Characterization and functional role of rapid- and slow-activating delayed rectifier K+ currents in atrioventricular node cells of guinea pigs.

The atrioventricular (AV) node is the only conduction pathway where electrical impulse can pass from atria to ventricles and exhibits spontaneous automaticity. This study examined the function of the rapid- and slow-activating delayed rectifier K+ currents (IKr and IKs) in the regulation of AV node automaticity. Isolated AV node cells from guinea pigs were current- and voltage-clamped to record the action potentials and the IKr and IKs current. The expression of IKr or IKs was confirmed in the AV node cells by immunocytochemistry, and the positive signals of both channels were localized mainly on the cell membrane. The basal spontaneous automaticity was equally reduced by E4031 and HMR-1556, selective blockers of IKr and IKs, respectively. The nonselective ß-adrenoceptor agonist isoproterenol markedly increased the firing rate of action potentials. In the presence of isoproterenol, the firing rate of action potentials was more effectively reduced by the IKs inhibitor HMR-1556 than by the IKr inhibitor E4031. Both E4031 and HMR-1556 prolonged the action potential duration and depolarized the maximum diastolic potential under basal and ß-adrenoceptor-stimulated conditions. IKr was not significantly influenced by ß-adrenoceptor stimulation, but IKs was concentration-dependently enhanced by isoproterenol (EC50: 15 nM), with a significant negative voltage shift in the channel activation. These findings suggest that both the IKr and IKs channels might exert similar effects on regulating the repolarization process of AV node action potentials under basal conditions; however, when the ß-adrenoceptor is activated, IKs modulation may become more important.

The bradycardic agent ivabradine decreases conduction velocity in the AV node and in the ventricles in-vivo.

Ivabradine blocks hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, thereby lowering the heart rate, an action that is used clinically for the treatment of heart failure and angina pectoris. We and others have shown previously that ivabradine, in addition to its HCN channel blocking activity, also inhibits voltage-gated Na channels in vitro at concentrations that may be clinically relevant. Such action may reduce conduction velocity in cardiac atria and ventricles. Here, we explore the effect of administration of ivabradine on parameters of ventricular conduction and repolarization in the surface ECG of anesthetized mice. We found that 5 min after i.p. administration of 10 mg/kg ivabradine spontaneous heart rate had declined by ~13%, which is within the range observed in human clinical studies. At the same time a significant increase in QRS duration by ~18% was observed, suggesting a reduction in ventricular conduction velocity. During transesophageal pacing at heart rates between 100 and 220 beats/min there was no obvious rate-dependence of ivabradine-induced QRS prolongation. On the other hand, ivabradine produced substantial rate-dependent slowing of AV nodal conduction. We conclude that ivabradine prolongs conduction in the AV-node and in the ventricles in vivo.

BRASH Syndrome with Hyperkalemia: An Under-Recognized Clinical Condition.

BRASH syndrome is characterized by bradycardia, renal failure, use of an atrioventricular nodal blocker (AVNB), shock, and hyperkalemia. These symptoms represent an ongoing vicious cycle in a patient with a low glomerular filtration rate taking an AVNB. Decreased clearance of the medication and hyperkalemia associated with renal failure synergize to cause bradycardia and hypoperfusion. This reaction causes renal function to worsen, thereby perpetuating the cycle of BRASH syndrome.

Differential effects of sevoflurane and propofol on swine cardiac conduction system.

OBJECTIVE: To compare the effects of sevoflurane and propofol on the porcine cardiac conduction system. STUDY DESIGN: A prospective, comparative study of electrophysiological properties of anaesthetics agents in an experimental porcine model. ANIMALS: A total of 36 hybrid Landrace-Large White pigs. METHODS: After premedication with 20 mg kg-1 of intramuscular ketamine, anaesthesia was induced with 4.5 mg kg-1propofol intravenously. In 18 consecutive animals, anaesthesia was maintained with propofol (13 mg kg-1 hour-1) and in the remaining 18 animals with 2.66% sevoflurane. The femoral artery and vein were canalized for invasive monitoring, analytical blood gas sampling and intracardiac catheter insertion. Following instrumentation and after a period of stabilization, a customary electrophysiological evaluation was performed. We compared the electrophysiology of the sinus and atrioventricular node (AV) node under sevoflurane or propofol anaesthesia, and the effects of both anaesthetics on atrial and ventricular refractoriness. RESULTS: There was a significant difference in sinus node recovery time between sevoflurane and propofol (907 ± 231 versus 753 ± 146 ms, p = 0.02). Sevoflurane in comparison with propofol significantly prolonged specialized AV conduction times, represented by an increased Wenckebach cycle length (272 ± 54 versus 235 ± 40 ms, p = 0.03) and AV nodal refractoriness (327 ± 34 versus 287 ± 30 ms, p = 0.002). In addition, sevoflurane prolonged ventricular refractoriness (298 ± 27 versus 255 ± 38 ms, p = 0.007) and the QT corrected interval (0.50 ± 0.05 versus 0.46 ± 0.09 ms, p = 0.005). CONCLUSIONS AND CLINICAL RELEVANCE: Sevoflurane in comparison with propofol, depresses several parameters of sinus and AV nodal function and prolongs the ventricular refractoriness of the porcine cardiac conduction system. These findings should be taken into consideration for the choice of anaesthetic agents in clinical and experimental settings.

Disruption of RHOA-ROCK Signaling Results in Atrioventricular Block and Disturbed Development of the Putative Atrioventricular Node.

The RHOA-ROCK signaling pathway is involved in numerous developmental processes, including cell proliferation, differentiation and migration. RHOA is expressed in the atrioventricular node (AVN) and altered expression of RHOA results in atrioventricular (AV) conduction disorders in mice. The current study aims to detect functional AVN disorders after disturbing RHOA-ROCK signaling in chicken embryos. RHOA-ROCK signaling was inhibited chemically by using the Rho-kinase inhibitor compound Y-27632 in avian embryos (20 experimental and 29 control embryos). Morphological examination of control embryos show a myocardial sinus venosus to atrioventricular canal continuity, contributing to the transitional zone of the AVN. ROCK inhibited embryos revealed lateralization and diminished myocardial sinus venosus to atrioventricular canal continuity and at the severe end of the phenotype hypoplasia of the AVN region. Ex ovo micro-electrode recordings showed an AV conduction delay in all treated embryos as well as cases with first, second (Wenkebach and Mobitz type) and third-degree AV block which could be explained by the spectrum of severity of the morphological phenotype. Laser capture microdissection and subsequent qPCR of tissue collected from this region revealed disturbed expression of HCN1, ISL1, and SHOX2. We conclude that RHOA-ROCK signaling is essential for normal morphological development of the myocardial continuity between the sinus venosus and AVN, contributing to the transitional zone, and possibly the compact AVN region. Disturbing the RHOA-ROCK signaling pathway results in AV conduction disturbances including AV block. The RHOA-ROCK inhibition model can be used to further study the pathophysiology and therapeutic strategies for AV block. Anat Rec, 302:83-92, 2019. © 2018 Wiley Periodicals, Inc.

Complete atrioventricular block associated with clozapine intoxication: case report.

Türe M, Bilici M, Akin A, Demir F, Balik H, Darakçi SM. Complete atrioventricular block associated with clozapine intoxication: case report. Turk J Pediatr 2019; 61: 618-621. Clozapine is one of the atypical anti-psychotic drugs used in the treatment of resistant schizophrenia. Although cardiac side-effects are rare, it has been reported that there may be development of myocarditis, dilated cardiomyopathy, postural orthostatic hypotension and prolonged QT duration. Complete atrioventricular (AV) block is characterized by the inability to transmit all of the atrial signal to the ventricles. Causes may be congenital, idiopathic or acquired which are associated with surgery, infection, or muscle disease. AV block is extremely serious and permanent pacemaker insertion is usually necessary for all patients. Complete AV block may develop due to clozapine intoxication through increase in vagal tonus, sinoatrial node (SN) and the inhibition of atrioventricular node signalling. The case presented here is of a 15-year old female patient who developed AV total cardiac block associated with the taking of clozapine in a suicide attempt.

Atrio-ventricular Block Following Neostigmine-Glycopyrrolate Reversal in Non-heart Transplant Patients: Case Report.

Neostigmine is the anticholinesterase drug most commonly used to reverse blockade or speed up recovery from neuromuscular blockade from nondepolarizing neuromuscular blocking drugs. Because of its cardiac muscarinic effects, prior or simultaneous administration of glycopyrrolate or atropine is usually recommended. There have been a few case reports of bradycardia, atrio-ventricular (AV) block, and cardiac arrest following neostigmine/glycopyrrolate administration to reverse neuromuscular block affecting several patients. In this report, we describe a case of 21-year-old with a history of seizure disorder and developmental delay that presented for dental surgery under general anesthesia and developed type I AV block following the simultaneous administration of neostigmine and glycopyrrolate to reverse a nondepolarizing neuromuscular block with rocuronium at the end of his surgery. We suggest that the chronic use of antiepileptic drugs in this patient in combination with neostigmine and glycopyrrolate lead to AV block in this patient. We also review similar cases reported in the literature and suggest an explanation for this observed phenomenon.

Complete Atrioventricular Block in an Elderly Patient Treated with Low-Dose Lacosamide.

Lacosamide, one of the last antiepileptic drugs marketed, can cause extension of PR interval. Precautions are recommended when used in elderly and with other drugs extending PR interval. Cases of severe third-degree atrioventricular block have been reported only in post-marketing case reports when used at high-doses and remain rare. We report the case of an 88-year-old woman treated with bisoprolol, who experienced a complete atrioventricular block after initiation of lacosamide for epilepsy associated with neurodegenerative disease. This dramatic event required a pacemaker implementation. Not being dose-dependent (initiation dosage used), it seemed partially explained by drug-drug interaction with bisoprolol.

Prospective Study of Adenosine on Atrioventricular Nodal Conduction in Pediatric and Young Adult Patients After Heart Transplantation.

BACKGROUND: Supraventricular tachycardia is common after heart transplantation. Adenosine, the standard therapy for treating supraventricular tachycardia in children and adults without transplantation, is relatively contraindicated after transplantation because of a presumed risk of prolonged atrioventricular block in denervated hearts. This study tested whether adenosine caused prolonged asystole after transplantation and if it was effective in blocking atrioventricular nodal conduction in these patients. METHODS: This was a single-center prospective clinical study including healthy heart transplant recipients 6 months to 25 years of age presenting for routine cardiac catheterization during 2015 to 2016. After catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose-escalation protocol until atrioventricular block was achieved. The incidence of clinically significant asystole (≥12 seconds after adenosine) was quantified. The effects of patient characteristics on adenosine dose required to produce atrioventricular block and duration of effect were also measured. RESULTS: Eighty patients completed adenosine testing. No patient (0%; 95% confidence interval, 0-3) required rescue ventricular pacing. Atrioventricular block was observed in 77 patients (96%; 95% confidence interval, 89-99). The median longest atrioventricular block was 1.9 seconds (interquartile range, 1.4-3.2 seconds), with a mean duration of adenosine effect of 4.3±2.0 seconds. No patient characteristic significantly predicted the adenosine dose to produce atrioventricular block or duration of effect. Results were similar across patient weight categories. CONCLUSIONS: Adenosine induces atrioventricular block in healthy pediatric and young adult heart transplant recipients with minimal risk when low initial doses are used (25 µg/kg; 1.5 mg if ≥60 kg) and therapy is gradually escalated. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02462941.

Multiple ion channel block by the cation channel inhibitor SKF-96365 in myocytes from the rabbit atrioventricular node.

The atrioventricular node (AVN) of the cardiac conduction system coordinates atrial-ventricular excitation and can act as a subsidiary pacemaker. Recent evidence suggests that an inward background sodium current, IB,Na, carried by nonselective cation channels (NSCCs), contributes to AVN cell pacemaking. The study of the physiological contribution of IB,Na has been hampered, however, by a lack of selective pharmacological antagonists. This study investigated effects of the NSCC inhibitor SKF-96365 on spontaneous activity, IB,Na, and other ionic currents in AVN cells isolated from the rabbit. Whole-cell patch-clamp recordings of action potentials (APs) and ionic currents were made at 35-37°C. A concentration of 10 µmol/L SKF-96365 slowed spontaneous action potential rate by 13.9 ± 5.3% (n = 8) and slope of the diastolic depolarization from 158.1 ± 30.5 to 86.8 ± 30.5 mV sec(-1) (P < 0.01; n = 8). Action potential upstroke velocity and maximum diastolic potential were also reduced. Under IB,Na-selective conditions, 10 µmol/L SKF-96365 inhibited IB,Na at -50 mV by 36.1 ± 6.8% (n = 8); however, effects on additional channel currents were also observed. Thus, the peak l-type calcium current (ICa,L) at +10 mV was inhibited by 38.6 ± 8.1% (n = 8), while the rapid delayed rectifier current, IKr, tails at -40 mV following depolarization to +20 mV were inhibited by 55.6 ± 4.6% (n = 8). The hyperpolarization-activated current, If, was unaffected by SKF-96365. Collectively, these results indicate that SKF-96365 exerts a moderate inhibitory effect on IB,Na and slows AVN cell pacemaking. However, additional effects of the compound on ICa,L and IKr confound the use of SKF-96365 to dissect out selectively the physiological role of IB,Na in the AVN.

Zebrafish heart as a model to study the integrative autonomic control of pacemaker function.

The cardiac pacemaker sets the heart's primary rate, with pacemaker discharge controlled by the autonomic nervous system through intracardiac ganglia. A fundamental issue in understanding the relationship between neural activity and cardiac chronotropy is the identification of neuronal populations that control pacemaker cells. To date, most studies of neurocardiac control have been done in mammalian species, where neurons are embedded in and distributed throughout the heart, so they are largely inaccessible for whole-organ, integrative studies. Here, we establish the isolated, innervated zebrafish heart as a novel alternative model for studies of autonomic control of heart rate. Stimulation of individual cardiac vagosympathetic nerve trunks evoked bradycardia (parasympathetic activation) and tachycardia (sympathetic activation). Simultaneous stimulation of both vagosympathetic nerve trunks evoked a summative effect. Effects of nerve stimulation were mimicked by direct application of cholinergic and adrenergic agents. Optical mapping of electrical activity confirmed the sinoatrial region as the site of origin of normal pacemaker activity and identified a secondary pacemaker in the atrioventricular region. Strong vagosympathetic nerve stimulation resulted in a shift in the origin of initial excitation from the sinoatrial pacemaker to the atrioventricular pacemaker. Putative pacemaker cells in the sinoatrial and atrioventricular regions expressed adrenergic ß2 and cholinergic muscarinic type 2 receptors. Collectively, we have demonstrated that the zebrafish heart contains the accepted hallmarks of vertebrate cardiac control, establishing this preparation as a viable model for studies of integrative physiological control of cardiac function by intracardiac neurons.

Non-invasive assessment of the effect of beta blockers and calcium channel blockers on the AV node during permanent atrial fibrillation.

AIM: We aimed at assessing changes in AV nodal properties during administration of the beta blockers metoprolol and carvedilol, and the calcium channel blockers diltiazem and verapamil from electrocardiographic data. METHODS: Parameters accounting for the functional refractory periods of the slow and fast pathways (aRPs and aRPf) were estimated using atrial fibrillatory rate (AFR) and ventricular response assessed from 15-min ECG segments recorded at baseline and on drug treatment from sixty patients with permanent AF. RESULTS: The results showed that AFR and HR were significantly reduced for all drugs, and that aRPs and aRPf were significantly prolonged in both pathways. The prolongation in aRP was significantly larger for the calcium channel blockers than for the beta blockers. CONCLUSIONS: The changes observed in the AV node parameters are in line with the results of previous electrophysiological studies performed in patients during sinus rhythm, therefore supporting the clinical value of the method.

The effects of serotonin on the electrophysiological properties of atrioventricular node during an experimental atrial fibrillation.

A few studies explored the atrioventricular (AV) nodal effects of 5-hydroxytyptamine (serotonin, 5-HT) during supraventricular tachyarrhythmia. The aims of the present study are to investigate (i) 5-HT effects on the rate-dependent electrophysiological functions of AV node during atrial fibrillation (AF) and (ii) the potential contribution of various 5-HT receptors and the role of the autonomic nervous system on 5-HT effects on AV nodal properties. The specific stimulation protocols were applied to detect the electrophysiological parameters of AV node in seven groups of isolated rabbit AV nodal preparations (N = 75) in the presence of 5-HT (0.5, 1, 5, 10, and 20 µM) and its receptor antagonists, nadolol and atropine. The simulated AF protocol was executed in a separate group, and specific indices, including mean His-His interval, a zone of concealment (ZOC), and concealed beats recorded. 5-HT (10-20 µM) increased significantly functional refractory period, Wenckebach cycle length, and excitability index (p < 0.05). The percentage of gap and echo beats was significantly decreased with increasing 5-HT concentrations (p < 0.05). Ketanserin and tropisetron increased significantly atrial-His conduction time, effective refractory period, and Wenckebach cycle length (p < 0.05). 5-HT effects on functional refractory period and Wenckebach cycle length were abrogated by tropisetron and nadolol (p < 0.05). 5-HT elicited prolongation of ZOC and nodal refractoriness (p < 0.05). We conclude that 5-HT elicited prolongation of the nodal refractoriness more than atrial-His conduction time leads to increase in the excitability index and ZOC without significant reduction of the ventricular rates during AF.

The effect of the sphingosine-1-phosphate analogue FTY720 on atrioventricular nodal tissue.

The sphingosine-1-phosphate (S1P) receptor modulator, fingolimod (FTY720), has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular (AV) conduction block have been reported in some patients after the first dose. The underlying mechanism of this AV node conduction blockade is still not well-understood. In this study, we hypothesize that expression of this particular arrhythmia might be related to a direct effect of FTY720 on AV node rather than a parasympathetic mimetic action. We, therefore, investigated the effect of FTY720 on AV nodal, using in vitro rat model preparation, under both basal as well as ischaemia/reperfusion conditions. We first look at the expression pattern of S1P receptors on the AV node using real-time PCR. Although all three S1P receptor isoforms were expressed in AVN tissues, S1P1 receptor isoform expression level was higher than S1P2 and S1P3. The effect of 25 nM FTY720 on cycle length (CL) was subsequently studied via extracellular potentials recordings. FTY720 caused a mild to moderate prolongation in CL by an average 9% in AVN (n = 10, P < 0.05) preparations. We also show that FTY720 attenuated both ischaemia and reperfusion induced AVN rhythmic disturbance. To our knowledge, these remarkable findings have not been previously reported in the literature, and stress the importance for extensive monitoring period in certain cases, especially in patients taking concurrently AV node blocker agents.

Electrocardiographic and electrophysiologic effects of dexmedetomidine on children.

BACKGROUND: Dexmedetomidine (DEX) is a highly selective alpha-2-adrenergic agonist approved for short-term sedation and monitored anesthesia care in adults. Its effects on the electrocardiography and cardiac conduction tissue are not well described in the literature. Therefore, we aimed to characterize the electrocardiographic and electrophysiologic effects of DEX in children. METHODS: Twenty children (11 boys and nine girls) between the ages of eight and 17 undergoing electrophysiology study and ablation of the supraventricular tachycardia had hemodynamic and cardiac electrophysiologic variables measured before and during the administration of DEX (1 microgram/kg IV over 10 minutes followed by a 10-minute continuous infusion of 0.5 microgram/kg/h). RESULTS: A significant decrease in heart rate was seen after the administration of DEX, but the systolic-diastolic-mean arterial pressure, respiratory rate, and end-tidal carbon dioxide did not change. Corrected sinus node recovery times and baseline sinus cycle lengths, which are markers of sinus nodal function, were both lengthened with the administration of DEX. Atrioventricular (AV) nodal function, as evidenced by the Wenckebach cycle length, the ventriculoatrial block cycle length, and AV nodal effective refractory periods, was lengthened significantly. We also found that DEX increased the atrial refractory period and diminished atrial excitability. CONCLUSIONS: DEX significantly depressed sinus and AV nodal function in pediatric patients without significant electrocardiogram interval changes, other than a trend toward lower heart rates. Although no spontaneous AV nodal block and no clinically significant bradycardia were seen, we recommend that DEX be used with caution in patients at risk for bradycardia and/or AV nodal dysfunction due to its associated comorbidities.

Overexpression of SCN5A in mouse heart mimics human syndrome of enhanced atrioventricular nodal conduction.

BACKGROUND: In enhanced atrioventricular (A-V) nodal conduction (EAVNC) syndrome, patients have short A-V conduction times. Multiple mechanisms have been proposed to explain EAVNC; however, the electrophysiological or molecular substrate responsible for it remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that overexpression of SCN5A in the mouse heart may provide an animal model mimicking EAVNC. METHODS: Electrocardiogram, atrial, His bundle, and ventricular electrograms were recorded from wild-type (WT) and transgenic (TG) mice overexpressing human SCN5A. The sodium current and NaV1.5 expression were measured using patch-clamp and immunohistochemistry techniques. RESULTS: The P-R interval in TG mice (13.6 ± 1.2 ms) was much shorter than that in WT mice (40.2 ± 0.59 ms). In TG isolated hearts, the A-V conduction time (14.4 ± 0.81 ms) during right atrial pacing was also shorter than that in WT hearts (39.5 ± 0.62 ms). Records of His bundle electrograms revealed that atrial-to-His and His-to-ventricular intervals were shorter in TG than in WT hearts. In addition, TG hearts had a shorter Wenckebach cycle length and A-V effective refractory period. The sodium current was 2-fold greater in TG ventricular myocytes than in WT ventricular myocytes. Flecainide prolonged the A-V conduction time in TG hearts to a value close to that in WT hearts. Nifedipine prolonged the atrial-to-His interval in WT hearts but not in TG hearts. Immunohistochemistry studies revealed increased NaV1.5 labeling in TG atrial and ventricular tissues, and NaV1.5 expression in A-V junction and A-V ring regions in TG hearts. CONCLUSION: Enhanced A-V conduction in mice overexpressing SCN5A in the heart mimics the human syndrome of EAVNC. Thus, variants in sodium channel expression in the A-V nodal region may be an electrophysiological substrate responsible for EAVNC.