Hannes Todt

Mode of QT correction for heart rate: Implications for the detection of inhomogeneous repolarization after myocardial infarction

In 22 conscious, chronically instrumented dogs, the relationship between R-R interval and QT interval was better explained by linear regression than by nonlinear regression according to Bazetts formula. The correction formula QTL = QT-0.1*(RR-1000), which is based on the assumption of a linear relationship between QT and R-R interval, was then compared with Bazetts formula regarding its capability to detect inhomogeneous repolarization 5 to 7 days after temporary occlusion of the left anterior descending coronary artery. This comparison was performed only in those dogs exhibiting changes in QRS duration of less than 5 msec in response to myocardial infarction (n = 12). In these animals, myocardial infarction resulted in a significant dispersion of repolarization between the left ventricular normal zone and the infarct zone and a shift to the right of strength-interval curves of the infarct zone with respect to the normal zone, indicating local dispersion of refractoriness. As opposed to QTc (Bazetts formula), QTL was significantly (p = 0.04) prolonged after occlusion. Hence the adequacy of QT correction contributes significantly to the detection of inhomogeneous ventricular recovery after acute myocardial infarction.

Holter monitoring in conscious dogs: assessment of arrhythmias occurring during ischemia and in the early reperfusion phase

Myocardial ischemic episodes of 5 min, 15 min, and 4 hr duration, with interposed reperfusion periods, were induced in the same conscious, chronically instrumented dogs. A drop in systolic blood pressure and an increase in heart rate and in the arrhythmic ratio (AR% = number of ectopic beats x 100/total number of beats, as assessed by Holter monitoring) was registered in response to the induction of myocardial ischemia. Reperfusion-induced salvage after coronary occlusion of 5 and 15 min duration was documented by an immediate return of systolic blood pressure, heart rate, and AR to the preocclusion control level. However, after coronary occlusion lasting for 4 hr, reperfusion induced a further drop in blood pressure and an increase in heart rate and in AR. We conclude that in conscious dogs, reperfusion-induced arrhythmias do not occur after short-lasting myocardial ischemic episodes. Reperfusion after long-lasting ischemia induces marked ventricular ectopic activity, yielding an arrhythmic ratio of more than 80%. Although these reperfusion-induced arrhythmias impair the hemodynamic state, they are well tolerated in the conscious dog and can be assessed by the Holter monitoring technique. This new experimental approach promises to be of clinical relevance for investigations on the therapeutic efficacy of new antiarrhythmic drugs.

Holter monitoring in conscious dogs: Assessment of arrhythmias occurring in the late reperfusion phase after coronary occlusion

Arrhythmias occurring in the late reperfusion phase, i.e., up to 3 days after episodes of 5 min, 15 min, and 4 hr of coronary occlusion (CAO), were investigated in six conscious, chronically instrumented dogs using the Holter monitoring technique. The arrhythmic ratio (AR% = number of premature ventricular complexes x 100/total number of beats) of a 24-hr preocclusion control record was 0.004% and did not differ from the values assessed for day 1 (0.004%) and 2 (0.001%) of the late reperfusion phase after 5 min CAO. After 15 min, CAO increased, but insignificantly elevated AR values were registered on days 1 (2.5%), 2 (0.26%), and 3 (0.1%) of the late reperfusion phase. On day 1 of the late reperfusion phase after 4 hr CAO, the AR increased markedly to 75%. On day 2 of this phase, the AR was lower (20%) but still significantly elevated. On day 3, the AR was 3.5%, a value still markedly, although not significantly, above the preocclusion control level. We conclude that in conscious dogs, arrhythmias in the late reperfusion phase do not occur after 5 min CAO. However, after 15 min CAO and, especially, after 4 hr CAO, an increase in arrhythmic activity occurs in the late reperfusion phase and gradually declines towards the preocclusion control level over a period of 3 days. Thus, it could be demonstrated that the long-term assessment of reperfusion arrhythmias by ECG monitoring using the Holter technique is feasible in conscious dogs. This method represents a promising approach to clinically relevant experimental investigations on the therapeutic efficacy of a new antiarrhythmic drugs.

Programmed electrical stimulation after myocardial infarction and reperfusion in conscious dogs

The hemodynamic and electrophysiologic variables and the inducibility of arrhythmias were studied before coronary artery occlusion (CAO, 4h) and on days 4, 14, and 28 of the late reperfusion phase in conscious, chronically instrumented dogs. Despite a lack of significant changes in the hemodynamic and the electrophysiologic variables, the response to programmed electrical stimulation (PES) before and after CAO with subsequent reperfusion varied substantially. Before intervention arrhythmias such as sustained ventricular tachycardia (SVT) or ventricular fibrillation (VFib) could not be induced by PES via ultrasonic crystals located subendocardially (LAD and LCX region) or via common stimulation electrodes (right ventricle) in any of six instrumented animals. All six animals were inducible after CAO and reperfusion. Five animals showed SVT and one animal showed VFib in response to stimulation on days 4 and 14 of the late reperfusion phase after CAO. On day 28 four animals showed SVT, and two showed VFib. Antiarrhythmic drug testing carried out in the late reperfusion phase with lidocaine (1 mg/kg bolus followed by continuous infusion) revealed 50% efficacy at a dosage of 40 micrograms/kg/min, 100% at 80 micrograms/kg/min, and 67% at 120 mu/kg/min. The persistent inducibility of arrhythmias for the entire experimental period of 24 days may be attributable to the following features of our model: 1. Electrical stimulation carried out from three different locations. 2. The use of up to three extrastimuli in the PES studies. 3. The use of conscious dogs during CAO, reperfusion, and PES. This novel experimental approach thus promises to be of clinical relevance for the investigation of new antiarrhythmic drugs.

Frequency-dependent effects of amitriptyline and maprotiline on conduction in the guinea pig His-Purkinje-system in vivo

In the Cardiac Arrhythmia Suppression Trial antiarrhythmic drug therapy with slow kinetic sodium channel blockers (class Ic antiarrhythmic drugs) was associated with excess mortality, presumably due to drug induced proarrhythmia. It has been suggested that the degree of rate-dependent conduction slowing produced by agents that have sodium channel blocking properties may be related to the proarrhythmic propensity of these agents.In the present study, rate-dependent conduction slowing by the antidepressants amitriptyline and maprotiline was investigated in anesthetized guinea pigs. After electrical ablation of the sinus node the left atrium was stimulated at cycle lengths between 200 ms and 500 ms. His bundle electrograms were registered by means of an epicardial electrode. Drugs were administered by i.v. infusion of 0.2 mg kg−1 min−1 for 30 min followed by 0.1 mg kg−1 min−1 for up to 30 min. Both drugs produced substantial rate-dependent conduction slowing within the His-Purkinje-system. The relationship between pacing rate and conduction slowing was well fitted by linear regression. The steepness of the regression line was significantly greater for amitriptyline than for maprotiline (slope factors: 9.10×10−4±7.85 × 10−5, n = 6, vs. 6.29×10−4±2.97×10−5, n=6, P<0.001), indicating that conduction slowing by amitriptyline exhibits a greater degree of rate-dependence than conduction slowing by maprotiline. On abruptly changing the driving cycle length from 500 ms to 300 ms, conduction slowing reached a new steady state with rate constants of 0.83±0.093 beat−1 (amitriptyline) and 0.14±0.05 beat−1 (maprotiline, P<0.001). Following interruption of rapid pacing at a cycle length of 250 ms, conduction slowing recovered with time constants of 332.4±52.8 ms (amitriptyline) and 1088.1 ± 143.5 ms (maprotiline, P = 0.001). Thus, amitriptyline exhibited fast kinetic properties similar to class Ib antiarrhythmic action while the slower kinetic properties of maprotiline resembled those of class Ia agents.

Prolongation of the QT interval by dofetilide modulates rate-dependent effects of mexiletine on intraventricular conduction

Prolongation of action potential duration during treatment with agents that possess class I antiarrhythmic activity may result in a clinically relevant increase in Na+ channel block. In order to test this hypothesis in vivo, the effect of QT prolongation on intraventricular conduction was assessed during administration of mexiletine. Epicardial His bundle recordings were made in anesthetized guinea pigs. After abolition of spontaneous sinus node activity by application of high-frequency current to the sinus node area, the hearts were paced via the left atrium. Administration of the class III antiarrhythmic agent dofetilide (10 micrograms/kg i.v.; n = 6) significantly prolonged QT intervals without a significant effect on HV intervals. Infusion of mexiletine (bolus 2 mg/kg + 0.18 mg/kg per min i.v.; n = 6) produced significant increases in HV intervals at cycle lengths of 200 and 300 ms. Subsequent addition of dofetilide (20 micrograms/kg i.v.) to mexiletine induced similar increases in QT intervals as single treatment with 10 micrograms/kg dofetilide and significantly enhanced the rate-dependent conduction slowing. Upon abruptly decreasing the pacing cycle length from 500 ms to 300 ms, conduction slowing developed with a rate constant of 1.0 +/- 0.2 beat-1 after mexiletine and with a rate constant of 1.1 +/- 0.2 beat-1 after subsequent addition of dofetilide (P = n.s.). After rapid stimulation at a cycle length of 250 ms the conduction slowing produced by mexiletine recovered with a time constant of 174 +/- 24 ms. No further change of this recovery time constant was observed after subsequent addition of dofetilide to mexiletine (160 +/- 19 ms, P = n.s.). Thus action potential duration, as reflected by the QT interval, is an important modulator of the magnitude Na+ channel block in vivo. The kinetic parameters of Na+ channel block produced by mexiletine, however, remain unchanged by prolongation of action potential duration after addition of dofetilide.

Effect of ajmaline on sustained ventricular tachycardia induced by programmed electrical stimulation in conscious dogs after myocardial infarction

SummaryAs yet the antiarrhythmic efficacy of ajmaline with regard to suppressing the induction of sustained ventricular tachycardia after myocardial infarction has not been determined. Therefore, programmed electrical stimulation was performed in 8 conscious, chronically instrumented mongrel dogs 8–20 days after a 4-hour occlusion of the left anterior descending coronary artery. At baseline all animals responded with sustained ventricular tachycardia. Thereafter, ajmaline was administered at two consecutive ix. doses: a bolus of 0.7 mg kg−1 followed by infusion of 2 mg kg−1 h−1 and infusion of 4 mg kg−1 h−1. The induction of sustained ventricular tachycardia was prevented in 2/8 animals by 2 mg kg−1 h−1 ajmaline and in 1/8 animals by 4 mg kg−1 h−1 ajmaline. During sinus rhythm only 4 mg kg−1 h−1 ajmaline significantly increased QRS-duration and intraventricular activation times, but during rapid right ventricular pacing (cycle length = 330 ms) both doses of ajmaline increased QRS duration and intraventricular conduction times. 4 mg kg−1 h−1 ajmaline also increased the cycle length of induced sustained ventricular tachycardia. In 3 animals induction of sustained ventricular tachycardia during infusion of 4 mg kg−1 h−1 ajmaline was achieved by introduction of less extrastimuli than at baseline. Furthermore the coupling intervals of extrastimuli that induced sustained ventricular tachycardia were substantially prolonged by this dose. Inhomogeneity of conduction between left ventricular normal zone and left ventricular infarct zone was significantly increased by 4 mg kg−1 h−1 ajmaline during rapid right ventricular pacing, but not during sinus rhythm.We conclude that ajmaline has only limited efficacy with regard to the prevention of induction of sustained ventricular tachycardia after myocardial infarction. Drug-induced increases in tachycardia cycle lengths, as observed under the higher dose of ajmaline, were associated with a rate-dependent rise in cardiac electrical instability.

Epicardial his bundle recordings in the guinea pig in vivo

In small animals, His bundle activity is commonly registered using intracavitary electrodes in Langendorff-perfused hearts. The present study evaluates the feasibility of epicardial registration of His bundle activity in 30 guinea pigs in vivo, anesthetized with 60 mg/kg sodium pentobarbital i.p. Following median sternotomy, a bipolar electrode, mounted on a flexible stand, was placed into the aortic-right atrial groove. His bundle activity was easily detected in all animals. Mean PA, AH, and HV intervals were 16.7 +/- 1.4 msec (range: 6.0-34.0 ms), 36.4 +/- 1.5 ms (range: 22.0-54.0 msec) and 14.4 +/- 0.4 msec (range: 9.0-20 msec), respectively. Administration of verapamil and vagal stimulation induced significant prolongations of AH intervals without affecting HV intervals; lidocaine prolonged both AH and HV intervals. Both at baseline and following drug administration there was excellent agreement between the AH and HV intervals assessed from simultaneously registered epicardial and endocardial His bundle electrograms (n = 12). The presented model provides reproducible values for atrioventricular (AV) nodal and His-to-ventricular conduction intervals in the guinea-pig in vivo and will, thus, be a valuable tool in electrophysiologic drug evaluation.

Kinetics of rate-dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

1 The effects of the class I antiarrhythmic agent, tocainide, on intraventricular conduction were assessed in guinea‐pigs, anaesthetized with pentobarbitone sodium 60 mg kg−1, i.p. 2 After electrical ablation of the sinus node, heart rate was controlled by atrial pacing. His bundle electrograms were recorded by means of an epicardial bipolar electrode. 3 During continuous stimulation, comparison of HV intervals measured at a cycle length of 475 ms, with HV intervals measured at a cycle length of 250 ms yielded the following results: 25.26 ± 0.64 ms versus 25.02 ± 0.70 ms (NS), at baseline, 26.65 ± 0.80 ms versus 29.881 1.13 ms (P < 0.001) after i.v. administration of 30 mg kg−1 tocainide, and 28.04 ± 0.64 ms versus 36.24 ± 1.31 ms (P < 0.001), after addition of 20 mg kg−1 tocainide. Thus, tocainide caused HV intervals to increase in a strictly rate‐dependent fashion. 4 In order to characterize the rate‐dependent class I activity of tocainide in terms of its binding kinetics to sodium channels, fractional sodium channel block was estimated from drug induced reductions of intraventricular conduction velocity (Δθ). On abruptly changing the drive cycle length from 500 ms to 250 ms, Δθ reached a new steady state with rate constants of 1.23 ± 0.09 beat−1 and 1.28 ± 0.09 beat−1, after administration of 30 mg kg−1 and addition of 20 mg kg−1 tocainide, respectively. At a basic drive cycle length of 250 ms Δθ recovered with time constants of 250.29 ± 23.32 ms and 183.04 ± 8.03 ms after administration of 30 mg kg−1 and addition of 20 mg kg−1 tocainide, respectively. 5 The experimentally determined kinetic parameters were implemented into a mathematical model that assumes drug binding to sodium channels in terms of a periodical two‐state process. Rate‐dependent reductions in conduction velocity during continuous stimulation after administration of tocainide were closely approximated by steady state reductions in sodium channel availability as calculated on the basis of the aforementioned model. 6 In agreement with previously published in vitro studies, our data, obtained in vivo, confirm the classification of tocainide as a class I antiarrhythmic agent with fast onset and offset kinetics. The kinetic parameters obtained in vivo can be used in order to predict steady state reductions in conduction velocity at a wide range of frequencies.

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

SummaryThe aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 μg/kg/min (i.v.). During 80 μg/kg/min lidocaine (mean plasma level 3.5 μg/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 μg/kg/min and 4 of 8 to 120 μg/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting.