A comparison of an A1 adenosine receptor agonist (CVT-510) with diltiazem for slowing of AV nodal conduction in guinea-pig.
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1. The purpose of this study was to compare the pharmacological properties (i.e. the AV nodal depressant, vasodilator, and inotropic effects) of two AV nodal blocking agents belonging to different drug classes; a novel A1 adenosine receptor (A1 receptor) agonist, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside (CVT-510), and the prototypical calcium channel blocker diltiazem. 2. In the atrial-paced isolated heart, CVT-510 was approximately 5 fold more potent to prolong the stimulus-to-His bundle (S-H interval), a measure of slowing AV nodal conduction (EC50 = 41 nM) than to increase coronary conductance (EC50 = 200 nM). At concentrations of CVT-510 (40 nM) and diltiazem (1 microM) that caused equal prolongation of S-H interval (approximately 10 ms), diltiazem, but not CVT-510, significantly reduced left ventricular developed pressure (LVP) and markedly increased coronary conductance. CVT-510 shortened atrial (EC50 = 73 nM) but not the ventricular monophasic action potentials (MAP). 3. In atrial-paced anaesthetized guinea-pigs, intravenous infusions of CVT-510 and diltiazem caused nearly equal prolongations of P-R interval. However, diltiazem, but not CVT-510, significantly reduced mean arterial blood pressure. 4. Both CVT-510 and diltiazem prolonged S-H interval, i.e., slowed AV nodal conduction. However, the A1 receptor-selective agonist CVT-510 did so without causing the negative inotropic, vasodilator, and hypotensive effects associated with diltiazem. Because CVT-510 did not affect the ventricular action potential, it is unlikely that this agonist will have a proarrythmic action in ventricular myocardium. (+info)
Modulation of AV nodal and Hisian conduction by changes in extracellular space.
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Previous studies have demonstrated that the extracellular space (ECS) component of the atrioventricular (AV) node and His bundle region is larger than the ECS in adjacent contractile myocardium. The potential physiological significance of this observation was examined in a canine blood-perfused AV nodal preparation. Mannitol, an ECS osmotic expander, was infused directly into either the AV node or His bundle region. This resulted in a significant dose-dependent increase in the AV nodal or His-ventricular conduction time and in the AV nodal effective refractory period. Mannitol infusion eventually resulted in Wenckebach block (n = 6), which reversed with mannitol washout. The ratio of AV nodal to left ventricular ECS in tissue frozen immediately on the development of heart block (n = 8) was significantly higher in the region of block (4.53 +/- 0.61) compared with that in control preparations (2.23 +/- 0.35, n = 6, P < 0.01) and donor dog hearts (2.45 +/- 0.18, n = 11, P < 0.01) not exposed to mannitol. With lower mannitol rates (10% of total blood flow), AV nodal conduction times increased by 5-10% and the AV node became supersensitive to adenosine, acetylcholine, and carbachol, but not to norepinephrine. We conclude that mannitol-induced changes in AV node and His bundle ECS markedly alter conduction system electrophysiology and the sensitivity of conductive tissues to purinergic and cholinergic agonists. (+info)
OBJECTIVES: The purpose of this study is to validate the use of tissue Doppler acceleration imaging (TDAI) for evaluation of the onset of ventricular contraction in humans. BACKGROUND: Tissue Doppler acceleration imaging can display the distribution, direction and value of ventricular acceleration responses to myocardial contraction and electrical excitation. METHODS: Twenty normal volunteers underwent TDAI testing to determine the normal onset of ventricular acceleration. Two patients with paroxysmal supraventricular tachycardia and 30 patients with permanent pacemakers underwent introduction of esophageal and right ventricular pacing electrodes, respectively, and were studied to visualize the onset of pacer-induced ventricular acceleration. Eight patients with dual atrioventricular (AV) node and 20 patients with Wolff-Parkinson-White (WPW) syndrome underwent TDAI testing to localize the abnormal onset of ventricular acceleration, and the results were compared with those of intracardiac electrophysiology (ICEP) tests. RESULTS: The normal onset and the onset of dual AV node were localized at the upper interventricular septum (IVS) under the right coronary cusp within 25 ms before the beginning of the R wave in the electrocardiogram (ECG). In all patients in the pacing group, the location and timing of the onset conformed to the positions and timing of electrodes (100%). In patients with WPW syndrome, abnormal onset was localized to portions of the ventricular wall other than the upper IVS at the delta wave or within 25 ms after the delta wave in the ECG. The agreement was 90% (18 of 20) between the abnormal onset and the position of the accessory pathways determined by ICEP testing. CONCLUSIONS: These results suggest that TDAI is a useful noninvasive method that frequently is successful in visualizing the intramural site of origin of ventricular mechanical contraction. (+info)
Anatomical study of truncus arteriousus communis with embryological and surgical considerations.
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Twelve specimens of truncus arteriosus communis have been studied anatomically, with special reference to the conal anatomy and to the associated cardiac anomalies which can create additional problems if surgical repair is planned. A wide spectrum of conal morphology has been observed, suggesting that differential conal absorption is a developmental characteristic of truncus arteriousus as well as of transposition complexes. The invariable absence of septation of the ventricular infundibula and semilunar valves, in spite of the variable anatomy of the free wall of the conus, indicates that all types of truncus arteriosus, ontogenetically, should be considered as a single undivided conotruncus. Various types of ventircular septal defect were found: (a) ventricular septal defect with absent crista, in which no remnants of conal septum are present; (b) supracristal ventricular septal defect, in which vestigial conal septum is seen in front of the membranous septum; (c) bulloventricular foramen, associated with univentricular origin of the truncus from the right ventricle. Frequent associated anomalies are underdevelopment of the aortic arch, truncal valve malformations, and obstructive ventricular septal defect. The AV conduction system studied in one case showed an arrangement similar to Fallot's tetralogy with the His bundle and the left bundle-branch in a safe position behind the posteroinferior rim of the defect. The postoperative fate of the frequently abnormal truncal valve and the theoretical indications for total repair for Type IV truncus are also discussed. (+info)
Electrophysiological effects of mexiletine in man.
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The electrophysiological effects of intravenous mexiletine in a dose of 200 to 250 mg given over 5 minutes, followed by continuous infusion of 60 to 90 mg per hour, were studied in 5 patients with normal conduction and in 20 patients with a variety of disturbances of impulse formation and conduction, by means of His bundle electrography, atrial pacing, and the extrastimulus method. In all but 2 patients the plasma level was above the lower therapeutic limit. Mexiletine had no consistent effects on sinus frequency and atrial refractoriness. The sinoatrial recovery time changed inconsistently in both directions; however, of the 5 patients in whom an increase was evident, 3 had sinus node dysfunction. In most patients mexiletine increased the AV nodal conduction time at paced atrial rates and shifted the Wenckebach point to a lower atrial rate. The effective refractory period of the AV node was not consistently influenced, while the functional refractory period increased in 12 out of 14 patients. The HV intervals increased by a mean of 11 ms in 8 patients and were unchanged in 17. Both the relative and effective refractory period of the His-Purkinje system increased after mexiletine. Non-cardiac side effects occurred in 7 out of 25 patients, and cardiac side effects, including one serious, in 2. The results indicate that mexiletine shares some electrophysiological properties with procainamide and quinidine, when given to patients with conduction defects, and that the drug should not be used in patients with pre-existing impairment of impulse formation or conduction. It has additional effects on AV nodal conduction which may be of value in the treatment of re-entrant tachycardias involving the AV node. (+info)
Monophasic action potentials of right atrium and electrophysiological properties of AV conducting system in patients with hypothyroidism.
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In 12 patients with manifest hypothyroidism right atrial monophasic action potentials showed a significant prolongation in comparison with data from normal or euthyroid patients. Atrial effective refractory periods were also significantly prolonged. After thyroid treatment the monophasic action potential duration and the effective refractory period of the right atrium were within normal ranges. In 6 hypothyroid patients studies of AV conduction with the aid of His bundle electrography and atrial pacing showed a supraHisian conduction delay which was manifest in one case and latent in another two. InfraHisian conduction delay was encountered in 2 cases. (+info)
The nerve supply and conducting system of the human heart at the end of the embryonic period proper.
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The nerve supply and conducting system were studied in a stage 23 human embryo of exceptional histological quality. The nerves on the right side arose from cervical sympathetic and from cervical and thoracic vagal filaments. Out of their interconnexions vagoxympathetic nerves emerged, which (1) sent a branch in front of the trachea to the aorticopulmonary ganglion, thereby supplying arterial and venous structures, and (2) formed the right sinal nerve, which supplied the sinu-atrial node, and gave filaments to the interatrial septum which could be traced to the atrioventricular node and pulmonary veins. The nerves on the left side arose similarly from cervical sympathetic and from cervical and thoracic vagal filaments. These formed several descending, ganglionated, vagosympathetic filaments that descended to the right of the arch of the aorta and entered the aorticopulmonary ganglion. Filaments leaving the ganglion supplied the pulmonary trunk, ascending aorta, interatrial septum, pulmonary veins, and, as the left sinal nerve, the fold of the left vena cava. The thoracic vagal filaments descended to the left of the arch of the aorta and supplied chiefly the arterial end of the heart. No thoracic sympathetic cardiac filaments were found. The sinu-atrial node began as a crescentic mass in front of the lower part of the superior vena cava. It gradually extended on each side of the superior vena cava and came to form its posterior wall at a more caudal level. The atrial myocardium that formed the septum spurium, venous valves, and interatrial septum could be traced from the sinu-atrial to the atrioventricular node. Myocardium also encircled the atrial aspects of the atrioventricular orifices, and could be traced caudally to the atrioventricular nde. The atrioventricular node was a conspicuous mass in the anterior and lower part of the interatrial septum, from which a clearly defined bundle left to enter the interventricular septum. Right and left limbs were observed, the former being a rounded bundle that passed immediately in front of the root of the aorta. (+info)
Atrioventricular nodal conduction during atrial fibrillation: role of atrial input modification.
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BACKGROUND: Posteroseptal ablation of the atrioventricular node (AVN) has been proposed as a means to slow the ventricular rate during atrial fibrillation (AF). The suggested mechanism is elimination of the AVN "slow pathway." On the basis of the unpredictable success of the procedure, we hypothesize that, in fact, the slow pathway is preserved. Therefore, the slowing of the ventricular rate results from reduced bombardment of the AVN. METHODS AND RESULTS: In 8 rabbit heart atrial-AVN preparations, cooling of the posterior and/or the anterior AVN approaches revealed nonspecific effects on the slow and fast pathway portions of the AVN conduction curve. In 13 other preparations, simulated AF during posterior cooling (n=6) prolonged the His-His (H-H) intervals but did not reveal specific slow pathway injury. In the remaining 7 preparations, AF was applied before and after posteroseptal surgical cuts. During AF with posterior origin, the cuts resulted in longer mean H-H along with slowing of the AVN bombardment rate. However, there was no change in the minimum observed H-H, suggesting an intact slow pathway. During AF with anterior origin, the mean and the shortest H-H remained unchanged before and after the cuts in all preparations. This was associated with the maintenance of high-rate AVN bombardment. CONCLUSIONS: Posteroseptal ablation does not eliminate the slow pathway. Ventricular rate slowing can be obtained if the ablation procedure results in a posteroanterior intra-atrial block leading to a reduction of the rate of AV nodal bombardment. (+info)