His-bundle Conduction Research Articles

Development of an Ovine Model of Pediatric Complete Heart Block

Complete heart block is a significant clinical problem that can limit the quality of life in affected children. To understand the pathophysiology of this condition and provide for development of novel therapies, we sought to establish a large animal model of permanent, pacemaker-dependent atrioventricular block (AVB) that mimics the size and growth characteristics of pediatric patients. We utilized nine immature lambs weighing 10.5 ± 1.4 kg. After implantation of dual-chamber pacemaker devices with fixed leads, AVB was produced by interrupting His-bundle conduction using radio-frequency ablation at the base of the non-coronary cusp of the aortic valve. Ablations (30 to 60 s in duration) were performed under fluoroscopic guidance with electrophysiological monitoring. Interrogation of pacemakers and electrocardiography (ECG) determined the persistence of heart block. Ovine hearts were also examined immunohistochemically for localization of conduction tissue. AVB was produced in eight animals using an atypical approach from the left side of the heart. One animal died due to ventricular fibrillation during ablation proximal to the tricuspid annulus and one lamb was sacrificed postoperatively due to stroke. Four sheep were kept for long-term follow-up (109.8 ± 32.9 d) and required continuous ventricular pacing attributable to lasting AVB, despite significant increases in body weight and size. We have created a large animal model of pediatric complete heart block that is stable and technically practicable. We anticipate that this lamb model will allow for advancement of cell-based and other innovative treatments to repair complete heart block in children.

Effect of pacing rate and beta blockade on cardiac refractory periods and his-bundle conduction

Effect of pacing rate and beta blockade on cardiac refractory periods and his-bundle conduction

A Feasible Approach for Direct His‐Bundle Pacing Using a New Steerable Catheter to Facilitate Precise Lead Placement

Much clinical evidence has shown that right ventricular (RV) apical pacing is detrimental to left ventricular function. Preservation of the use of the His-Purkinje (H-P) system may be ideal in heart block that is restricted to the AV node, but may be of no benefit when H-P disease exists. To investigate the feasibility of direct His-bundle pacing (DHBP) using a new system consisting of a steerable catheter and a new 4.1 F screw-in lead. Between May and December 2004, 26 patients (19 male, mean age: 77 +/- 5 years) with a standard pacemaker (PM) indication and preserved His-bundle conduction were enrolled and DHBP was attempted. DHBP was achieved in 24 patients (92%); two patients were paced in the His area, but the paced QRS morphology and duration were different from the native QRS. The mean time for lead positioning was 19 +/- 17 minutes, the mean fluoroscopy time was 11 +/- 8 minutes, and the total procedure time (skin-to-skin including positioning of a quadripolar diagnostic catheter for His recording) was 75 +/- 18 minutes. In DHBP pacing, the acute pacing threshold was 2.3 +/- 1.0 V at a pulse duration of 0.5 msec, and the sensed potentials were 2.9 +/- 2.0 mV. At a 3-month follow-up examination, the same QRS duration and morphology recorded on implantation were observed in all patients. The pacing threshold was 2.8 +/- 1.4 V, and sensed potentials were 2.5 +/- 1.8 mV; the sensing configuration was changed from bipolar to unipolar in 6 patients to resolve undersensing issues. No major complications were observed. This feasibility study shows that DHBP can be accomplished with a new system consisting of a steerable catheter and an active fixation lead in 92% of the patients in whom it was attempted.

Connexin40-deficient mice exhibit atrioventricular nodal and infra-Hisian conduction abnormalities.

Previous electrophysiologic investigations have described AV conduction disturbances in connexin40 (Cx40)-deficient mice. Because expression of Cx40 occurs predominantly in the atria and His-Purkinje system of the mouse heart, the AV conduction disturbances were thought to be secondary to disruption in His-Purkinje function. However, the lack of a His-bundle electrogram recording in the mouse has limited further investigation of the importance of Cx40. Using a novel technique to record His-bundle recordings in Cx40-deficient mice, we define the physiologic importance of deficiencies in Cx40. Ten Cx40-/- mice and 11 Cx40+/+ controls underwent a blinded, in vivo, closed chest electrophysiology study at 9 to 12 weeks of age. In the Cx40-/- mice, the PR interval was significantly longer compared with Cx40+/+ mice (44.6+/-6.4 msec vs 36.0+/-4.1 msec, P = 0.002). Not only the HV interval (14.0+/-3.0 msec vs 10.4+/-1.2 msec, P = 0.003) but also the AH interval (33.2+/-4.8 msec vs 27.1+/-3.7 msec, P = 0.006), AV Wenckebach cycle lengths, and AV nodal effective and functional refractory periods were prolonged in Cx40-/- compared with Cx40+/+ mice. Cx40-deficient mice exhibit significant delay not only in infra-Hisian conduction, as would be expected from the expression of Cx40 in the His-Purkinje system but also in the electrophysiologic parameters that reflect AV nodal conduction. Our data suggest a significant role of Cx40 in atrionodal conduction and/or in proximal His-bundle conduction.

CP-96,345, a non-peptide antagonist of substance P. III. Cardiovascular effects in mammals unrelated to actions on substance P receptors.

The cardiovascular effects of CP-96,345, a non-peptide antagonist of substance P, were analyzed in vivo and in vitro. In the anaesthetized rat, the i.v. injection of 3 mumol kg-1 of CP-96,345 induced a fall in mean arterial blood pressure and a reduction in heart rate. Similar effects were obtained with the enantiomer CP-96,344 (2R,3R)-cis-isomer of CP-96,345) which does not interact with substance P receptors. Both enantiomers, at a concentration of 10 microM, decreased the beating frequency of the isolated atria and of the isolated perfused heart of the guinea-pig to a similar extent, and caused transient coronary dilatation. CP-96,345 (10 microM) decreased the spontaneous sinus rate, prolonged the atrioventricular-nodal conduction interval and the His-bundle conduction interval of the perfused guinea-pig heart. The intraventricular spread of conduction was markedly inhibited. During programmed stimulation 10 min after the beginning of the drug application, the effective refractory periods evaluated by stimulation with premature beats, as well as rate dependent effective refractory periods, of the atrioventricular node, of the atrial and of the ventricular myocardium, were prolonged. Sinus node recovery time was also prolonged. It was concluded that these cardiac effects of CP-96,345 were not caused by an action of the compound on substance P receptors.

The effects of the propranolol enantiomers on the intracardiac electrophysiological activities of Langendorff perfused hearts.

The optical isomers of the beta blocking agent propranolol exert beta receptor blocking as well as membrane stabilizing effects. The latter is thought to be responsible for the antiarrhythmic effect of the drug. In this study we quantified the electrophysiological effects of both isomers of propranolol on the conduction and pacemaker system of the heart. The experiments were performed on isolated hearts using a special ECG recording and stimulation technique. To abolish isoproterenol's beta adrenergic stimulatory effect on heart rate, 30-times higher concentrations of (+)propranolol were necessary than of (-)propranolol in order to be consistent. Both isomers caused a similar and marked slowing of conduction velocity through the bundle of His and ventricular myocardium. Also, heart rate, as well as atrio-ventricular conduction velocity were significantly slowed by a concentration of 10 microM of either drug, (-)propranolol being slightly more effective. Only in the presence of (-)propranolol did significant changes of atrio-ventricular and His-bundle conduction occur at a concentration of 1 microM. During programmed stimulation sinus node recovery time was more prolonged by (-)propranolol than during perfusion with (+)propranolol. The highest rate of pacing with 1:1 conduction of the sino-atrial conduction, the atrial and ventricular myocardium was significantly depressed to a comparable degree by either isomers of propranolol. These effects appear to be primarily responsible for the antiarrhythmic effects of both isomers. Because of the minor effects of (+)propranolol on sinus- and AV-node activity, as well as on beta adrenergic receptors, this isomer may have potential clinical importance in the treatment of arrhythmias.

Assessment of the conduction of the cardiac impulse by a new epicardiac surface and stimulation technique (SST-ECG) in Langendorff perfused mammalian hearts

The assessment of the effects on the conduction of the cardiac impulse and of refractoriness simultaneously from multiple cardiac structures is important to evaluate the mode of action of new compounds, as well as to investigate undesired cardiac side effects. The measurements of intracardiac electrical activities of special structures have required catheter methods or averaging techniques to produce clear deflections of low-level potential wave forms. We have developed an epicardial surface electrocardiogram (S-ECG) recording technique to detect continuously sinus node and His-bundle activities in spontaneously beating Langendorff perfused heart preparations. A bipolar surface stimulation technique electrocardiogram (ST-ECG) could be combined with this S-ECG method to assess the effect of pacing at maximal rate on the refractoriness of the sino-atrial, AV-nodal, and His-bundle conduction, as well as that of the atrial and ventricular myocardium. Epicardial surface electrodes were also used for vector analysis of the signals, which include those of the sinus node and His-bundle potentials, in addition to the usual atrial and ventricular loops. The present results demonstrate that this new epicardial surface ECG recording technique, combined with the described SST-ECG, provided a way to improve or replace more elaborate intracardiac techniques used in isolated hearts or in animal experiments.

The influence of elevated Mg2+ concentrations on cardiac electrophysiologic parameters

This study was performed to evaluate the direct effects of magnesium ions on cardiac conduction velocities and on refractoriness using a modified Langendorff perfusion system and a special ECG recording and stimulation technique. An increase of the MG2+ concentration to 2.3 mM had no detectable effects. Higher concentrations of up to 4.6 mM decreased the spontaneous sinus rate and the conduction velocity through the AV node and the His bundle in a concentration-dependent manner. During stimulation with premature beats, in the presence of 4.6 mM of Mg2+, the effective and relative refractory periods (ERP, RRP) of sinoatrial, AV nodal, and His bundle conduction and the ERP of the ventricular myocardium were significantly prolonged, whereas the ERP of the atrial myocardium remained unaffected. The refractoriness of sinoatrial, AV nodal, and His bundle conduction, and of the ventricular myocardium, were also prolonged during pacing with a stepwise increased pacing rate. These observations suggest a marked rate-dependent inhibitory effect of magnesium on the refractoriness of the His-bundle conduction and of the ventricular myocardium, which might be an important factor in the antiarrhythmic effectiveness of magnesium in ventricular tachyarrhythmias.