Peripheral and autonomic nervous system involvement in chronic GM2-gangliosidosis.

GM2-gangliosidosis (McKusick 268800 and 272800) is a rare hereditary, progressive disorder of ganglioside metabolism caused by deficiency of lysosomal beta-hexosaminidase (EC 3.2.1.52) activity. It is characterized by severe central nervous system involvement. Involvement of the peripheral and autonomic nervous system has been suspected but rarely documented in published case reports in the chronic form of the disease. Four patients, aged 24-29 years, with chronic GM2-gangliosidosis were examined prospectively for evidence of peripheral and autonomic nervous system dysfunction. All had nerve conduction studies, sympathetic skin responses and cardiac monitoring during the head tilt-table test. Three patients had objective evidence of autonomic dysfunction with abnormal sympathetic nervous skin responses and axonal sensorimotor polyneuropathy. None of the patients had evidence of significant cardiovascular autonomic dysfunction on the head tilt-table test. The peripheral and autonomic nervous system may be involved in patients with chronic GM2-gangliosidosis. In some cases, this may be clinically significant. On the other hand, cardiovascular autonomic instability is apparently not a significant problem in young adult patients with the disease.

Role of adenosine receptors in the paradoxic bradycardia response of rats to inferior vena cava occlusion during an infusion of isoproterenol.

BACKGROUND: In susceptible humans, vasodepressor reactions are induced by restriction of venous return (upright tilting) and administration of isoproterenol. Because paradoxic bradycardia is a major manifestation of vasodepressor reactions, and allowing for extrapolation between paradoxic bradycardia in rats and vasodepressor reactions, we examined whether adenosine receptors mediate the paradoxic bradycardia reaction. METHODS AND RESULTS: Paradoxic bradycardia was induced in rats by inferior vena cava occlusion during an isoproterenol infusion. We studied whether dipyridamole, an adenosine transport inhibitor, and aminophylline (nonselective) or DPCPX (selective) A1 antagonists augmented or inhibited paradoxic bradycardia, respectively, during inferior vena cava occlusion. The maximum changes in R-R during 60 seconds of inferior vena cava occlusion were that (1) in control, the rate accelerated (DeltaR-R, -9.7+/-0.8 ms, P<0.001); (2) during isoproterenol (0.8 microg . min-1), paradoxic bradycardia occurred (DeltaR-R, +92.0+/-32.0 ms, P<0.001); (3) during isoproterenol but after dipyridamole, paradoxic bradycardia occurred at a much lower dose of isoproterenol (0.2 microg . min-1), and the magnitude was increased at all doses (at 0.8 microg . min-1 isoproterenol, DeltaR-R, +195.6+/-27.6 ms, P<0.001 versus isoproterenol alone, DeltaR-R, +92.0+/-32 ms); (4) during isoproterenol and dipyridamole, atropine did not block paradoxic bradycardia, but cervical vagotomy inhibited paradoxic bradycardia (DeltaR-R, +5.6+/-1.8 ms, P<0.001 compared with isoproterenol and dipyridamole alone); and (5) during isoproterenol alone, aminophylline or DPCPX blocked paradoxic bradycardia (DeltaR-R, -5.4+/-1.0 ms, and DeltaR-R, -2.6+/-0.5 ms, respectively, each P<0.001 compared with isoproterenol alone). CONCLUSIONS: The adenosine A1 receptor mediates the paradoxic bradycardia reflex during inferior vena cava occlusion in the face of isoproterenol via vagal afferents.

Induction of paradoxic bradycardia in rats by inferior vena cava occlusion during the administration of isoproterenol: the essential role of augmented sympathetic tone.

INTRODUCTION: Testing human susceptibility for vasodepressor reactions involves combining venous return restriction by passive upright tilting and administering isoproterenol. While sympathetic tone is usually increased by the stimuli that incite a vasodepressor reaction, it is not known if the increased sympathetic tone is an essential or passive component of the mechanism that triggers the reaction. Given that paradoxic bradycardia is a major manifestation of vasodepressor reactions and allowing for the possible extrapolation between paradoxic bradycardia in rats and vasodepressor reactions, we examined the role of sympathetic tone in the paradoxic bradycardia reaction. Paradoxic bradycardia was induced in rats by inferior vena cava occlusion during an isoproterenol infusion. To examine the role of increased sympathetic tone on this reaction, we studied whether carotid artery perfusion (80 to 100 mmHg) during inferior vena cava occlusion, a maneuver that blunts the rise in sympathetic tone, inhibits paradoxic bradycardia. METHODS AND RESULTS: The maximum changes in R-R were measured during 60 seconds of inferior vena cava occlusion as follows: (a) in control the heart rate accelerated (delta R-R - 10.2 +/- 2.3 msec, P < 0.001); (b) during an infusion of isoproterenol, paradoxic bradycardia occurred (delta R-R + 140.6 +/- 18.2 msec, P < 0.001), and this was inhibited by common carotid artery perfusion (delta R-R - 6.6 +/- 1.5 msec, P < 0.001); and (c) following carotid sinus denervation and during an infusion of isoproterenol, paradoxic bradycardia was induced without and with carotid artery perfusion (delta R-R + 122.6 +/- 12.0 msec, P < 0.001; delta R-R + 151.8 +/- 12.7 msec, P < 0.001, respectively). CONCLUSIONS: Since carotid artery perfusion during inferior vena cava occlusion inhibits paradoxic bradycardia only when the carotid sinus is innervated, we conclude that carotid artery perfusion blocks the reaction by increasing carotid sinus afferents, thereby limiting the increased sympathetic tone during inferior vena cava occlusion, and not as a result of cerebral perfusion. Thus, the paradoxic bradycardia resulting from inferior vena cava occlusion requires activation of sympathetic tone as a result of carotid sinus hypotension.

Verapamil blockade of the paradoxic bradycardia in rats induced by inferior vena cava occlusion during the administration of isoproterenol or calcium: the role of Ca2+.

It has been postulated that the vasodepressor reaction results from a vigorous ventricular contraction in the face of a reduced cardiac volume. Paradoxic bradycardia is a major manifestation of vasodepressor reactions. Allowing for the possible extrapolation between paradoxic bradycardia in rats and vasodepressor reactions, we examined calcium's role, an essential component of cardiac contraction, in the paradoxic bradycardia reaction. Paradoxic bradycardia was induced in rats by inferior vena cava occlusion during an isoproterenol infusion, and we examined calcium's role by studying whether verapamil inhibits and CaCl2 causes paradoxic bradycardia, respectively. The maximum changes in R-R were measured during 60 s of inferior vena cava occlusion under the following conditions: (i) in control, the rate accelerated (R-R-21.8 +/- 2.4 ms (mean +/- SE), p < 0.001); (ii) during isoproterenol, paradoxic bradycardia occurred (R-R 98.0 +/- 8.1 ms, p < 0.001), and this was inhibited by verapamil (R-R 5.0 +/- 2.1 ms, p > 0.05) and restored by CaCl2 (R-R 109.3 +/- 6.5 ms, p < 0.001); (iii) during CaCl2 (without isoproterenol), paradoxic bradycardia also occurred (R-R 82.1 +/- 22.9 ms, p < 0.001), and this was also inhibited by verapamil (R-R -18.5 +/- 4.7 ms, p < 0.001). We conclude that verapamil inhibits the inferior vena cava occlusion induced paradoxic bradycardia caused by either isoproterenol or calcium, and these findings support the concept that increased cardiac contractile force triggers a vasodepressor reaction.

Paradoxic bradycardia (vasodepressor reaction) induced by inferior vena cava occlusion: the role of alpha- and beta-adrenergic receptors and their interaction.

Vasodepressor reactions, characterized by paradoxic bradycardia, were induced in rats when the inferior vena cava was occluded during an infusion of isoproterenol. The effects of alpha-adrenergic receptors and their interaction with beta-adrenergic receptors on the vasodepressor reaction were examined. Inferior vena cava occlusion was performed for 60 s, and the maximum changes in R-R were measured in 44 rats: (i) in control conditions, during phenylephrine (alpha 1-adrenergic agonist), and during a combined infusion of phenylephrine and isoproterenol the R-R shortened significantly (-16.8 +/- 1.4, -24.1 +/- 2.2, and -4.9 +/- 1.2 ms, respectively); (ii) isoproterenol and phentolamine and prazosin (nonselective and selective alpha-adrenergic antagonists) prolonged the R-R paradoxically (+89.2 +/- 9.5, +58.9 +/- 4.1, and +64.4 +/- 10.2 ms, respectively); (iii) atropine and right vagotomy did not affect the phentolamine-induced R-R prolongation (+66.0 +/- 2.4 and +73.8 +/- 13.7 ms, respectively), but it was blocked by left vagotomy (-9.6 +/- 1.1 ms); (iv) propranolol inhibited the prazosin-induced R-R prolongation (-14.3 +/- 2.8 ms,); (v) epinephrine (alpha- and beta-adrenergic agonist) shortened the R-R interval (-9.5 +/- 2.2 ms), but following prazosin, epinephrine induced R-R prolongation (+13.7 +/- 6.0 ms,); (vi) norepinephrine induced R-R prolongation (+21.0 +/- 6.7 ms). It was concluded that (i) paradoxic bradycardia (vasodepressor reaction) dependent on vagal afferents can be induced by reduced venous return in the presence of excess exogenous beta 1-adrenergic stimulation (isoproterenol) or when endogenous alpha-adrenergic tone is antagonized (phentolamine or prazosin); (ii) the reaction can be blocked by alpha 1-adrenergic stimulation; and (iii) epinephrine does not induce paradoxic bradycardia, whereas norepinephrine does, and this may be due to the stronger alpha-stimulating properties of epinephrine.

Vasodepressor reaction induced by inferior vena cava occlusion and isoproterenol in the rat. Role of beta 1- and beta 2-adrenergic receptors.

BACKGROUND: Testing for the susceptibility of vasodepressor reaction in humans involves the combination of restriction of venous return by passive upright tilting and the administration of isoproterenol. We developed an experimental rat model in which vasodepressor reactions are induced when the inferior vena cava is occluded during an infusion of isoproterenol. The reactions are characterized by the development of paradoxical bradycardia during the period of inferior vena cava occlusion. METHODS AND RESULTS: Inferior vena cava occlusion was performed for 60 seconds, and the maximal changes in RR interval were measured during seven states as follows: (1) when inferior vena cava occlusion was performed under control conditions in 40 rats, the rate accelerated in all 40 rats (delta RR, -15.6 +/- 1.9 milliseconds in 25 rats, P < .001; delta RR, -13.3 +/- 1.7 milliseconds in 10 rats, P < .001); (2) when inferior vena cava occlusion was performed in 25 rats during an infusion of isoproterenol, a vasodepressor reaction was observed in all rats as the heart rate slowed (delta RR, +92.7 +/- 8.3 milliseconds, P < .001); (3) when inferior vena cava occlusion was performed in 10 rats during an infusion of dobutamine, a selective beta 1-agonist, a vasodepressor reaction was observed in all rats as the heart rate slowed (delta RR, +63.3 +/- 10.6 milliseconds, P < .001); (4) when inferior vena cava occlusion was performed in 5 rats during an infusion of salbutamol, a selective beta 2-agonist, vasodepressor reaction was not observed as the heart rate accelerated in all rats (delta RR, -11.4 +/- 2.8 milliseconds, P < .002); (5) the vasodepressor reaction induced by either dobutamine or isoproterenol was inhibited by atenolol, a selective beta 1-adrenergic receptor antagonist; (6) the vasodepressor reaction induced by isoproterenol was inhibited by propranolol (lipophilic) and sotalol (nonlipophilic) beta-blockers and there was a dose-dependent attenuation by propranolol of the maximal RR interval slowing during inferior vena cava occlusion; and (7) butoxamine, a selective beta 2-adrenergic receptor antagonist, attenuated but did not block the vasodepressor reaction observed during an infusion of isoproterenol. CONCLUSIONS: Reduced cardiac volume combined with beta 1-adrenergic stimulation can stimulate a vasodepressor reaction in rats. beta 2-Adrenergic receptors play little or no role in the reaction. The vasodepressor reaction can be blocked by selective or nonselective beta 1-adrenergic antagonists independent of the drug's ability to penetrate the central nervous system. The application of these findings to humans remains to be elucidated.

Vasodepressor reaction induced by inferior vena caval occlusion and isoproterenol.

UNLABELLED: Testing for the susceptibility for vasodepressor reaction in humans involves the combination of restriction of venous return by passive upright tilting and the administration of isoproterenol. To explore the basis of the vasodepressor test in humans, the present experiment examined whether a reduced cardiac volume coupled with adrenergic stimulation causes a vasodepressor reaction in rats. Vasodepressor reaction was defined as paradoxical heart rate slowing in conjunction with hypotension during inferior vena caval occlusion. Inferior vena caval occlusion was performed for 60 s and the maximum changes in R-R were measured during seven states as follows. (A) Under control conditions inferior vena caval occlusion alone accelerated the rate in 32 of 32 rats (delta R-R, -13.9 +/- 1.7 ms, p less than 0.001). (B) When inferior vena caval occlusion was performed during an infusion of isoproterenol (0.5-1.0 micrograms.min-1), a vasodepressor reaction was observed in all rats as the heart rate slowed (delta R-R, +138.1 +/- 14.8 ms, p less than 0.001). The vasodepressor reaction was further examined during isoproterenol and inferior vena caval occlusion under five additional states. (C) After atropine the vasodepressor reaction was unchanged (delta R-R, +132.7 +/- 24.8 ms, p less than 0.001). (D) After bilateral vagotomy the paradoxical slowing was eliminated. (E) After intrapericardial lidocaine the paradoxic slowing was eliminated. (F) After bilateral stellectomy nonsignificant slowing was still present, but this was markedly reduced when compared with B (p less than 0.001). (G) Following chronic chemical sympathetic denervation with 6-hydroxydopamine the paradoxic bradycardia was eliminated. CONCLUSIONS: (1) Reduced cardiac volume combined with adrenergic stimulation can stimulate a vasodepressor reaction; (2) the vasodepressor reaction requires signalling by the afferent but not efferent vagal fibers; (3) the bradycardia is mainly due to withdrawal of sympathetic efferent tone.

Localization of the reflex pathway responsible for the vasodepressor reaction induced by inferior vena caval occlusion and isoproterenol.

Vasodepressor reactions were induced in 27 rats by a combination of inferior vena caval occlusion and an infusion of isoproterenol. A vasodepressor reaction was defined as paradoxical heart rate slowing during inferior vena caval occlusion. The R-R intervals were measured at 5-s intervals before, during, and after 60 s of inferior vena caval occlusion. The purpose of this study was to examine the role of the right and left vagus nerve and the right and left stellate ganglia in this reflex. Under control conditions inferior vena caval occlusion accelerated the rate (R-R, -15.9 +/- 0.9 ms). During an infusion of isoproterenol (0.5-1.0 micrograms.min-1), inferior vena caval occlusion produced paradoxical rate slowing, i.e., a vasodepressor reaction (R-R, +75.0 +/- 2.2 ms). The vasodepressor reaction was examined during inferior vena caval occlusion and isoproterenol under the following additional states: atropine methyl bromide or right vagotomy did not alter the reaction; left vagotomy eliminated the reaction; and right or left stellectomy greatly reduced the vasodepressor reaction. We conclude the following: (1) left vagal afferents mediate the vasodepressor reaction; (2) cardiac sympathetic fibers participate in the vasodepressor reaction by withdrawing efferent tone through the right stellate ganglion, and by generating the afferent signal, which triggers the vasodepressor reaction through the left stellate ganglion.

The effects of sympathetic denervation on spontaneous ventricular defibrillation in the rat.

Ventricular tachycardia or ventricular fibrillation was electrically induced in 38 normal rats (group 1) and 24 sympathetically denervated rats (6-hydroxydopamine) (group 2). The time for spontaneous reversion to sinus rhythm was measured during (1) control, (2) isoproterenol, and (3) the combination of isoproterenol and phenylephrine. The time for spontaneous reversion was the same in both groups in the three states. The reversion time was prolonged threefold by isoproterenol, and restored to control values when phenylephrine was added to the infusion of isoproterenol. The tachycardia duration and the refractory period were inversely related: log10 (tachycardia duration) = 3.466-0.091 (refractory period). Ventricular tachycardia/fibrillation induction was examined as follows: (i) Ventricular tachycardia/fibrillation was induced in 100% of normal rats (group 1), but only 42% of the denervated rats (group 2, p less than 0.001); (ii) during isoproterenol, ventricular tachycardia/fibrillation was induced in 100% of rats of both groups; and (iii) when phenylephrine was added to isoproterenol, ventricular tachycardia/fibrillation was induced in 100% of group 1 rats versus 82% of group 2 rats, (p = NS). These observations suggest (1) the induction of ventricular tachycardia/fibrillation is highly dependent on intact sympathetic innervation, and (2) exogenous adrenergic agonists modulate the duration of ventricular fibrillation through their effects on ventricular refractory period, independent of sympathetic innervation.

Effects of posture, Valsalva maneuver and respiration on atrial flutter rate: an effect mediated through cardiac volume.

The effects of passive upright tilting from 0 degrees to +60 degrees (n = 27), Valsalva maneuver (n = 16) and respiration (n = 10) on the rate of atrial flutter were studied in 27 patients. After tilting to +60 degrees, the atrial flutter cycle length shortened in all patients from 247.5 +/- 7 to 236.7 +/- 6.9 ms (range of shortening 1 to 21 ms, p less than 0.001). The Valsalva maneuver (strain of 40 mm Hg) shortened the flutter cycle length during the strain (phase 2) from 242.2 +/- 4.6 to 230.5 +/- 5 ms (range of shortening 2 to 19 ms, p less than 0.001). In 10 patients whose respiration was monitored, the flutter cycle length consistently prolonged during inspiration and shortened during expiration. Combined beta-adrenergic and muscarinic receptor blockade in six patients did not significantly alter the flutter cycle length at rest or the effects of the various maneuvers on the changes in flutter cycle length. This study revealed that the atrial flutter cycle length can be shortened by passive upright tilting, the strain phase of the Valsalva maneuver and expiration. Changes in flutter cycle length were independent of autonomic tone, implying that by decreasing cardiac volume, these maneuvers affect characteristics of the atrial flutter circuit, thereby producing dynamic changes in the rate of atrial flutter.

The mechanism of flutter interval alternans.

The mechanism of atrial flutter alternans was investigated by observing the effects of ventricular systole on flutter intervals in a patient with atrioventricular dissociation. Interval measurements were made both from atrial electrograms recorded from an esophageal electrode, and from surface ECG recordings. Flutter cycle intervals that occurred during a well-defined period subsequent to ventricular systole were consistently prolonged by up to 30 msec relative to the baseline flutter cycle interval. This prolongation was observed in two vastly different electrode configurations, implying that motion artifact was not predominantly responsible. We concluded that, by altering the characteristics of the flutter reentry circuit, transient increases in atrial volume and/or pressure arising during ventricular systole were responsible for the lengthening of the flutter cycle intervals.

Cardiac innervation after double lung transplantation. Toronto Lung Transplant Group.

Double lung transplantation has been successfully introduced for patients with end-stage pulmonary disease and preserved cardiac function. An advantage of this operation compared with heart-lung transplantation is retention of the recipient's heart. The operative dissection, however, may lead to interruption of sympathetic and parasympathetic pathways to the heart and consequent denervation of the native heart. The cardiac innervation of seven double lung transplant recipients was investigated by the heart rate response to carotid sinus massage, the Valsalva maneuver, intravenous injection of atropine, and exercise. Five single lung and two heart-lung transplant recipients were studied for comparison. Of the seven double lung transplant recipients, three had abnormal responses to carotid sinus massage, six to the strain phase of the Valsalva maneuver, and five to the release phase of the Valsalva maneuver. Three of six double lung transplant recipients tested had no response to intravenous injection of atropine, and five of seven patients had an abnormal recovery of heart rate after maximal exercise. No patient had a normal response to all interventions, and three patients had responses compatible with complete cardiac denervation. It is concluded that cardiac denervation may occur after double lung transplantation, most likely caused by surgical interruption of sympathetic and parasympathetic pathways during dissection of the recipient's trachea.

The protective effect of vagus nerve stimulation on catecholamine-halothane-induced ventricular fibrillation in dogs.

Parasympathetic neural activity modulates some ventricular arrhythmias in man. Therefore, a canine model of arrhythmias produced by the interaction of halothane and catecholamines was used to study the effects of vagal stimulation on the induction of ventricular fibrillation. The dose of catecholamine required to induce ventricular fibrillation was determined during a constant heart rate. Vagal stimulation reversibly raised the norepinephrine dose that produced ventricular fibrillation from 16.4 +/- 2.4 to 30.0 +/- 3.8 micrograms (p less than 0.001, n = 10), and the epinephrine dose from 15.5 +/- 2.0 to 22.5 +/- 2.6 micrograms (p less than 0.001, n = 5). Following atropine, vagal stimulation failed to raise the threshold dose of norepinephrine (16.8 +/- 2.4 vs. 18.3 +/- 3.3 micrograms, nonsignificant, n = 6) or epinephrine (15.5 +/- 2.0 vs. 16.0 +/- 2.3 micrograms, nonsignificant, n = 5). Ligation of the cervical vagus nerves did not affect the epinephrine threshold dose (16.3 +/- 3.3 vs. 17.5 +/- 2.7 micrograms, nonsignificant, n = 5). Following elevation of basal vagal tone by morphine premedication, the norepinephrine threshold of 53.0 +/- 9.2 micrograms declined by a nonsignificant amount to 46.5 +/- 11.5 micrograms after vagotomy (nonsignificant, n = 5). Thus resting vagal tone does not prevent catecholamine-halothane-induced ventricular fibrillation, whereas increasing vagal tone by electrical stimulation substantially protects against this arrhythmia. The protection is mediated through a muscarinic cholinergic receptor.

Isoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons.

The ability of isoproterenol to induce symptoms and laboratory findings of a vasodepressor reaction was tested in 48 patients, ages 17 to 74, divided into 4 groups according to the reason for their referral. Group 1 comprised 12 patients with vasodepressor syncope, group 2 had 8 patients with syncope of unknown origin, group 3 included 11 patients with syncope due to seizures in 2 and ventricular tachycardia in 9, group 4 had 17 patients with various arrhythmias not associated with syncope. Isoproterenol boluses were administered starting at 2 micrograms and increased in 2-micrograms steps to a maximum of 8 micrograms at 0 degree and +60 degrees. The responses at 0 degrees were all normal. At +60 degrees a vasodepressor reaction consisting of syncope or near syncope, hypotension and bradycardia was produced by isoproterenol (mean dose 6.0 +/- 0.26 micrograms) in 8 patients from group 1 (66.6%), 4 from group 2 (50%), 0 from group 3 and 4 from group 4 (23.5%). Three of the 4 patients in group 4 had a remote history of classic vasodepressor syncope. The overall sensitivity and specificity of the test were 73 and 85%, respectively, while the predictive accuracy of a test with positive or negative outcome were 69 and 89%, respectively. Muscarinic receptor blockade with atropine in 4 patients prevented isoproterenol-induced bradycardia but not hypotension or symptoms of fainting. Beta-adrenergic receptor blockade with propranolol inhibited all aspects of the isoproterenol-induced faint. Thus, the administration of isoproterenol during a passive upright tilt may identify persons who suffer from or are prone to a vasodepressor reaction.

Modulation of an idioventricular rhythm by vagal tone.

A 28 year old man with a stable permanent idioventricular rhythm of 80 to 85 beats/min, with all the characteristics of a pacemaker, is described. This pacemaker was slowed by maneuvers that enhanced vagal tone, including carotid sinus massage, the postrelease phase of the Valsalva maneuver and phenylephrine. The pacemaker was also slowed by a cholinesterase inhibitor (edrophonium hydrochloride) and accelerated by a muscarinic receptor blocking drug (hyoscine butylbromide). The actions of these maneuvers and agents were independent of sympathetic tone as propranolol pretreatment did not alter their effects. Similarly, propranolol did not affect the pacemaker rate. The pacemaker was not dependent on a slow inward current because verapamil did not affect its rate. The pacemaker accelerated in response to increased sympathetic tone induced by exercise and upright tilting and to the adrenergic agonist isoproterenol. The pacemaker was localized to the high posterior septal region of the left ventricle underneath the mitral valve. This report describes in a man an idioventicular pacemaker that is innervated by sympathetic and vagal fibers and responsive to alterations in tone of both limbs of the autonomic nervous system. It offers the first clear proof that a ventricular pacemaker can be innervated and controlled by the vagus nerve and provides its location.

Spontaneous termination of paroxysmal supraventricular tachycardia following disappearance of bundle branch block ipsilateral to a concealed atrioventricular accessory pathway: the role of autonomic tone in tachycardia diagnosis.

We present a case of an 18-year-old man with a history of palpitations in whom episodes of paroxysmal supraventricular tachycardia were easily initiated by administered atrial premature beats. In all 15 control episodes of tachycardia, functional left bundle branch block (LBBB) seen at the onset, resolved within 10-20 cycles (mean, 13.1 +/- 0.95). The tachycardia ended with the normalized QRS complex in each episode. Eleven episodes ended because of block within the antegrade pathway (ended with a P-wave), and four episodes stopped because of block within the retrograde pathway (ended without a P-wave). During the administration of isoproterenol (1 mg/min IV) all six episodes of tachycardia had LBBB but these did not end when LBBB disappeared spontaneously. When LBBB subsided, the mean tachycardia cycle interval shortened from 328.5 +/- 1.4 to 264.2 +/- 2.1 ms (p less than 0.001). Each episode of tachycardia was then terminated by carotid sinus massage. The disappearance of LBBB in control conditions presented the retrograde and antegrade limbs of the reentrant circuit with an early impulse that stopped the tachycardia. After isoproterenol administration, the tachycardia did not end following disappearance of LBBB, thus enabling the tachycardia cycle interval to shorten by a mean of 64.3 +/- 1.9 ms. This extent of tachycardia acceleration is diagnostic of the participation of a concealed, left free-wall bypass tract.

[In vitro electrophysiological effects of sodium dantrolene on isolated preparations of Purkinje fibers and ventricular myocardium of sheep]. / Effets électrophysiologiques in vitro du dantrolène sodium sur des préparations isolées de fibres de Purkinje et de myocarde ventriculaire de mouton.

Dantrolene sodium is a drug used in the treatment of spasticity and malignant hyperthermia. It is known to have a myorelaxant effect related to inhibition of the "release" of calcium by the sarcoplasmic reticulum of striated skeletal muscle. A direct cardiac effect which has only recently been suspected was demonstrated in vitro on isolated preparations of sheep Purkinje fibres and ventricular myocardium. Dantrolene caused a spectacular lengthening of the duration of the action potential of Purkinje fibres. This could be due either to an action on the slow calcium current or to stimulation of an ingoing sodium current sensitive to tetrodotoxin (TTX). This effect on the cardiac action potentials could explain the antiarrhythmic properties of dantrolene sodium during attacks of malignant hyperthermia.

On-line epicardial mapping of intraoperative ventricular arrhythmias: initial clinical experience.

An on-line automatic mapping system was developed for beat by beat display of epicardial activation during ventricular tachycardia induced at the time of cardiac surgery. A sock array of 110 button electrodes was used to record and display local activation on a video monitor at 8.3 ms intervals. On instant replay in slow motion, epicardial pacing sites were accurately localized to the nearest electrode. Local unipolar electrograms were also recorded, first from the sock array, then from an array of 16 transmural needle electrodes. The epicardial display was verified by retrospective manually derived maps using the recorded epicardial electrograms. In four patients with coronary artery disease and recurrent inducible ventricular tachycardia, earliest epicardial activation was located on slow motion replay within 1 minute. Subendocardial sites of early activation were located within 10 minutes by replay of electrograms from the needle array before ventriculotomy. Transmural and endocardial resection of these sites prevented inducibility of the tachycardia on postoperative electrophysiologic study in three of the four patients. There has been no clinical recurrence of ventricular tachycardia after 3 to 14 months of follow-up despite cessation of antiarrhythmic therapy in three of the patients. This technique has unique advantages over existing mapping methods. It provides beat by beat display of activation sequences so that clinical tachycardias that are short in duration or pleomorphic in configuration now become amenable to mapping. In addition, it markedly shortens total time on cardiopulmonary bypass.