Changes In Sinus Cycle Length Research Articles

Effect on sinus cycle length and atrioventricular node function after high-power short-duration versus conventional radiofrequency catheter ablation in paroxysmal atrial fibrillation

BackgroundThe efficacy and safety of high-power, short-duration (HPSD) radiofrequency catheter ablation for atrial fibrillation (AF) have been demonstrated in several studies. We aimed to evaluate and compare the effects of the conventional method and the HPSD method for AF ablation on the sinus and AV node function in patients with paroxysmal AF.MethodsThe medical records of patients with paroxysmal AF who underwent pulmonary vein isolation (PVI) were retrieved from a prospectively collected AF ablation registry at a large-sized tertiary center. The HPSD group (n = 41) was distinguished from the conventional ablation group (n = 198) in terms of the power (50 W vs. 20–40 W) and duration (6–10 s vs. 20–30 s) of radiofrequency energy delivery during PVI. Peri-procedural changes in cardiac autonomy were assessed in terms of the changes in sinus cycle length (SCL), block cycle length (BCL), and effective refractory period (ERP) of the atrioventricular node (AVN).ResultsThe SCL, BCL, and ERP of the AVN at baseline and post-ablation were not significantly different between the conventional ablation group and the HPSD group. Shortening of the SCL, BCL, and ERP of the AVN was observed immediately after AF ablation in both groups. One-year recurrence of AF/atrial flutter (35.1% vs. 20.3%; P = 0.011) and atrial flutter (13.8% vs. 4.7%; P = 0.015) were higher in the HPSD group than in the conventional ablation group.ConclusionBoth the HPSD and the conventional ablation method resulted in post-ablation vagal modification as evidenced by the shortening of SCL, BCL, and ERP of the AVN. One-year recurrence of atrial flutter and AF/atrial flutter was higher in patients who underwent the HPSD method.

Atrioventricular nodal reentrant tachycardia in children: effect of slow pathway ablation on fast pathway function.

Prior studies in adults have shown significant shortening of the fast pathway effective refractory period after successful slow pathway ablation. As differences between adults and children exist in other characteristics of AV nodal reentrant tachycardia (AVNRT), we sought to characterize the effect of slow pathway ablation or modification in a multicenter study of pediatric patients. Data from procedures in pediatric patients were gathered retrospectively from five institutions. Entry criteria were age <21 years, typical AVNRT inducible with/without isoproterenol infusion, and attempted slow pathway ablation or modification. Dual AV nodal pathways were defined as those with > or =50 msec jump in A2-H2 with a 10-msec decrease in A1-A2. Successful ablation was defined as elimination of AVNRT inducibility. A total of 159 patients (age 4.4 to 21 years, mean 13.1) were studied and had attempted slow pathway ablation. AVNRT was inducible in the baseline state in 74 (47%) of 159 patients and with isoproterenol in the remainder. Dual AV nodal pathways were noted in 98 (62%) of 159 patients in the baseline state. Ablation was successful in 154 (97%) of 159 patients. In patients with dual AV nodal pathways and successful slow pathway ablation, the mean fast pathway effective refractory period was 343+/-68 msec before ablation and 263+/-64 msec after ablation. Mean decrease in the fast pathway effective refractory period was 81+/-82 msec (P < 0.0001) and was not explained by changes in autonomic tone, as measured by changes in sinus cycle length during the ablation procedure. Electrophysiologic measurements were correlated with age. Fast pathway effective refractory period was related to age both before (P = 0.0044) and after ablation (P < 0.0001). AV block cycle length was related to age both before (P = 0.0005) and after ablation (P < 0.0001). However, in dual AV nodal pathway patients, the magnitude of change in the fast pathway effective refractory period after ablation was not related to age. Lack of clear dual AV node physiology is common in pediatric patients with inducible AVNRT (38%). Fast pathway effective refractory period shortens substantially in response to slow pathway ablation. The magnitude of change is large compared with adult reports and is not completely explained by changes in autonomic tone. Prospective studies in children using autonomic blockade are needed.

Changes in sinus node function in a rabbit model of heart failure with ventricular arrhythmias and sudden death.

Heart failure is associated with profound changes in the balance of the autonomic nervous system, such as vagal withdrawal and increased catecholamine levels. It is not known whether the intrinsic sinus node function changes during the progression of heart failure. We implanted transmitters for Holter recording in an established rabbit model of heart failure (n=9) and observed changes in sinus cycle length and the occurrence of arrhythmias during the progression of heart failure. The in vitro sinus cycle length and the responses to acetylcholine and norepinephrine in the isolated right atria were analyzed in 12 rabbits with heart failure and in 6 control rabbits. In vivo cycle length increased in some animals and decreased in others. Sudden death occurred in 3 of 9 rabbits. These rabbits had developed a shorter cycle length than the surviving rabbits. Ventricular tachycardias developed in all but 1 rabbit. The in vitro sinus cycle length increased in heart failure. The response to acetylcholine also increased in heart failure, whereas the response to norepinephrine was unchanged. Changes in intrinsic sinus node function during the progression of heart failure cannot explain the observed decreases in heart rate variability and/or baroreflex sensitivity in this disease, because increased responsiveness to acetylcholine would be expected to cause the opposite.

Ganglionic mechanisms contribute to diminished vagal control in heart failure.

Previous work has shown that spontaneous and stimulated vagal activity is diminished in heart failure (HF) despite upregulation of functional postsynaptic cholinergic mechanisms. We therefore examined function of the postganglionic neuron in the paced canine model of HF as a possible site for diminished control. We measured sinus cycle length changes in response to electrical stimulation of preganglionic and postganglionic parasympathetic neurons innervating the sinoatrial node in control and HF dogs (both, n=8). Cervical vagus stimulation (preganglionic) demonstrated attenuated responses in the HF group at all levels of stimulation (P<0.05). Stimulation of the right atrial fat pad, containing both postganglionic nerves and terminals of preganglionic neurons, showed no such difference between control and HF (200+/-25 versus 192+/-18 ms). To ensure that preganglionic input and different levels of baseline sympathetic activity did not contribute to the group difference, similar stimulations were done in the presence of ganglionic and beta-adrenergic blockade. Under these conditions, postganglionic stimulation showed smaller changes in sinus cycle length, but the HF group response remained significantly higher than in controls (76+/-10 versus 20+/-2 ms; P<0. 01), indicating that the difference was independent of preganglionic input and sympathetic activity. A component of attenuated parasympathetic control in HF is located within the peripheral efferent limb. This defect is located within the parasympathetic ganglion. Future work should be focused on determining mechanisms of attenuated ganglionic transmission so that means targeted at restoring vagal activity can be developed.

Acute Effects of Intravenous Magnesium on Ventricular Refractoriness and Monophasic Action Potential Duration in Humans

The objective of this study was to examine the antiarrhythmic mechanisms of magnesium (Mg). The 12 patients who were selected for the study were given 12 mmol Mg sulphate followed by an infusion of 8 mmol/h. Ventricular effective refractory period (VERP). monophasic action potential duration at 50% and 90% repolarization during spontaneous rhythm (MAPD50, MAPD90) and atrial pacing at a cycle length of 600 ms (MAPD(50)600, MAPD(90)600) were measured before and after the intervention. Plasma magnesium concentration rose from 0.83 +/- 0.05 to 1.85 +/- 0.24 mmol/l (p < 0.001). Shortening of MAPD(50) (250 +/- 45 vs 240 +/- 46 ms; p < 0.05), MAPD(90) (294 +/- 42 vs 283 +/- 41 ms; p < 0.05) and shortening of sinus cycle length (SCL) (783 +/- 153 vs 742 +/- 160 ms; p < 0.01) were detected. During controlled cycle length, magnesium decreased MAPD(50)600 (230 +/- 28 vs 221 +/- 28 ms; p < 0.01), MAPD(90)600 (274 +/- 25 vs 261 +/- 29 ms; p < 0.01) and VERP (247 +/- 25 vs 241 +/- 21 ms: p < 0.05). QRS duration, QT interval and blood pressure remained unchanged. The change in SCL correlated with the change in MAPD(50) (r = 0.58; p < 0.05) and MAPD(90) (r = 0.55; p = 0.06 ) but not with MAPD(50)600, MAPD(90)600 or VERP. Magnesium acutely shortens ventricular monophasic action potential duration and refractoriness. This effect is partly mediated by mechanisms that increase heart rate. The reductions might bring salutary effects in arrhythmias evoked by prolonged repolarization.

The effects of isoproterenol on the cardiac conduction system: site-specific dose dependence.

Isoproterenol is used to assess and facilitate AV nodal conduction, and thus potentiate the induction of supraventricular arrhythmias. It is commonly administered in increasing doses until a predetermined decrease in sinus cycle length, usually 20% to 30%, occurs. This regimen may result in undesirable side effects. We have observed that effects of isoproterenol on the AV node may occur prior to achieving the target sinus cycle length. The purpose of this study was to determine whether the sinus and AV nodes have equal sensitivity to isoproterenol. Thirty-eight consecutive patients, who underwent electrophysiologic evaluation for a variety of indications, were given incremental doses of isoproterenol at 0.007, 0.014, 0.021, and 0.028 microgram/kg per minute. Sinus cycle length and AV node function were assessed at baseline and after 5 minutes at each dose. The percent change from baseline in AV node function was compared with the change in sinus cycle length at each dose interval. Significantly greater decreases were observed in the anterograde and retrograde AV nodal Wenckebach cycle length (P < 0.0001) than in the sinus cycle length at the lowest isoproterenol dose (0.007 microgram/kg per min). These differences were not apparent at higher doses. A sustained supraventricular tachycardia was inducible in 15 of 38 patients in the presence of isoproterenol, of which 40% occurred at the lowest dose. The AV node is more sensitive than the sinus node to the effects of isoproterenol. Lower doses of isoproterenol than those commonly used may often facilitate the induction of a supraventricular tachyarrhythmia, thus reducing side effects.

Temperature dependency of the vagal chronotropic response in the young puppy: An `environmental–autonomic interaction'

We investigated the effects of mild hypothermia (34.3±0.2°C [mean±SD]), hyperthermia (40.8±0.2°C) and hypoxia (Pa O 2 =43±4 mmHg) on the response of heart rate to continuous right vagus nerve stimulation (the `vagal chronotropic response') in young puppies, aged 5–22 days. Puppies were anesthetized with α-chloralose, vagotomized and pre-treated with propranolol (1 mg/kg i.v.) and phentolamine (1 mg/kg, 1–2 mg/kg/h i.v.). Hypoxia ( n=9) did not significantly alter the resting sinus cycle length and did not alter the response of sinus cycle length to a 30 s train of 8 Hz right vagal stimulation. Mild hypothermia ( n=8) increased the resting sinus cycle length by 16±4% and greatly augmented the vagal chronotropic response (from 76±27% change in the sinus cycle length (normothermia) to 155±38% (hypothermia)). Both the sinus cycle length and the vagal chronotropic response returned towards pre-hypothermia values with rewarming. Mild hypothermia also increased the negative chronotropic response to 20 μg/kg/min i.v. of methacholine (12±2% change in the sinus cycle length (normothermia) versus 24±14% (hypothermia)), suggesting that a postsynaptic mechanism is involved in the hypothermia-induced augmentation of the cardiac vagal chronotropic response. In contrast to hypothermia, mild hyperthermia ( n=8) decreased the resting sinus cycle length slightly (−5±5% change) and significantly attenuated the cardiac vagal chronotropic response (from 88±28% change in sinus cycle length (normothermia) to 50±26% (hyperthermia)). These changes were also reversible with the re-establishment of normothermia. This demonstrates that clinically relevant, environmentally-induced changes in body temperature can directly and reversibly modify parasympathetic efferent responses.

Postnatal Maturation of the Response of the Canine Sinus Node to Critically Timed, Brief Vagal Stimulation

We have previously demonstrated that vagal phase-response curves (PRC), which characterize the effects of critically timed, brief vagal stimuli on sinus node automaticity, exhibit a fundamentally different shape in the canine newborn than in the adult. In this study we analyzed the changes in sinus cycle length in response to critically timed, brief vagal stimuli, delivered to the decentralized cervical right and left vagosympathetic trunks, in two older age groups: 14 1-mo-old puppies (ages 21-36 d), and eight 2-mo-old puppies (ages 56-62 d). Vagal PRC were constructed by plotting the magnitude (percent change) of the vagal chronotropic response as a function of the phase of the cardiac cycle at which the vagus nerve was stimulated. At 1 mo of age adult-type PRC were observed, but in only six of the puppies (43%) and only in response to right vagal stimulation. By 2 mo of age adult-type PRC were observed in seven of eight puppies (88%) in response to right vagal stimulation and in three of eight (38%) in response to left vagal stimulation. Thus, clear developmental changes in the phase dependence of the vagal chronotropic response can be tracked over the first 2 mo of life in the dog.

Time-Dependent Changes in the Chronotropic Response to Vagal Stimulation in the Newborn Canine

We characterized changes in the vagal chronotropic response during 3-min trains of vagal stimulation at 3, 5, and 8 Hz in anesthetized, chemically sympathectomized (6-hydroxydopamine) newborn canines (< 15 d of age). In response to vagal stimulation, the sinus cycle length gradually increased (within 30 s) to a maximum value that was dependent upon the stimulation frequency (p < 0.001). The chronotropic response then attenuated over the remainder of the vagal train. However, unlike in adult dogs, the degree of attenuation of the vagal chronotropic response (fade) was also highly dependent upon the frequency of vagal stimulation in the range 3-8 Hz (p < 0.002). We then compared the maximum change in sinus cycle length and fade in a group of neonates while stimulating the vagus at 3 Hz before and after the administration of physostigmine (0.2 mg/kg i.v.). Physostigmine resulted in a significant increase not only in the maximum percent change in sinus cycle length but in the magnitude of attenuation of the vagal response as well. Therefore, unlike the adult, in the newborn the magnitude of both the vagal response and fade are dependent upon concentrations of acetylcholine released in response to modest levels of vagal stimulation (< or = 8 Hz). This may be the result of differences between the newborn and the adult in the prestreceptor mechanisms of fade or in the susceptibility of the muscarinic receptor to desensitization by the neurotransmitter acetylcholine.

Electrophysiological effects of intravenous rilmenidine in man

Ten patients (44 y), 6 with the Wolff-Parkinson-White syndrome, and none with hypertensive disease, underwent electrophysiological studies before and after intravenous infusion of a single dose of 1 mg rilmenidine administered over 15 min. The regimen produced a mean plasma rilmenidine concentration of 3.16 ng.ml-1 at the end of the infusion. There was no significant change in sinus cycle length, PR interval, QRS, QT duration or in PA, AH and HV intervals. Estimated sinoatrial conduction time and corrected sinus node recovery time did not significantly change. In one patient, however, an abnormal pause was noted after termination of rapid atrial pacing. The right atrial effective refractory period decreased from 209 to 194 ms. There was no significant change in the anterograde and retrograde block cycle length or in the refractoriness of the nodal, ventricular and accessory pathways. The cycle length of induced reciprocating tachycardia decreased slightly from 374 to 351 ms. No patient exhibited an abnormal response to the carotid sinus massage. The findings indicate that intravenous administration of 1 mg rilmenidine exerts modest effects on the electrophysiological parameters of the human heart.

Characterization of responses of neonatal sinus and AV nodes to critically timed, brief vagal stimuli

We studied the responses of sinus cycle length and atrioventricular (AV) nodal conduction to brief, critically timed vagal stimuli in 25 neonatal (9.6 +/- 3.1 days) canines. Vagal stimuli were delivered to the right or left decentralized cervical vagosympathetic trunk as either a single, brief stimulus train or a repetitive, phase-coupled train with both stimulation paradigms programmed to scan the entire cardiac cycle. The effects of brief vagal stimuli on cardiac cycle length were measured while the heart was beating spontaneously, and the vagal effects on AV nodal conduction were measured while the cycle length was held constant by atrial pacing at 300 ms. Neither changes in sinus cycle length nor AV nodal conduction demonstrated classical phase dependency, i.e., a gradual increase in the magnitude of the vagal response as stimuli are delivered progressively later in the cardiac cycle until the latency period (that point in the cardiac cycle at which vagal stimulation no longer affects the next cardiac cycle) is reached. Phase-response curves (PRCs) to single and repetitive stimuli typically exhibited either a flat response or a small decrease in magnitude as the latency period of the PRC was approached. Thus the neonatal sinus and AV node PRCs exhibit a different configuration than that reported in the adult.

The Relationship Between Sinoatrial Conduction Time and Sinus Cycle Length Revisited

In 1974 we reported an inverse relationship between sinoatrial conduction time (SACT) and sinus cycle length (SCL) during sinus arrhythmia utilizing the indirect atrial premature stimulation technique for estimating SACT, However, this behavior seemed anomalous try analogy with the AV node. Subsequent to 1974, methodological considerations about and limitations of the indirect techniques for estimating SACT became apparent, making us question our former impression. When the capability to directly record sinus node electrograms was developed and established in the 1980s, we had the means to reevaluate the SACT/SCL relationship. This report presents our findings in 40 patients: the SACT/SCL relationship is direct, not inverse. Moreover, we also show that during the phasic fluctuations of sinus arrhythmia, the P‐P alterations are initiated more frequently by changes in sinoatrial conduction time than by changes in sinus cycle length.

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 adenosine in the transplanted human heart. Evidence of supersensitivity.

After cardiac transplantation, the denervated donor atria and ventricles demonstrate increased sensitivity to infusions of sympathomimetic amines. Recently, supersensitivity of the canine sinus and atrioventricular (AV) nodes to acetylcholine has also been demonstrated after parasympathetic denervation. Acetylcholine and the endogenous nucleoside adenosine exert similar electrophysiological effects in both the sinus and AV nodes, and share a common transduction process. We, therefore, hypothesized that after orthotopic cardiac transplantation, the donor (denervated) sinus node would demonstrate greater sensitivity to exogenous adenosine than the recipient (innervated) sinus node. The effects of incremental doses of intravenous adenosine (37-112 micrograms/kg) on changes in sinus cycle length (SCL) (delta SCLmax%), changes in PR interval (delta PRmax%), time to peak effect (sec), and duration of electrophysiological effects (sec) were prospectively measured in 28 orthotopic cardiac transplant patients and nine control subjects. The baseline SCL was 795 +/- 71 msec for the control subjects, 891 +/- 43 msec for the recipient atria, and 700 +/- 18 msec for the donor atria (p less than 0.05, donor vs. recipient). The delta SCLmax% for each dose of adenosine was similar in the innervated control and recipient atria. In contrast, the donor sinus node demonstrated a threefold to fourfold increased response to adenosine as compared with the recipient sinus node and a threefold to sixfold increased response as compared with control subjects. Similarly, the donor AV node demonstrated a threefold to fivefold increase in PR interval as compared with control subjects. The duration of sinus node slowing in the denervated atria was threefold to fivefold longer than in the recipient and control atria (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Mathematical model of the changes in heart rate elicited by vagal stimulation.

We developed a mathematical model of the underlying cellular mechanisms responsible for the changes in sinus cycle length (SCL) elicited by vagal stimulation in intact animals. The model incorporated a stimulation-mediated depletion of the releasable pool of acetylcholine (ACh) in the nerve endings, the in vitro reaction kinetics of acetylcholinesterase, and the electrical activity of a pacemaker cell with six membrane ionic currents. SCL increased linearly with the frequency of simulated vagal stimulation, as it does in animal experiments, because the concentration of ACh in the neuroeffector junction [( ACh]) saturated as the frequency of stimulation was increased and because SCL increased geometrically in response to increases in [ACh]. The dependence of SCL on the timing of vagal stimulation in the cardiac cycle resulted, in part, from the dependence of [ACh] on SCL. Simulated vagal stimulation entrained the sinus node because the rate of activation and inactivation of ACh-activated K+ channels depended only weakly on membrane potential during diastolic depolarization. SCL increased geometrically with [ACh], because 1) during diastolic depolarization, the amplitude of the ACh-activated K+ current was approximately equal to the amplitude of the sum of the other ionic currents, 2) [ACh] was low enough to saturate neither acetylcholinesterase nor the cellular system that activates the ACh-activated K+ channels, 3) the pacemaker cell membrane behaved electrotonically like a capacitor, and 4) the sum of all the ionic currents increased linearly with the amplitude of the ACh-activated K+ current.

Electrophysiologic alterations produced by hypoxia in the canine heart

The purpose of this study was to test whether hypoxia caused simultaneous stimulation of sympathetic and vagal cardiac nerves. To do this, we determined in chloralose-anesthetized, open-chest dogs, changes in sinus cycle length (SCL), atrioventricular nodal conduction time (AH interval), and effective refractory periods (ERP) of the right atrium (RA) and left ventricle (LV) during hypoxia induced by either hypoventilation or by breathing 10% oxygen in nitrogen. We found that hypoventilation decreased arterial pH (mean ± SE: 7.365 ± 0.011 versus 7.244 ± 0.013, p < 0.001) and Po 2 (105.2 ± 3.6 versus 50.5 ± 2.0 mm Hg, p < 0.001), and increased Pco 2 (24.4 ± 0.7 versus 41.9 ± 1.1 mm Hg, p < 0.001). SCL (373 ± 19 versus 485 ± 35 msec, p < 0.001), AH interval (92 ± 4 versus 111 ± 6 msec, p < 0.005), and LVERP (159.8 ± 3.2 versus 162.0 ± 3.3, p < 0.05) lengthened, while RAERP shortened (137.7 ± 2.6 versus 128.8 ± 3.5, p < 0.001). After bilateral vagotomy, these electrophysiologic changes were attenuated, and transection of ansae subclaviae following vagotomy did not affect hypoventilation-induced changes that were present after vagotomy alone. In contrast, breathing 10% oxygen decreased Po 2 (104.2 ± 3.3 versus 48.1 ± 1.7, p < 0.001) but did not change pH and Pco 2. SCL lengthened slightly (444 ± 15 versus 463 ± 17, p < 0.001), but other measured electrophysiologic parameters were not affected. The norepinephrine concentration in the coronary sinus blood increased by 109% to 121% during hypoxia induced by both methods. Hypoventilatory hypoxia blunted sympathetic-induced shortening of LVERP and potentiated vagally-induced SCL lengthening. Nelther type of hypoxia affected induction of atrial and ventricular tachyarrhythmias by programmed electrical stimulation. We conclude that the electrophysiologic response during hypoventilatory hypoxia is due primarily to heightened vagal tone. Norepinephrine concentration in the coronary sinus blood more than doubled, but did not alter cardiac electrophysiologic properties, possibly because of simutaneous increase in vagal tone, or possibly due to the release of adenosine or other factors that impaired cardiac electrophysiologic response to elevated norepinephrine levels.

Effect of autonomic nervous system modulation on retrograde atrioventricular nodal conduction in the human heart.

Although the influence of the autonomic nervous system on anterograde atrioventricular nodal conduction is well established, its effect on retrograde atrioventricular nodal conduction has not been examined systematically. Since retrograde atrioventricular nodal conduction in subjects with normal anterograde conduction may vary from intact retrograde conduction to complete retrograde block when assessed during ventricular pacing, in this study patients with (a) intact retrograde atrioventricular nodal conduction (group 1) were studied during parasympathetic (vagal) stimulation by carotid sinus pressure and during sympathetic inhibition (propranolol 0.2 mg.kg-1 intravenously) and (b) retrograde atrioventricular nodal block (group 2) were studied during vagal blockade (atropine 0.04 mg.kg-1 intravenously) and during sympathetic stimulation (isoproterenol 1-4 micrograms.min-1 infusion). In both groups changes in sinus cycle length and anterograde atrioventricular nodal conduction were measured. In group 1 vagal stimulation by carotid sinus pressure in 20 patients caused the cycle length at which retrograde atrioventricular nodal block was induced to be significantly lengthened from a mean(SD) of 375(59) to 451(51) ms in six patients; caused complete retrograde block in 10 patients; and had no effect in four patients. Sympathetic inhibition by propranolol in another 15 patients delayed the onset of pacing induced retrograde atrioventricular nodal block from a mean(SD) of 340(60) to 418(80) ms in 11 patients; caused complete retrograde atrioventricular nodal block in three patients; and had no effect in one patient. In group 2 vagal blockade by atropine caused a 1:1 retrograde response during ventricular pacing up to a mean(SD) cycle length of 470(135) ms in six out of eight patients. The infusion of isoproterenol caused the retrograde atrioventricular nodal block to be abolished and 1:1 conduction to be resumed up to a ventricular pacing mean(SD) cycle length of 364(57) ms in six out of eight patients. It is concluded that (a) the autonomic nervous system modulates retrograde atrioventricular nodal conduction in a similar manner to its anterograde counterpart and (b) that since retrograde atrioventricular nodal conduction was reversible after the administration of either atropine or isoproterenol retrograde atrioventricular nodal block may be dynamic (physiological) rather than fixed (anatomical) in nature.

Phasic effects of postganglionic vagal stimulation on atrioventricular nodal conduction.

The effects of postganglionic vagal stimulation (PGVS) on atrioventricular nodal conduction were studied in 15 rabbit atrial-atrioventricular nodal preparations. PGVS was introduced, and sinus cycle length was scanned as independent bursts of subthreshold stimuli were produced in the sinus node and atrioventricular node (AVN). Changes in conduction of atrial impulses to the bundle of His were studied under the following experimental conditions: changes in sinus cycle length resulting from vagal influence on the sinus node, direct vagal stimulation exclusively to the AVN, and during both simultaneous or nonsimultaneous vagal stimulation to sinus node and AVN. The results of the present study showed that the direct effect of PGVS on AVN conduction time at a constant sinus cycle length is phase dependent with maximal prolongation achieved in the first or second beat after introduction of the burst. The interval between the onset of PGVS producing maximal prolongation of conduction time and the following atrial beat was designated the "optimal effective phase." It was shown that the optimal effective phase was a constant parameter for a given preparation and in the present experiments was 321 +/- 16 ms. However, when PGVS was introduced in combination to both nodes while scanning the cycle length, AVN conduction was variable, reflecting both the direct effects of PGVS on the AVN as well as the indirect effects resulting from changes in the sinus cycle length. Notably, it was found that simultaneous PGVS to both the sinus node and AVN usually diminished, whereas appropriate nonsimultaneous PGVS accentuated the typical phasic dependency of AVN conduction time. Additionally, vagally induced prolongation of the sinus cycle length was found to be accompanied by changes in the time of depolarization of the inputs to the AVN, thus influencing AVN conduction and facilitating reentry. These interactions between changes in the sinus cycle length and concomitant changes in the effectiveness of vagal influence on the AVN can be used to explain complexities of AVN conduction during increased vagal activity.

Vagally induced hyperpolarization in atrioventricular node.

The effects of postganglionic vagal stimulation on atrioventricular nodal conduction were studied in 12 rabbit atrial-atrioventricular nodal preparations. Vagal stimulation was introduced in the sinus and atrioventricular nodes, separately or in combination, using single bursts of subthreshold stimuli. The sinus cycle length was scanned to identify the phasic effect of vagal stimulation. Action potentials from cells in the AN, N, and NH regions of the atrioventricular node were recorded by microelectrode techniques. Vagally induced hyperpolarization of cells in the atrioventricular node resulted in a phase-dependent prolongation of conduction time and reflected the level of residual hyperpolarization at the moment of arrival of the next atrial beat at the atrioventricular nodal input region. Vagally induced hyperpolarization was membrane potential dependent, although its overall time course was similar at different phases. Increased diastolic depolarization followed the maximal hyperpolarization. This "rebound" observed at certain phases was responsible for paradoxical shortening of the conduction time after vagal stimulation. The predominant effects of local vagal stimulation in the atrioventricular node were observed in cells in or near the N region. Slower rate of rise, shorter amplitude and duration, as well as step formations were among the changes in action potentials recorded from these cells. The effects of vagal stimulation were inhomogeneous between different regions of the atrioventricular node as well as within the N region, producing alternative pathways of conduction and the potential for reentry. The concomitant changes in sinus cycle length resulting from vagal stimulation in the sinus node region altered the phasic effects of vagal stimulation introduced in the atrioventricular node. This was related to a direct influence of the prolonged sinus cycle length on atrioventricular nodal refractoriness as well as an indirect effect on the degree of residual vagally induced hyperpolarization at the moment of arrival of the delayed atrial beat. These findings provide mechanistic explanations for the complex effects of vagal stimulation on atrioventricular nodal conduction.

Cardiovascular effects of ZSY-27 [5-methyl-6-(4-pyridinyl)-2H-1,4-thiazine-3(4H)-one X hydrochloride] in the dog cross-circulated atrial preparation.

A new cardiotonic compound, 5-methyl-6-(4-pyridinyl)-2H-1,4-thiazine-3(4H)-one X hydrochloride (ZSY-27), was investigated in cross-circulated dog atrial muscle preparations. When ZSY-27 was intravenously administered to the donor dog, a dose-dependent depressor effect with slight sinus tachycardia was induced in the donor dog. At the same time, a significant dose-dependent increase in developed tension was usually observed in an isolated atrium perfused with donor's arterial blood, but there were no significant changes in sinus cycle length and sinoatrial conduction time. The ZSY-27-induced positive inotropic effect was not significantly influenced by treatment with propranolol in doses which completely inhibited norepinephrine-induced positive chronotropic and inotropic effects. When ZSY-27 was injected into the cannulated sinus node artery of the isolated atrium, dose dependent positive chronotropic and inotropic effects were induced. The dominant increases in developed tension by ZSY-27 were similar to effects of other phosphodiesterase inhibitors, such as papaverine and aminophylline. From these results, it is concluded that ZSY-27 has non-adrenergic, cardiotonic properties with a depressor effect.