Search

Alterations in cardiac impulse conduction may exert both beneficial and detrimental effects. The assessment of ventricular conduction properties is of paramount importance both in clinical and in experimental settings. Currently the duration of the QRS complex is regarded as hallmark of in-vivo assessment of global ventricular conduction time. In addition, the amplitude of the QRS complex has been suggested to reflect ventricular conduction time in man and in rats. Here, for the first time, we systematically investigated the relationship between QRS duration ("QRS") and QRS amplitude ("RS-height"; RSh) in the murine ECG obtained during anesthesia. In mice harbouring a homozygous knockout of the transmembrane protein podoplanin (PDPN-/-; n = 10) we found both a shorter QRS and a greater RSh than in wild-type animals (n = 13). In both genotypes cumulative i.p. administration of 5 mg/kg and 10 mg/kg of the Na channel blocker flecainide resulted in dose-dependent QRS increase and RSh decrease, whereby the drug-induced changes in RSh were greater than in QRS. In both genotypes the flecainide-induced changes in QRS and in RSh were significantly correlated with each other (R = -0.56, P = 0.004). Whereas dispersion of QRS and RSh was similar between genotypes, dispersion of the ratio QRS/RSh was significantly smaller in PDPN-/- than in wild-types. We conclude that in the murine ECG QRS is inversely related to RSh. We suggest that both parameters should be considered in the analysis of ventricular conduction time in the murine ECG., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Ivabradine blocks hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, thereby lowering the heart rate, an action that is used clinically for the treatment of heart failure and angina pectoris. We and others have shown previously that ivabradine, in addition to its HCN channel blocking activity, also inhibits voltage-gated Na channels in vitro at concentrations that may be clinically relevant. Such action may reduce conduction velocity in cardiac atria and ventricles. Here, we explore the effect of administration of ivabradine on parameters of ventricular conduction and repolarization in the surface ECG of anesthetized mice. We found that 5 min after i.p. administration of 10 mg/kg ivabradine spontaneous heart rate had declined by ~13%, which is within the range observed in human clinical studies. At the same time a significant increase in QRS duration by ~18% was observed, suggesting a reduction in ventricular conduction velocity. During transesophageal pacing at heart rates between 100 and 220 beats/min there was no obvious rate-dependence of ivabradine-induced QRS prolongation. On the other hand, ivabradine produced substantial rate-dependent slowing of AV nodal conduction. We conclude that ivabradine prolongs conduction in the AV-node and in the ventricles in vivo., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Whereas isolated heart preparations or anesthetized animals have been used to assess the actions of beta-adrenoceptor antagonists upon reperfusion-induced arrhythmias, this study evaluated the possible antiarrhythmic effects of beta-adrenoceptor antagonism in conscious animals. Conscious, chronically instrumented dogs were subjected to a temporary occlusion of the left anterior descending coronary artery for 4 h. After the first hour of reperfusion, flestolol (N-(1,1-dimethyl-2- ureidoethyl)-2-hydroxy-3-(O-fluorobenzoyloxy)-propylamine sulfate), an ultra short-acting beta-adrenoceptor antagonist, was administered i.v. at infusion rates of 1 and 2.6 micrograms/kg per min. A control group received the equivalent volume of saline during this period. Delayed reperfusion-induced arrhythmias were evaluated by using a computerized analysis system. Treatment with flestolol did not affect the total number of beats, the number of normal and ectopic beats, and the arrhythmic ratio, i.e. the ratio of ectopic beats to the total number of beats. Hence, beta-adrenoceptor antagonism does not appear to suppress delayed ectopic activity during coronary reperfusion in conscious dogs.