Ventricular Fibrillation Threshold Determination Research Articles

研究会 第22回 理論心電図研究会 心室細胞閾値をめぐる諸問題 電気的心室細動閾値測定法の問題点

研究会 第22回 理論心電図研究会 心室細胞閾値をめぐる諸問題 電気的心室細動閾値測定法の問題点

Intracellular Ca2+ handling and vulnerability to ventricular fibrillation in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) with ventricular hypertrophy show an increased vulnerability for the development of potentially lethal ventricular arrhythmias such as ventricular fibrillation (VF). The mechanisms of this increased vulnerability are not fully understood but may be related to abnormal intracellular Ca2+ ([Ca2+]i) handling under stress conditions. We therefore investigated whether [Ca2+]i handling is abnormal in hypertrophied hearts of SHR without heart failure during stimulation stress, and if so whether abnormal [Ca2+]i handling is a determinant of the increased vulnerability to VF in SHR. [Ca2+]i was measured by indo-1 surface fluorescence in perfused hearts of 8- to 10-month-old control Wistar-Kyoto rats (WKY) and age-matched SHR. The state of [Ca2+]i handling was analyzed during three different forms of stimulation stress: rapid pacing, the long rest period after cessation of rapid pacing, and preprogrammed ventricular stimulation that was simultaneously used for the determination of VF threshold. The pulse number VF threshold was used as an index to determine vulnerability to VF and to analyze the relationship of [Ca2+]i handling to vulnerability. Although VF thresholds were lower in SHR than in WKY, we found that both demonstrated similar [Ca2+]i handling during stimulation stress. The extent and rate of [Ca2+]i accumulation during rapid pacing and those of the [Ca2+]i decline after cessation of pacing were similar in SHR and WKY. In addition, the relationship between [Ca2+]i and VF threshold was unaltered in SHR. Thus, we conclude that [Ca2+]i handling is normal in hypertrophied hearts of SHR without heart failure during stimulation stress and that it is not a determinant of the increased vulnerability to VF in SHR.

Change of a beneficial effect into an untoward effect by ischaemia: effect of quinidine-like drugs on vulnerability to ventricular fibrillation

The effects of three quinidine-like drugs, disopyramide, lidocaine and flecainide were investigated in anaesthetized, open-chest pigs on vulnerability to ventricular fibrillation under normal conditions and under myocardial ischaemia conditions. Vulnerability to fibrillation was evaluated by electrical ventricular fibrillation threshold (VFT), measured with 100 ms duration diastolic impulses the intensity of which was increased by steps of 1.0 or 0.5 mA. Impulses were delivered at the rate of 180 beats · min −1. The ventricles were subjected to pacing at the same rate before the VFT determination, particularly throughout periods of ischaemia of increasing duration (30, 60, 90, 120, 150 s), separated by appropriate intervals for reproducibility of the results. Monophasic action potential (MAP) duration and conduction time were monitored in the ischaemic area under pacing. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin. The three drugs were i.v. administered in clinical dose range (1.00 mg · kg −1 plus 0.04 mg · kg −1 · min −1). In the absence of ischaemia, they increased almost equally VFT (from about 7 to 10 mA), despite 25% prolongation of conduction time. But, none of them was able to impede the increasingly marked fall of VFT caused by ischaemia: at 30 s, they had already lost any capacity for raising VFT and, beyond this time, they even aggravated its fall which led to spontaneous fibrillation when VFT approached 0 mA. The faster fall of VFT shortened time to onset of fibrillation ( 20 24 fibrillations for the three drugs at 150 s as against 12 24 in control period), the ischaemia-induced reduction of MAP duration (by 20%) being also hastened and slowing of conduction enhanced, given the addition of the depressant effects of ischaemia and drugs on conduction. Consequently, the antifibrillatory properties normally manifested by the studied drugs are first suppressed, then inverted by ischaemia.

Arrhythmia inducibility and ventricular vulnerability in a chronic feline infarction model

Ventricular tachyarrhythmias are the cause of sudden cardiac death in ischemic heart disease. Reliable animal models are necessary to study techniques for identifying individuals at risk and to develop effective modes of therapy. The purpose of the present study was to evaluate the inducibility of ventricular tachyarrhythmias and vulnerability to ventricular fibrillation and to correlate these findings with changes in ventricular refractoriness in a chronic feline model. Twelve conditioned cats were randomly divided into two groups: group A, sham-operated controls (n = 5); or group B, permanent occlusion of the left anterior descending coronary artery (n = 7). Two weeks later, the following measurements were made: (1) assessment of refractory periods at several ventricular sites; (2) inducibility to ventricular tachyarrhythmias; and (3) determination of ventricular fibrillation threshold. After electrophysiologic testing, the animals were killed and the hearts were studied histologically. Ventricular fibrillation thresholds were significantly lower in group B compared with group A (13 ± 3 vs 46 ± 9 mA; p < 0.01). One of the sham-operated controls had induction of nonsustained ventricular tachycardia, while six of the group B animals had reproducible, inducible ventricular tachyarrhythmias ( p < 0.01). There was a significant dispersion in effective refractory periods between normal and infarcted sites in group B (46 ± 6 msec) not seen in group A (12 ± 2 msec, p < 0.01). The group A cats demonstrated minimal damage to the myocardium or cardiac architecture. Group B cats demonstrated extensive, transmural, homogeneous infarcts of approximately 30% of the anterior wall of the left ventricle. The chronically infarcted feline heart appears to be a reliable model to evaluate vulnerability to ventricular tachyarrhythmias. Moreover, temporal dispersion of refractoriness observed in infarcted animals, applicable to clinical measurement, may serve as a marker of chronic vulnerability.

Time dependency of ventricular fibrillation thresholds determined using trains of stimuli.

When determining ventricular fibrillation threshold (VFT), considerable time elapses from beginning a VFT measurement until the actual occurrence of ventricular fibrillaion (VF). We have defined this elapsed time as the "time to VF" and examined the effect of varying time to VF on the measured value of VFT. We induced VF in anesthetized dogs with a 100-Hz train of 16 4-ms stimuli applied to the right ventricular epicardium. The time to VF was varied by changing either the increment of fibrillation current increase (0.5, 1.0, or 2.0 mA) from one train to the next and/or the number of atrial paced beats between trains (6-192 beats). For 0.5-mA current increments, as time to VF increased from 66 to 454 s, VFT fell progressively from 15.3 +/- 4.8 to 6.7 +/- 1.1 mA. When time to VF exceeded 454 s, VFT increased again. Current increments of 1.0 and 2.0 mA had a similar time dependency of VFT. For any time to VF the VFT was lower when small current increments (i.e., more trains) were used to induce VF. Pretreatment with reserpine in six dogs abolished the time dependency. We conclude that time elapsed from the beginning of a VFT determination until VF actually occurs and the total number of trains used are important determinants of the VFT, probably because of local catecholamine release by the stimuli.

Effects of encainide (MJ9067) on the ventricular fibrillation threshold in anesthetized dogs.

The right ventricular epicardial ventricular fibrillation threshold (VFT) was determined during paced supraventricular rhythm using 100 Hz trains of stimuli at 15 min intervals in dogs before and during the intravenous administration of encainide, a new antiarrhythmic drug. With each VFT determination, simultaneous blood samples were obtained for determination of drug concentration. In 6 control dogs, VFT determined every 15 min during a 210 administered as a 90 min intravenous infusion at three successive rates (0.01, 0.02 and 0.04 mg/kg/min) for 30 min each. VFT measured at 5 and 20 min of each infusion increased from a mean control of 11.5 +/- 1.5 (+/-SE) to 20.2 +/- 2.2 mA (p less than 0.01) after 20 min of the third infusion. The maximal effect occurred during the second infusion with plasma concentration of 594 +/- 46 ng/ml and then reached a plateau. In group II (n = 6), encainide was administered in four successive sequences, each one including a bolus loading intravenous dose followed by a 45 min intravenous infusion. VFT measured at 30 and 45 min of each infusion when the encainide plasma concentration was close to a steady state increased significantly (p less than 0.01) after the second infusion from 11.8 +/- 2 to 27.3 +/- 4 mA. Two dogs in group II developed transient complete atrioventricular block at an encainide plasma concentration of greater than 800 ng/ml. These results show that the new antiarrhythmic drug encainide increases the VFT in anesthetized dogs.

Effects of tocainide on ventricular fibrillation threshold: Comparison with lidocaine

Right ventricular epicardial ventricular fibrillation threshold was determined during paced supraventricular rhythm using 100 hertz trains of stimuli at 15 minute intervals in dogs before, during and after a 90 minute infusion of tocainide, an orally effective antiarrhythmic drug. With each ventricular fibrillation threshold determination, simultaneous blood samples were obtained for determination of drug concentration. Concentration-response curves for dogs receiving tocainide showed that in general there is no measurable increase in ventricular fibrillation threshold at concentrations of less than 6 to 10 μg/ml. At 10 μg/ml the mean ventricular fibrillation threshold increased 28 percent (range 14 to 67 percent), at 15 μg/ml 53 percent (range 28 to 111 percent) and at 20 μg/ml 71 percent (range 37 to 143 percent). There was a wide range of interanimal sensitivity to tocainide, but for each animal there was a significant relation between increase in ventricular fibrillation threshold and log plasma concentration. Similar observations for lidocaine revealed that in general there was no measurable effect below 1.3 to 4 μg/ml, a 77 percent mean increase (range 2 to 146 percent) at 4 μg/ml, a 136 percent mean increase (range 55 to 235 percent) at 6 μg/ml and a 177 percent mean increase (range 76 to 299 percent) at 8 μg/ml. Tocainide also increased the ventricular fibrillation threshold during induced premature ventricular beats. In this model, tocainide significantly increased ventricular fibrillation threshold; however, this increase was less than that observed at clinically tolerated lidocaine plasma concentrations.