to the mean explains the diurnal variation in the modulation of electrocardiographic variables during the treatment with antiarrhythmic agents. In part 1, in 34 subjects, ambulatory ECG monitorings were repeated twice, and the corrected QT interval (QTc) at a heart rate of 60 beats/min was calculated separately for the daytime and night. The individual diurnal QTc variation (day-night difference) of the first recording (4.4 +/- 3.3%) was significantly correlated with that of the second recording (5.0 +/- 3.1%; r = 0.61; p < 0.0001), and naturally, the second measurement tended to be lower than the first value in those with relatively greater baseline diurnal QTc variation and vice versa (p < 0.005). In part 2, 30 subjects undertook ambulatory ECG recordings before and during treatment with class Ia antiarrhythmic drugs. Mean QTc changes in the daytime and in the night with the drugs were comparable (18 +/- 17 ms and 19 +/- 15 ms). However, the day-night difference of postdrug QTc changes in each subject was inversely correlated with baseline diurnal QTc variation (r = -0.64; p < 0.0001). These observations in part 2 were comparable with those in part 1, and individual day-night difference in QT prolongation with antiarrhythmic drugs seemed to be a chance occurrence. It was suggested that the law of regression to the mean is appreciably reflected in the ostensible intraday variation of pharmacologic modulation of electrocardiographic variables.

Success rate versus defibrillation energy temporal profile and the most efficient defibrillation threshold

To determine the temporal profile of the energy requirement for defibrillation, shocks were delivered to canine hearts after 5, 10, or 20 seconds from the onset of fibrillation with a combination of patch and catheter electrodes. A total of 956 fibrillation-defibrillation sequences were performed at one of four energy levels appropriately selected for each period of fibrillation in 10 anesthetized dogs. The energy values related to 50% (E50) and 80% (E80) of the predicted success were calculated from a logistic regression curve. The E50 and E80 values at 10 seconds after the onset of fibrillation were less than those at 20 seconds after the onset by 7.1% +/- 18.3% and 9.7% +/- 21.4%, respectively; differences were not significant. At 5 seconds after the onset, the differences were 15.3% +/- 14.2% (p less than 0.02) and 16.4% +/- 12.7% (p less than 0.01), respectively. The defibrillation energy efficiency was assessed by dividing the success rate (SR) of fibrillation by the applied energy (E). The maximal SR/E at 5, 10, and 20 seconds of fibrillation was achieved at the energy corresponding to the SRs of 88.8% +/- 4.5%, 90.4% +/- 3.9%, and 88.1% +/- 4.6%, respectively. We conclude that the energy requirement for defibrillation increases with the duration of fibrillation, even shortly after the onset of fibrillation, and the maximal energy efficiency is attained at the energy associated with the SR of approximately 90%.

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.

The effect of an unsuccessful subthreshold shock on the energy requirement for the subsequent defibrillation

The effect of an unsuccessful subthreshold shock on the energy requirement for the subsequent defibrillation was studied in 10 anesthetized dogs. Defibrillation was achieved with a spring catheter electrode in the superior vena cava and a patch electrode on the anteroapical ventricular wall. Success rates of defibrillation 20 seconds from the onset of ventricular fibrillation were determined at three energy levels with and without a preceding subthreshold shock. Altogether, 637 episodes of fibrillation-defibrillation were performed (63.7 +/- 6.7 per dog). Predicted energy levels for defibrillation success rates of 50% and 80% (E50 and E80) acquired from a logistic regression curve were 0.0303 +/- 0.0064 and 0.0367 +/- 0.0069 joule/gm, respectively, without subthreshold shocks. E50 and E80 with an unsuccessful subthreshold shock resulted in comparable values (E50: 0.0325 +/- 0.0041 joule/gm; E80: 0.0.380 +/- 0.0100 joule/gm). Our results suggest that an unsuccessful low-energy shock does not alter the energy requirement for subsequent defibrillation with an implantable defibrillator.

Effect of isoproterenol on facilitation of electrical defibrillation by E-4031.

Summary To determine whether isoproterenol could reverse enhancement of electrical defibrillation effectiveness by class III antiarrhythmic agents, we measured the internal defibrillation threshold (DFT) in 12 anesthetized dogs during infusion of (a) saline (baseline), (b) isoproterenol, (c) isoproterenol + E4031 (a new class III anti-arrhythmic agent), and (d) E4031 alone. The isoproterenol infusion was adjusted so that heart rate (HR) was at least 30 beats/min greater than baseline. E4031 was given as a 40-μg/kg bolus at the beginning of the third stage of the study, followed by constant infusion at 2 μg/kg/min. Eight dogs completed the study. Although the energybased DFT was not affected by isoproterenol (from 6.1 ± 1.5 to 6.0 ± 1.7 J), it was decreased to 3.7 ± 1.6 J in the third stage by infusion of E4031 and isoproterenol (p < 0.01 vs. baseline and vs. isoproterenol). After the discontinuation of isoproterenol in the fourth stage, i.e., during infusion of E4031 alone. DFT was 3.4 ± 1.6 J (p < 0.01 vs. baseline and vs. isoproterenol). Therefore, isoproterenol did not antagonize the effect of E403I on the DFT, suggesting the possible clinical usefulness of class III agents for facilitating defibrillation even in the presence of augmented sympathetic activity.

The Defibrillation Success Rate Versus Energy Relationship: Part II—Estimation with the “Bootstrap”

Seventy or so defibrillation trials were typically attempted to determine the relationship between defibrillation success rate and energy (DSRE). Clinically, it may be desirable to estimate the DSRE relationship with fewer trials. We used the statistical resampling technique called the “bootstrap” to determine the number of defibrillation trials necessary for an accurate estimation of the DSRE relationship. The bootstrap technique assumes that the observed database is the maximum likelihood sample of the estimated population. The observed database is repeatedly resampled to produce a large bootstrap database and the bootstrap best estimate of a statistic is determined. DSRE data were obtained from ten dogs (20.5 ± 3.5 kg). We bootstrapped our experimental DSRE data by two methods: (1) randomly choosing with replacement a specified number of defibrillation trials per energy; and (2) randomly choosing with replacement a specified number of defibrillation trials per bootstrap replication. For both bootstrap techniques, 100 replications were made. We performed a linear regression analysis on the bootstrap success rates and the observed success rates determined from 71.0 ± 6.8 defibrillation attempts from each of the ten dogs. We concluded that 28 defibrillation trials are necessary to estimate the observed DSRE relationship with a correlation coefficient of 0.95.