Prolongation Of Sinus Cycle Length Research Articles

COMPARISON OF HEART RATE AND BLOOD PRESSURE RESPONSE TO ULTRASOUND-GUIDED CAROTID SINUS MASSAGE IN THE SUPINE VERSUS UPRIGHT POSITION

Carotid Sinus Massage (CSM) is recommended in the work-up of syncope. Opinions vary as to whether CSM is best done supine or upright to evoke a significant hemodynamic response. CSM was performed in 39 patients ( 23M/16F; age 49±17) undergoing tilt table testing for suspected neurocardiogenic syncope. Right and left Carotid Artery (CA) bifurcations were located by ultrasound (US), marked in ink, and CSM performed at this location supine on the right (RCSMsup) and left (LCSMsup). The participant was then tilted (60°) and CSM repeated 4-6 minutes following tilt on the right (RCSMtilt) and left (LCSMtilt). CSM was done for 10 sec while the breath was held beginning 5 sec after end-expiration. In 17 participants, sham CSM was also done supine (RCSMsham, LCSMsham) while the breath was held and a finger was place on the skin without pressure. The difference (Δ) between maximum sinus cycle length (SCL) during CSM and SCL just prior to CSM, as well as Δ between minimum systolic blood pressure (SBP) during CSM and that just prior to CSM and Δ diastolic (D)BP were measured. No significant ΔSCL was observed with RCSMsham (13±38 ms) and LCSMsham (10±40 ms). SCL prolongation of at least 50 ms (Mean+1SD of sham effect) occurred in 28/39 subjects to at least one of RCSMsup or LCSMsup, but only in 22/39 on tilt. However, there was no statistically significant difference in effect of CSM supine or upright (ΔRCSMsup: 61± 82 ms; ΔRCSMtilt: 42± 89 ms; ΔLCSMsup: 47± 67 ms; ΔLCSMtilt: 38± 52 ms) using t-test or non-parametric testing (Friedmann). Similarly, there was no difference in ΔSBP whether supine or upright (ΔRCSMsup : -7±17 mm Hg; ΔRCSMtilt : -7±17 mm Hg; ΔLCSMsup : -6±12 mm Hg; ΔLCSMtilt: -5±15 mm Hg) or in ΔDBP (ΔRCSMsup: -4±11 mm Hg; ΔRCSMtilt: -5±11 mm Hg; ΔLCSMsup: -4±8 mm Hg; ΔLCSMtilt: -4±11 mm Hg). A non-significant tendency to greater prolongation of SCL in the older group (n = 28; age > 40) with ΔRCSMsup 71±92 ms vs in the younger group (n=11; age ≤ 40) ΔRCSMsup 36±38 ms was absent with tilt and was not observed with LCSM either supine or upright. Using US localization of the CA bifurcation, there is no added value to performing CSM in the upright position compared to supine testing. In fact, there is a tendency to a lesser bradycardic response and no greater BP lowering in the upright position.

Electromechanical and atrial and ventricular antiarrhythmic actions of CIJ-3-2F, a novel benzyl-furoquinoline vasodilator in rat heart

This study was designed to examine the antiarrhythmic efficacy and the underlying mechanisms of the benzyl-furoquinoline vasodilator, CIJ-3-2F, in rat cardiac preparations. Conduction electrograms and left ventricular pressure were determined in Langendorff-perfused hearts. Action potentials were assessed with microelectrode techniques, calcium transients by fura-2 fluorescence and ionic currents by whole-cell patch-clamp techniques. In isolated hearts, CIJ-3-2F prolonged sinus cycle length, QT interval, Wenckebach cycle length, atrio-His bundle and His bundle-ventricular conduction intervals, refractory periods in atrium, AV node, His-Purkinje system and ventricle, and also increased left ventricular pressure. CIJ-3-2F reduced the incidences of both ischaemic and reperfusion-induced ventricular arrhythmias and prevented the induction of atrial tachyarrhythmias. In both atrial and papillary muscles, CIJ-3-2F decreased upstroke velocity and prolonged duration of the action potential. In ventricular myocytes, CIJ-3-2F moderately increased the amplitude of [Ca(2+)]i transients and cell shortening. CIJ-3-2F inhibited the transient outward K(+) current (Ito ) (IC₅₀ = 4.4 μM) with accelerated inactivation, a slower rate of recovery from inactivation and use-dependency. CIJ-3-2F also suppressed the steady-state outward K(+) current (Iss , IC₅₀ = 3.6 μM, maximum inhibition = 65.7%) and both the inward Na(+) current (INa , IC₅₀ = 2.8 μM) and L-type Ca(2+) current (ICa,L , IC₅₀ = 4.9 μM, maximum inhibition = 69.4%). CIJ-3-2F blocked Na(+) and Ito channels and, to some extent, also blocked Ca(2+) and Iss channels, modifying cardiac electromechanical function. These effects are likely to underlie its antiarrhythmic properties.

Animal studies on the mechanisms and radiofrequency catheter ablation of the syncope with vasovaga1 syncope -radiofrequency ablation of cardiac nerve attenuates bezold-jarisch reflex in canine

Background: The Bezold–Jarisch Reflex (BJR) is one of the main causes for Vasovaga1 Syncope (VVS). Blocking the efferent pathways of the vagus ganglia in the heart may attenuate the BJR. Objective: To observe the influence of radiofrequency catheter ablation of the interventricular sulcus fat and endocardial nerve potential on Bezold-Jarisch Reflex (BJR) induced by veratridine in canine. Methods: Six mongrel dogs were anesthetized and their chest were opened through a right thoracotomy to expose the Interventricular sulcus fat. Veratridine was injected into the left ventricle at bolus doses of 15 ug/kg through a catheter to induce BJR. The Sinus Cycle Length (SCL), Systolic Arterial Pressure (SAR), Diastolic Arterial Pressure (DAP), Mean Arterial Pressure (MAP), Left Ventricle Systolic Pressure (LVSP), Left Ventricle Diastolic Pressure (LVDP) and Mean Left Ventricle Pressure (MLVP) were measured under the baseline and after ablation of fat pad; the changes of the above parameters (ΔSCL, ΔSAP, ΔDAP, ΔMAP, ΔLVSP, ΔLVDP and ΔMLVP) were calculated. Then the same dose of veratridine was injected under mapping along the mitral annulus, and potential nerve ablation and the changes of the above parameters were observed. Results: BJR was successfully induced in the 6 animals; the animals has prolonged Sinus Cycle Length (SCL) and decreased MAP and MLVP. After ablation, the prolongation of SCL after injection of veratridine was markedly reduced [229.2±92.3] ms vs [39.3±14.1] ms, p< 0.01.All the pressures were decreased after injection of veratridine, with significant decrease found only for DAP and MAP both p< 0.05. Conclusion: Ablation of the interventricular sulcus fat and endocardial nerve potential fat can effectively attenuate the decrement of heart rate and the decrement of DAP and MAP during the BJR induced by veratridine, which provides a basis for the treatment of VVS.

Bilateral atrial ganglionated plexus involvement in atrial responses to left-sided plexus stimulation in canines

Given the clinical interest concerning 'reflex vagal' responses to identify left atrial (LA) targets for ablative therapy of atrial fibrillation, we investigated whether vagal and bilateral atrial neural pathways may be involved in chronotropic and atrial repolarization responses to LA ganglionated plexus (GP) stimulation. Unipolar electrograms were recorded from 191 right atrial (RA) and LA sites in anaesthetized canines prior to and during electrical stimulation of the right vagus nerve (VgN), left VgN, or LAGP at baseline and following (i) bilateral VgN decentralization, and radiofrequency ablation of (ii) periaortic/superior vena cava (Ao/SVC) and (iii) RAGP in 14 animals (anterograde group), and in the reverse order in 7 (retrograde). Repolarization changes were also measured in similar preparations during Ao/SVC (n = 8) and RAGP stimulation (n = 23). Sinus cycle length (SCL) prolongation, and RA and LA repolarization changes (affected atrial surface area) were induced during LAGP stimulation. SCL prolongation and RA repolarization changes were unaffected by VgN decentralization but reduced following Ao/SVC and RAGP ablation in the anterograde group. In the retrograde group, chronotropic and RA repolarization changes were reduced following RAGP and abolished following Ao/SVC ablation. In contrast, LA repolarization responses to LAGP stimulation were reduced following VgN decentralization and each subsequent ablation step, with small residual responses after completing the anterograde protocol. Ao/SVC and RAGP stimulation exerted predominant influences in adjacent regions as well as demonstrating LA extensions. Vagal as well as bilateral atrial neural pathways are involved in mediating chronotropic and LA repolarization responses to LAGP stimulation.

Radiofrequency ablation of cardiac nerve attenuates Bezold–Jarisch reflex in canine

BackgroundThe Bezold–Jarisch reflex (BJR) is one of the main causes for vasovagal syncope (VVS). Blocking the efferent pathways of the vagus ganglia in the heart may attenuate the BJR.ObjectiveTo observe...

Spinal Cord Stimulation Causes Potentiation of Right Vagus Nerve Effects on Atrial Chronotropic Function and Repolarization in Canines

Experimental evidence suggests that spinal cord stimulation (SCS) can cause augmentation of parasympathetic influences on the heart via enhanced vagus nerve (VgN) activity. Herein, we investigated whether this might lead to enhanced inducibility of vagally mediated atrial tachyarrhythmias (AT) and whether such actions depend on intact autonomic neural connections with central neurons. Epidural SCS electrodes were implanted at T1-T4 in anesthetized canines. Sinus cycle length prolongation, atrial repolarization changes (191 epicardial electrode sites), and AT inducibility in response to right VgN stimuli applied at the cervical level were determined before and during SCS. VgN-induced sinus cycle length prolongation was potentiated during SCS among the animals with intact neural connections or bilateral vagotomy proximal to the stimulation site, whereas such prolongation was unaffected by SCS among animals with bilateral decentralization of stellate ganglia. Likewise, the atrial surface area in which VgN-induced repolarization wave form changes were identified was significantly augmented during SCS among the former but not among the latter. AT facilitation occurred during SCS in the majority of animals with intact neural connections, particularly among those displaying relatively greater potentiation of vagally mediated sinus cycle length prolongation. The data indicate that SCS may cause potentiation of parasympathetic influences on the atria in response to cervical VgN stimulation. Such SCS effects appear to be mediated via decreased tonic inhibitory sympathetic influences in the presence of intact stellate ganglion connections to central neurons.

α3 and not α6 subunit containing nAChR mediate cardiac cholinergic ganglionic transmission

The subunit composition of nicotinic acetylcholine receptors (nAChR) that mediate synaptic transmission in autonomic pathways remain incompletely elucidated. Conotoxin (ctx) MII blocks the majority (~70%) of cholinergic ganglionic transmission in vivo but acts on both α3/β2 and α6/β2 nAChR (only 5.6-fold higher affinity for α3/β2 vs. α6/β2). We used a more specific nAChR blocker to investigate the hypothesis that α6/β2 nAChR play a functional role in ganglionic transmission. Methods 4 dogs were anesthetized and underwent cervical vagal nerve stimulations (VSTIM). The artery supplying the sinus node was perfused with Tyrodes solution in vivo. Sinus cycle length (SCL) was measured after 3, 5, and 10 Hz VSTIM before and after perfusion with ctx MII-H9A;L15A (2020-fold higher affinity for α6/β2 vs. α3/β2). Results At baseline VSTIM prolonged SCL by 345±38, 476±43, 901±125 msec. Perfusion with ctx MII-H9A;L15A resulted in similar responses to VSTIM (300±29, 449±37, 866±125 msec, p>0.05, ANOVA) suggesting that blockade of α6/β2 did not alter responsiveness. Hexamethonium abolished responses to VSTIM confirming that the ganglion was perfused entirely by the cannulated sinus node artery. Conclusion The previously reported blockade in this ganglion by ctx MII is attributable specifically to α3/β2 nAChR and not α6 containing receptors.

Termination of paroxysmal supraventricular tachycardia by tecadenoson (CVT-510),a novel A1-adenosine receptor agonist

ObjectivesThe aim of this study was to evaluate tecadenoson safety and efficacy during conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. BackgroundTecadenoson (CVT-510), a novel adenosine receptor (Ado R) agonist, selectively activates the A1Ado R and prolongs atrioventricular (AV) nodal conduction at doses lower than those required to cause A2Ado R-mediated coronary and peripheral vasodilation. Unlike adenosine, which non-selectively activates all four Ado R subtypes and produces unwanted effects, tecadenoson appears to terminate AV node-dependent supraventricular tachycardias without hypotension and bronchoconstriction. MethodsIn this open-label, multicenter, dose escalation study, tecadenoson was administered to 37 patients (AV node re-entrant tachycardia, n = 29; AV re-entrant tachycardia, n = 8) with inducible PSVT sustained for ≥1 min during an electrophysiology study. Seven regimens (0.3 to 15 μg/kg) of up to two identical tecadenoson intravenous bolus doses were administered. ResultsAfter the first or second bolus, PSVT converted to sustained sinus rhythm for ≥5 min in 86.5% (32/37) of the patients, with 91% (29/32) of the conversions occurring after the first bolus (most within 30 s), coincident with anterograde conduction block in the AV node. No effects on sinus cycle length (SCL) or systolic blood pressure were observed. The atrial-His (AH), but not the His-ventricular (HV) interval was prolonged up to 5 min after the final tecadenoson bolus, returning to baseline by 10 min. Tecadenoson was generally well tolerated. ConclusionsIn this study, tecadenoson rapidly terminated sustained PSVT by depressing AV nodal conduction without causing hypotension. After sinus rhythm restoration, there was minimal AH interval prolongation without HV interval or SCL prolongation.

Electrophysiologic and antiarrhythmic effects of the new class III antiarrhythmic drug KCB-328 in experimental canine atrial flutter.

The electrophysiologic and antiarrhythmic effects of a new class III antiarrhythmic drug (KCB-328), a delayed rectifier potassium current (IKr) blocker with minimal reverse use-dependent effect on atrial repolarization, were evaluated in the canine night atrial crush-injury model of atrial flutter (AFL). Ten anesthetized, open-chest dogs, were studied after right atrial crush-injury. Atrial effective refractory period (ERP), conduction velocity (CV), wavelength, and dispersion of refractoriness were determined during programmed stimulation (S1S2 at S1S1 = 200, 300, 400, and 500 msec) at four sites via a mapping plaque sutured on the right atrial free wall. Right and left ventricular ERP were similarly measured at single sites. Electrophysiological parameters were determined at baseline and following sequential cumulative doses of KCB-328 (10, 30, 100, and 300 microg/kg). Sustained AFL was inducible in 7/10 dogs by rapid pacing following baseline electrophysiologic measurements. KCB-328 significantly prolonged sinus cycle length, but had no effect on PR interval, and prolonged QTc only at the highest dose level. KCB-328 significantly prolonged atrial ERP and wavelength and ventricular ERP, and significantly reduced dispersion of atrial refractoriness. KCB-328 significantly prolonged AFL cycle length, and increasing doses progressively terminated sustained AFL and prevented its reinduction by pacing. No adverse hemodynamic or ventricular proarrhythmic effects were observed. The electrophysiologic profile of KCB-328 in this canine model of AFL, particularly its lack of reverse use-dependent effect on atrial refractoriness, suggests that it may have significant antiarrhythmic potential in treatment of atrial arrhythmias.

Effect of aging on the negative chronotropic and anti-beta-adrenergic actions of adenosine in the rat heart.

The effect of aging on the antiadrenergic actions of adenosine was studied in vitro and in vivo by using adult (6-month-old) and old (24-month-old) male Fischer 344 rats. In anesthetized animals, adenosine (0.01-0.1 micromol/kg), given as a rapid bolus into the right atrium, exerted a negative chronotropic effect manifested by a dose-dependent transient prolongation of sinus cycle length (SCL). This effect was similar in both age groups (n = 6, each; i.e., the percentage maximal prolongation of SCL (%deltaSCL) ranged from 12 +/- 2% to 63 +/-14% in the adult and from 20 +/- 7% to 57 +/- 15% in the old rats. In the presence of isoproterenol (0.2 microg/kg/min), the negative chronotropic action of adenosine was potentiated in the adult rats much more than in the old rats [i.e., %deltaSCL ranged from 60 +/- 28% to 183 +/- 48% vs. 40 +/- 12% to 70 +/- 13%, respectively (p < 0.05, adult vs. old)]. In the isolated perfused hearts, isoproterenol (1 microM for 1 min) exerted similar chronotropic and inotropic effects in adult (n = 9) and old hearts [n = 6; i.e., heart rate, left ventricular pressure (LVP), and LVdp/dt increased by 56 +/- 3%, 17 +/- 1%, and 37 +/- 2%, and 57 +/- 2%, 17 +/- 1%, and 35 +/- 3%, respectively, in the absence of, and by 27 +/- 2%, 7 +/- 1%, and 19 +/- 2% and 41 +/- 3%, 12 +/- 1%, and 25 +/-2% in the presence of adenosine (5 microM for 1 min)]. Adenosine administration after isoproterenol caused only an insignificant increase in coronary blood flow. Finally, the adenosine attenuation of either isoproterenol- or forskolin-induced production of 3',5'-cyclic adenosine monophosphate (cAMP) was significantly less in atrial membranes isolated from old versus adult rats (n = 6, each). It was concluded that in the old Fischer 344 rat hearts, the antiadrenergic action of adenosine is attenuated as compared with its action in adult rat hearts.

Clinical study on accentuated antagonism in the regulation of heart rate in children.

Facial immersion testing in cold water (< 4 degrees C) was performed to study the responses of sinus cycle length to increased parasympathetic tone before and 5 min after exercise testing in 27 children. There were no episodes of sinus arrest or extrasystole during the facial immersion testing. The resting sinus cycle lengths were significantly shorter after (539 +/- 68 msec) than before (597 +/- 96 msec) exercise testing (p < 0.001). The maximal sinus cycle lengths before and after exercise testing during cold water facial immersion testing did not differ significantly (928 +/- 167 msec and 909 +/- 128 msec, respectively). Vagal chronotropic responses were calculated from the control sinus cycle lengths and the maximal sinus cycle lengths during facial immersion testing. Facial immersion caused greater prolongation of sinus cycle length after than before exercise (73 +/- 27% and 54 +/- 26%, respectively; p < 0.005). We speculate that this augmentation of vagal activity represents accentuated antagonism in these children, i.e., the same parasympathetic stimulus causes a greater response in the presence of a stronger background sympathetic activity.

Inhibition by E-4031 of the prolongation of the first returning cycle length after overdrive in anesthetized dog hearts.

Prolongation of the functional recovery of the sinoatrial (SA) nodal pacemaker activity after overdrive, "overdrive suppression," is determined by intrinsic pacemaker activity, pacemaker site, and SA conduction. We investigated the effects of E-4031, a blocker of a rapid type of the delayed rectifier K+ current (Ikr) and stimulation of the intracardiac parasympathetic nerves to the SA nodal region (SAP) on the prolongation of the first returning cycle length (1st RCL) after overdrive in autonomically decentralized hearts of open-chest anesthetized dogs. Second and third RCLs also were measured. We determined SA node recovery time (SNRT) and corrected SNRT (CSNRT) after atrial pacing at rates of 120, 150, and 200% of the control rate for 1 min and also determined SA conduction time (SACT) by the constant-atrial-pacing method. E-4031 (0.1-3 micromol/kg i.v.) increased the sinus cycle length (SCL) and SNRT dose dependently. However, E-4031 decreased CSNRT when the pacing rate was low or the number of pacing stimuli was small, although the agent did not induce a significant change in CSNRT when sufficient pacing stimuli were applied. E-4031 decreased SACT dose dependently. After E-4031 treatment. we observed changes in atrial electrical configurations, suggesting the possibility of pacemaker shift. When SAP stimulation increased SCL, SNRT, CSNRT, and SACT, E-4031 selectively inhibited the prolongation of SCL by SAP stimulation but did not affect the prolongation of CSNRT or SACT. These results suggest that functional recovery of the SA nodal pacemaker activity after overdrive is regulated by Ikr at least in part and that Ikr inhibition attenuates prolongation of the SCL but not the 1st RCL induced by parasympathetic nerve activation in the heart in situ.

Inhibition of Delayed Rectifier K+ Current by Dofetilide and E-4031 Differentially Affects Electrical Cardiac Responses to Vagus Stimulation in Anesthetized Dogs

Vagal activation influences various cardiac functions as well as occurrence of arrhythmias. Inhibition of a rapid type of delayed rectifier K+ current (Iκr) has been reported to be effective for the treatment of both ventricular and supraventricular arrhythmias. However, it is unknown how Ikr inhibition modulates the cardiac responses to vagal activation in situ. We analyzed the effects of Ikr inhibitors, dofetilide and E-4031, and a class I antiarrhythmic agent, disopyramide, on electrical cardiac responses to vagus stimulation in anesthetized dogs. Dofetilide (0.003-0.3 μmol/kg, i.v.), E-4031 (0.01-1 μmol/kg, i.v.) and disopyramide (2.9-29 μmol/kg, i.v.) prolonged sinus cycle length (SCL), right atrial effective refractory period (AERP) and ventricular effective refractory period (VERP) dose-dependently. During cervical vagus stimulation-induced prolongation of SCL, atrio-His (AH) interval and VERP and shortening of AERP, dofetilide and E-4031 inhibited the prolongation of SCL but potentiated the shortening of AERP. Dofetilide and E-4031 did not affect prolongations of AH interval and VERP. On the other hand, disopyramide inhibited all electrical cardiac responses to vagus stimulation. These results suggest that IKr, inhibition differentially modulate cardiac responses to vagus activation probably due to a different role of IKr in each cardiac function in the heart in situ.

Effects of N6-endonorbornan-2-yl-9-methyladenine, N0861, on negative chronotropic and vasodilatory actions of adenosine in the canine heart in vivo.

The pharmacology of N6-endonorbornan-2-yl-9-methyladenine (N0861), a new selective antagonist of adenosine at the A1 adenosine receptor subtype (A1-AdoR), was studied in vivo using a canine model. First, the pharmacokinetics of N0861 were determined in anesthetized dogs. The time-dependent decay of plasma levels of N0861 fitted a two-compartment polyexponential model with alpha-phase t1/2 = 3.80 min and beta-phase t1/2 = 80.55 min. Secondly, the effect of N0861 on the negative chronotropic and vasodilatory actions of adenosine in the canine heart were determined. N0861 attenuated the negative chronotropic action of adenosine (1-6 mumol/kg; rapid bolus into the right atrium) on sinus node pacemaker activity in a dose-dependent manner (pA2 = 4.23). For example, the maximal prolongation of sinus cycle length induced by 6 mumol/kg adenosine was 82 +/- 13% under baseline conditions and 57 +/- 10, 34 +/- 5 and 34 +/- 6% during infusion of N0861 at incremental rates leading to plasma levels of 7.75 +/- 1.02, 14.15 +/- 0.87, and 19.71 +/- 1.83 micrograms/mL, respectively. In contrast, N0861 did not inhibit but had a tendency to potentiate the vasodilatory action of adenosine (thought to be mediated by the A2 adenosine receptor subtype (A2-AdoR)) on the left anterior descending and circumflex coronary arteries. These data indicate that two different receptors, similar to the typical A1-AdoR and A2-AdoR, mediate the electrophysiologic and vasodilatory actions of adenosine in the canine heart, respectively, and that N0861 is a selective antagonist of adenosine at A1-AdoR in the canine heart in vivo.

Efficacy and electrophysiologic effects of oral sotalol in patients with sustained ventricular tachycardia caused by coronary artery disease

The efficacy of oral sotalol in preventing sustained ventricular tachycardia induction by invasive electrophysiological testing was assessed in 22 patients (60 ± 9 years) with prior myocardial intarction. Programmed stimulation consisted of two basic drives followed by up to three extrastimuli at two right ventricular sites. At baseline, sustained monomorphic ventricular tachycardia was inducible in all patients. With sotalol (360 ± 172 mg/day), it was no longer inducible in 10 patients; in 12 others, it remained inducible and its cycle length was only minimally prolonged (322 ± 42 to 345 ± 44 msec, p < 0.05). Sotalol markedly prolonged sinus cycle length, uncorrected QT interval, and right ventricular effective and functional refractory periods, but had little effect on ventricular conduction time either in sinus rhythm or with right ventricular pacing. There was no significant difference in drug dose or in electrophysiologic effect of drug that related to efficacy, nor was there any correlation between drug-induced prolongation of ventricular tachycardia cycle length and its effects. Six patients received oral sotalol over the long term without spontaneous recurrence of ventricular tachycardia (follow-up: 23 ± 18 months). These results demonstrate that sotalol is effective (45%) against sustained ventricular tachycardia induction at moderate doses and is well tolerated over a long term in the setting of remote myocardial infarction. However, its electrophysiologic effects as measured at invasive testing are not predictive of efficacy against ventricular tachycardia induction.

Reverse use-dependent effects of sotalol demonstrated by recording monophasic action potentials of the right ventricle

In 22 patients referred for electrophysiologic study, monophasic action potentials (MAP) were recorded from the right ventricular aspect of the ventricular septum. The duration of MAP at 90% (MAP 90) and 30% (MAP 30) repolarization was measured in sinus rhythm, at a constant atrial paced cycle length of 600 ms for 3 minutes and at constant ventricular paced cycle lengths of 600, 500, 400 and 300 ms for 20 beats. Programmed ventricular stimulation from the apex of the right ventricle was performed at a basic drive cycle length of 400 ms and MAP 90 and MAP 30 of premature beats was determined. Changes of MAP duration were assessed 20 minutes after administration of intravenous sotalol 1.5 mg/kg. Sotalol significantly increased MAP 90 and MAP 30 in sinus rhythm. This was independent from sinus cycle length prolongation as evidenced by a significant prolongation of MAP 90 and MAP 30 with constant atrial pacing after sotalol. With slow ventricular stimulation frequencies and with long coupling intervals at programmed ventricular stimulation, sotalol significantly prolonged MAP 90 and MAP 30; with high stimulation frequencies and at short coupling intervals the action potential-prolonging effect of sotalol was diminished, indicating a reverse use-dependent effect of sotalol on repolarization of the right ventricle in humans.

Effect of continuous enhanced vagal tone on atrioventricular nodal and sinoatrial nodal function in humans.

A constant intravenous infusion of phenylephrine (0.74 +/- 0.41 micrograms/kg/min) was given to 10 patients to cause a continuous augmentation in reflex vagal tone. After the infusion, the diastolic blood pressure increased from 76 +/- 7 to 89 +/- 11 mm Hg (p less than 0.01). The sinus cycle length and atrial-His (AH) interval were measured, and incremental atrial pacing was performed before and during phenylephrine infusion until atrioventricular (AV) nodal block was achieved. For each patient, the AV nodal function curve (i.e., the AH interval plotted as a function of the atrial pacing cycle length) was compared during both the control state and phenylephrine infusion; the AH intervals during each condition at chosen short (AHS) and long (AHL) cycle lengths were compared. The sinus cycle length increased during phenylephrine infusion from 941 +/- 294 to 1,115 +/- 347 msec (p = 0.013). The AH interval during sinus rhythm was not significantly prolonged (77 versus 82 msec, p = NS). The shortest atrial pacing cycle length yielding 1:1 AV nodal conduction increased during phenylephrine infusion from 412 +/- 120 to 575 +/- 211 msec (p less than 0.01). Of note, the degree of sinus cycle length prolongation did not correlate with the degree of prolongation in the shortest atrial pacing cycle length yielding 1:1 AV nodal conduction. The AV nodal function curve was shifted markedly to the right and only slightly upward.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased vagal cardiac nerve traffic prolongs ventricular refractoriness in patients undergoing electrophysiology testing

Stimulation of the vagus nerve in animals causes prolongation of sinus cycle length, abioventricular nodal conduction and ventricular refractoriness. Vagal stimulation appears to have a protective effect in animal models of sudden death. The electrophysiologic effects of enhanced vagal activity on right ventricular (RV) refractoriness in man have not been studied previously. The comparative effects of enhanced vagal tone (neck suction to −60 mm Hg) on sinus cycle length and RV refractoriness were assessed in 26 patients. The electrophysiologic effects of vagal activation by stimulation of carotid baroreceptors with neck suction were compared to the effect of carotid and aortic baroreceptor stimulation with phenylephrine infusion in 12 patients. During neck suction, mean sinus cycle length (819 ± 32 ms) was prolonged by 146 ± 20 ms (p < 0.0001). The mean RV effective refractory period (ERP) and functional refractory period (FRP) were prolonged by 4 ± 1 ms and 5 ± 1 ms (p = 0.0001 and 0.0002, respectively). The mean change in RV ERP and FRP correlated with the peak change in sinus cycle length during neck suction (r = 0.46 and r = 0.58, respectively). intravenous phenyl phrine infusion, the mean change in RV ERP and FRP was S ± 2 ms (p < 0.04) and 10 ± 3 ms (p < 0.01), respectively. These results show that reflex vagal stimulation with neck suction or phenylephrine infusion causes a small but significant prolongation in RV refractoriness. These findings imply that the potential benefits of enhanced vagal tone in preventing sudden death may be indirectly mediated by changes in ventricular refractoriness.

Electrophysiological effects of intravenous sotalol in acute myocardial infarction: A double-blind placebo-controlled study

Controlled studies of the electrophysiological effects of beta-blockade in acute myocardial infarction have not previously been published. In this controlled, double-blind study 20 patients were randomized to treatment with placebo or sotalol administered as a continuous infusion for 12 h. Programmed electrical stimulation was performed from the right atrium. After 60 min of infusion in the sotalol-treated patients (n = 10) there was a significant prolongation of sinus cycle length (+15%) and sinus node recovery time (+28%). The AV nodal effective refractory period was prolonged by 15% after 45 min of infusion. Variables reflecting myocardial repolarization, atrial effective refractory period and QT interval, were increased by 20% and 10%, respectively. In the placebo group, except at 12 h, there was a general pattern of slightly diminishing values for all measured variables. The electrophysiological changes in the sotalol-treated group could be explained by the combined Class II and III activities of this drug. The infusion of sotalol was well tolerated, and the anticipated electrophysiological and Class II and III antiarrhythmic effects were observed, despite the acute myocardial infarction.

Cardiac Electrophysiologic Effects of Orally Administered DPI 201–106 in Conscious Canines

This study assessed the cardiac electrophysiologic effects of DPI 201-106 (DPI), a novel orally absorbable positive inotropic agent, the administration of which has been associated with electrocardiographic (ECG) QT and T-wave changes. In the intact conscious dog, oral administration of both 8 and 16 mg/kg DPI produced marked sinus cycle length prolongation (8 mg/kg, + 11%; 16 mg/kg, + 9%) within 60 min of DPI administration (p less than 0.05 vs. baseline). DPI also tended to prolong right atrial refractory periods, and increase sinus node recovery time. In addition, DPI exhibited a negative dromotropic effect on the atrioventricular (AV) node, prolonging both AV node effective and functional refractory periods and tending to increase the minimum atrial paced cycle length at which AV conduction of 1:1 was maintained. DPI also significantly increased right ventricular effective refractory period (ERP) at both doses studied and increased ventricular functional refractory period (FRP) at the 16-mg/kg dose. Finally, although DPI administration was associated with QT interval prolongation, this effect was slight when corrected for sinus cycle length (SCL) (QTc, +3%). When administered concomitantly with propranolol and atropine or after surgical cardiac denervation, DPI-induced electrophysiologic changes were largely attenuated or abolished. Thus, findings in this study indicate that the apparent cardiac electrophysiologic effects of DPI are predominantly of neurally mediated origin in this animal model.