Increased capture threshold in permanent His-bundle pacing associated with flecainide.

A 64-year-old man underwent implantation of a permanent His-bundle pacemaker. A marked rise in the selective His-bundle capture threshold was noted 1 month after the patient started flecainide acetate for rhythm control of recurrent, symptomatic atrial flutter and atrial fibrillation. The capture threshold subsequently normalized 4 days after discontinuing flecainide and switching to dofetilide. To our knowledge, this is the first documented case of a rise in selective His-bundle capture threshold associated with flecainide acetate. Further studies are needed to characterize this association which could result in higher capture thresholds, decreased battery longevity, and mimic His-bundle lead failure.

Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction.

PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I  were measured. METHODS: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval. RESULTS: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers. CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.

Effects of the antianginal drug trapidil on atrioventricular conduction disturbances during acute myocardial ischemia.

Adenosine and related compounds have been shown to produce atrioventricular (AV) conduction block during acute myocardial ischemia. We investigated the effects of the antianginal drug trapidil, which has been shown to inhibit phosphodiesterase, on AV conduction disturbances in a canine model of acute myocardial ischemia. In 35 anesthetized dogs, the AV node artery was cannulated and perfused with arterial blood. Adenosine (300 µg, 650 µg, or 1000 µg) was injected into the AV node artery. With administration of adenosine at 300 µg, 650 µg, or 1000 µg, the atrio-His (AH) interval was increased by 14.6 ms, 22.3 ms, and 29.7 ms, respectively. The effects of adenosine were potentiated by pretreatment with intravenous dipyridamole (250 µg/kg), an inhibitor of adenosine uptake, but the effects of adenosine were attenuated with intravenous trapidil (3 mg/kg), an inhibitor of phosphodiesterase. AV node artery occlusion resulted in prolongation of the AH interval in 4 of 12 dogs. The ischemia-induced AH prolongation was potentiated with intravenous dipyridamole and attenuated with intravenous trapidil. AV conduction disturbances associated with inferior myocardial infarction may be related in part to endogenously released adenosine, and trapidil may be useful in treating AV block associated with acute AV node ischemia.

Inducible recombination in the cardiac conduction system of minK: CreERT² BAC transgenic mice.

Inducible Cre recombination is a powerful technology that allows for spatial and temporal modulation of gene expression in vivo. Diseases of the cardiac conduction system (CCS) pose a significant clinical burden but are not currently well understood at the molecular level. To enable inducible recombination in the murine CCS, we created a minK:CreERT(2) bacterial artificial chromosome (BAC) transgenic mouse line. Cre activity is present after tamoxifen administration in the atrioventricular (AV) node, AV bundle, and bundle branches of adult transgenic mice. We anticipate that by enabling inducible recombination specifically in the AV node, bundle, and bundle branches, minK:CreERT(2) BAC transgenic mice will prove useful in advancing our understanding of CCS disease and function.

High-dose remifentanil suppresses sinoatrial conduction and sinus node automaticity in pediatric patients under propofol-based anesthesia.

BACKGROUND: We sought to determine the effect of remifentanil on sinus node function and the atrial-His (AH) interval in pediatric patients undergoing radiofrequency catheter ablation. METHODS: Sixty pediatric patients with Wolff-Parkinson-White syndrome were prospectively enrolled in this study. General anesthesia was induced and maintained with a continuous infusion of propofol. We recorded the calculated sinoatrial conduction time (CSACT), corrected sinus node recovery time (CSNRT), and AH interval when the patients were in a stable anesthetic state and compared the values before and during remifentanil administration at a moderate dose (0.2 µg · kg(-1) · min(-1)) or a high dose (0.4 µg · kg(-1) · min(-1)). Data are expressed as mean (95% confidence interval). RESULTS: At the moderate dose, remifentanil prolonged CSNRT (from 177 [117-237] milliseconds to 245 [167-322] milliseconds after administration; P=0.016), but had no effect on either CSACT (P=0.59) or AH interval (P=0.11). However, high-dose remifentanil prolonged both CSNRT (from 201 [144-260] milliseconds to 307 [232-382] milliseconds after administration; P=0.019) and CSACT (from 48 [31-65] milliseconds to 78 [59-96] milliseconds after administration; P=0.038), but had no effect on the AH interval (P=0.058). The interaction in CSNRT between remifentanil administration and its dose was not different (P=0.44). CONCLUSION: Remifentanil may inhibit both intraatrial conduction and sinus node automaticity, but it has no effect on conduction through the atrioventricular node. Dose dependency was not observed within the range of 0.2 to 0.4 µg · kg(-1) · min(-1) of remifentanil.

Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction.

We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K(+) current [I(Ks); long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K(+) current [I(Kr); long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking I(Kr) and I(Ks).

Comparison of electropharmacological effects of bepridil and sotalol in halothane-anesthetized dogs.

BACKGROUND: Bepridil is known to have a multiple ion channel-blocking property in the heart, which has been applied for the treatment of atrial fibrillation and drug-refractory ventricular tachyarrhythmias. In this study, the electro-pharmacological effects of bepridil were compared with those of dl-sotalol, a representative class III antiarrhythmic drug, using the halothane-anesthetized canine model. METHODS AND RESULTS: Cardiovascular and electrophysiological variables were measured under the halothane anesthesia. Intravenous administration of bepridil (0.3 mg/kg, n=4) delayed the intraventricular conduction and prolonged the ventricular effective refractory period, whereas dl-sotalol (0.3 mg/kg, iv, n=4) inhibited atrioventricular conduction and prolonged the atrial and ventricular effective refractory period. The additional administration of 10 times the higher dose of bepridil or dl-sotalol (ie, 3 mg/kg, iv, n=4 for each group) decreased blood pressure, suppressed ventricular contraction and sinus automaticity, and prolonged the atrial and ventricular effective refractory period and monophasic action potential duration, in addition to the effects of the low dose. CONCLUSIONS: The electropharmacological effects of bepridil and dl-sotalol were similar, although their potency for each cardiovascular variable varied significantly. These findings can be useful when selecting these drugs according to the pathophysiological condition of a patient.

Effect of autonomic blockade on ventricular repolarization shortening: response to behavioral stimulus in paced dogs.

Autonomic tone has been suggested to be a significant determinant of ventricular repolarization duration with both rate dependent and independent effects. Using the His bundle-paced dog, a model that eliminates the need for QT correction factors, we explored the rate-independent effects of sympathetic and parasympathetic blockade on ventricular repolarization shortening following an excitatory stimulus. Six male His bundle-paced beagle dogs were paced at 80 bpm and fitted with jackets, surface ECG electrodes, and radiotelemeters. Dogs were given propranolol, atropine methyl nitrate, or the appropriate control in a four-period crossover design. Doses were based on literature reviews and unpublished pharmacokinetic/pharmacodynamic modeling to provide efficacious beta- and parasympathetic blockade throughout the data collection period. Data collection began at 11 am and concluded at 11 am the following day, with event stimuli provided by investigators entering the room at 5 pm and at 7 am the following morning. One minute of ECG data were sampled every 15 min and these means were averaged to generate hourly means for the 24 hour data collection period. Treatment with atropine attenuated RT interval shortening when compared with the vehicle group at both the 5 pm and 7 am stimulus. In contrast, propranolol was not associated with significant effects on RT interval duration at either time point. These results suggest that parasympathetic withdrawal is the primary factor responsible during both awake hours (5 pm) and in the transition from deep sleep to the awake state (7 am) in the facilitation of RT interval shortening following an excitatory stimulus. The attenuation of RT interval shortening following atropine treatment may be a direct effect, or an indirect effect requiring an excited state to become evident. The use of a model that eliminates the need to apply correction factors to repolarization indices helps to clarify the role of the autonomic nervous system on ventricular repolarization.

Analysis of proarrhythmic potential of antipsychotics risperidone and olanzapine in anesthetized dogs.

In vitro electrophysiological studies have shown that second-generation antipsychotic drugs risperidone and olanzapine inhibit rapidly activating delayed rectifier K(+) currents and prolong action potential duration of the isolated ventricular myocardium. In this study, we analyzed in vivo cardiohemodynamic and electrophysiological profiles of risperidone and olanzapine using the halothane-anesthetized canine model to clarify their proarrhythmic potential. A clinically relevant dose of risperidone (0.03 mg/kg, i.v.) did not affect the ventricular repolarization process, whereas the supra-therapeutic doses (0.3 and 3 mg/kg, i.v.) prolonged the duration of monophasic action potential of the ventricle. Furthermore, the terminal repolarization period, an index of extent of electrical vulnerability, was prolonged after the supra-therapeutic doses. In contrast, therapeutic to supra-therapeutic doses of olanzapine (0.03-3 mg/kg, i.v.) hardly affected the ventricular repolarization process. Therefore, more caution has to be paid on the use of risperidone than olanzapine for patients with risks of the elevated plasma concentration.

[Amiodaron effects on atrioventricular conduction].

AIM: To assess short- and long-term effects of amiodaron on atrioventricular conduction (AVC) of the heart. MATERIAL AND METHODS: Amiodaron was given to 477 patients (mean age 48.7 +/- 0.7 years) with various arrhythmias caused, as a rule by coronary heart disease. A mean saturation dose was 809.4 +/- 13.4 mg/day, a mean maintanence dose--263.5 +/- 5.4 mg/day. Mean follow-up 20.85 +/- 1.2 months. The frequency of AVC disorders was estimated at regular Holter monitoring. RESULTS: In saturation, atrioventricular block of the first degree arose in 17.2% patients, of the second and third degree--only in one patient. AVC disorders disappeared at reduction of amiodaron dose. Only in one patient the drug was discontinued because of recurrent block of the third degree and bradycardia. CONCLUSION: In saturation, ECG records lengthening of P-R intervals by 18.9%, on the average. Maintenance therapy increases the length of P-R interval by 8.1%, on the average.

Cardiomyocyte apoptosis in cocaine-induced myocarditis with involvement of bundle of His and left bundle branch.

Cocaine abuse can cause degenerative and inflammatory alterations of the myocardium. Cocaine-induced myocarditis has been previously described, but mostly in chronic cocaine addicts. Among several pathogenetic mechanisms of cocaine-related myocardial damage, the myocardial adrenergic stress and cardiomyocytes apoptosis have been recently proposed. We report an unusual case of myocarditis involving the bundle of His and left bundle branch and cardiac myocytes apoptosis in otherwise healthy occasional cocaine abuser.

The antipsychotic and antiemetic drug prochlorperazine delays the ventricular repolarization of the in situ canine heart.

Electropharmacological effect of the antipsychotic and antiemetic drug prochlorperazine was assessed using the halothane-anesthetized in vivo canine model (n = 5). Up to 10 times higher than the clinically relevant doses of prochlorperazine (< or = 3 mg/kg, i.v.) did not induce cardiohemodynamic collapse in the model. Meanwhile, clinically relevant to supratherapeutic doses (0.3 - 3 mg/kg, i.v.) prolonged the ventricular repolarization period in a dose-related and reverse-use dependent manner that could become proarrhythmic substrates. Thus, caution has to be paid on the use of prochlorperazine particularly for patients with risks of the elevated plasma drug concentration, compromised cardiac repolarization, and/or frequent ventricular premature beats.

Progressive facilitation of antegrade conduction via an accessory pathway in a patient with Wolff-Parkinson-White syndrome and permanent atrial fibrillation.

The case of a 64-year-old man with Wolff-Parkinson-White syndrome and permanent atrial fibrillation (AF) is reported. The patient was admitted due to electrocardiographic feature of AF with rapid conduction over the left-sided accessory pathway. Administration of pirmenol effectively suppressed the ventricular response via an accessory pathway. A transesophageal echocardiography detected an uncertain thrombus in the left atrial appendage. During the 33-month follow-up period, the ventricular response via an accessory pathway was progressively facilitated. Radiofrequency catheter ablation using a transseptal approach was performed during AF, resulting in complete elimination of the antegrade accessory pathway conduction.

Effects of acute systemic endothelin receptor blockade on cardiac electrophysiology in vivo.

BQ-123, a selective endothelin-A receptor antagonist, has been demonstrated to suppress arrhythmias. However, the role of physiologic levels of endogenous endothelin-1 (ET-1) with respect to electrophysiologic properties of the heart is unknown. BQ-123 (0.45, 0.9, 1.8, 3.6, 7.2, and 14.4 microg/kg/min; n = 10) or saline (control, n = 5) was administered IV for 15 minutes of continuous-rate infusion at incremental doses to anesthetized normal pigs. BQ-123 had no effect on PR and QT interval, QRS duration, intraatrial and AV nodal conduction time as well as the atrial, AV nodal, and ventricular effective refractory periods. As compared with baseline, BQ-123 at 7.2 and 14.4 microg/kg/min caused an increase in heart rate (99 +/- 17 versus 110 +/- 14 and 118 +/- 14 bpm, respectively; P < 0.05), shortened sinus node recovery time (818 +/- 165 versus 641 +/- 69 and 609 +/- 74 milliseconds, respectively; P < 0.05) and decreased mean arterial pressure at 14.4 microg/kg/min (95 +/- 18 versus 80 +/- 11 mm Hg; P < 0.05). We conclude that in the normal pig, physiologic levels of ET-1 have no effect on conduction properties of atrial, AV nodal, or Purkinje fibers. However, antagonism of ET-1 by BQ-123 unmasks the effect of ET-1 on maintenance of vasomotor tone, which in turn may affect heart rate and sinus node automaticity in the intact pig.

Structure-affinity relationships of 5'-aromatic ethers and 5'-aromatic sulfides as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic agents.

Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A(1) adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A(1) adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A(1) adenosine receptor could avoid this deleterious effect. 5(') Phenyl sulfides (e.g., 17, EC(50)=1.26 microM) and phenyl ethers (e.g., 28, EC(50)=0.2 microM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPgammaS binding data suggesting partial activity of the A(1) adenosine receptor, and PK results for 5(') modified adenosine derivatives are shown.

Supraventricular tachycardia in children.

The mechanisms causing different supraventricular tachycardias can be identified with the aid of the 12-lead ECG using Tipple's approach. The main aims of this retrospective study were to use the 12-lead ECG to determine the underlying mechanisms of supraventricular arrhythmias and to evaluate the effectiveness of the treatment modalities used. Forty-one patients were included in the study. The main findings were: nine of the 41 patients had atrial tachycardias while junctional tachycardia occurred in 32/41 of our patients. The underlying mechanisms causing the junctional tachycardias were: AVNRT (n = 21), AVRT (n = 10) and JET (n = 1). Of the 10 patients presenting with AVRT, eight were less than one year old. AVNRT occurred more often in the older age group (>1 year of age). Fifteen of the 41 patients had spontaneous cessation of their supraventricular tachycardia. The drug most commonly used during the acute and long-term phases was digoxin. Amiodarone was used in six patients with an 80% success rate. In the early 80s verapamil was used in five patients with a 100% success rate. It is important to note that verapamil is no longer used in children due to its side effects. Lately, adenosine phosphate is the drug of choice in most supraventricular tachycardias. The management of supraventricular tachycardias in paediatric practice is mainly based on clinical studies and individual experience. Care must therefore be taken to choose medication regimens that are likely to be effective with the minimum risk of potentiating abnormal haemodynamics or conduction.

Effects of intravenous nifekalant, a class III antiarrhythmic drug, on atrial vulnerability parameters in patients with paroxysmal atrial fibrillation.

Nifekalant, a class III antiarrhythmic drug, has been shown to suppress ventricular tachyarrhythmias, but its effects on AF are unclear. The aim of this study was to clarify the effects of nifekalant on the atrial vulnerability parameters in patients with paroxysmal AF. The study included 18 patients with paroxysmal AF who underwent electrophysiological study before and after intravenous infusion of nifekalant. The atrial electrophysiological parameters including the atrial effective refractory period (AERP), maximum intraatrial conduction delay, and wavelength index, calculated as the ratio of AERP to the maximum conduction delay, were quantitatively measured at baseline and during nifekalant infusion. The mean AERP was significantly prolonged from 214 +/- 27 ms at baseline to 242 +/- 39 ms after nifekalant (P < 0.001). Although earlier studies have shown that nifekalant does not affect the atrial conduction time, the mean maximum conduction delay of the study patients was significantly prolonged from 59 +/- 19 ms at baseline to 72 +/- 28 ms after nifekalant (P = 0.015). There was no significant difference in the wavelength index at baseline (4.1 +/- 1.7) and after nifekalant (4.1 +/- 2.5). However, when the differences of AERP and wavelength index were defined as each parameter during nifekalant infusion minus that at baseline, the difference of AERP showed a direct positive correlation with that of the wavelength index (P = 0.013). In conclusion, nifekalant may be effective in the prevention of AF due to prolongation of the AERP. However, in those patients who have a lesser degree of prolongation of the AERP by nifekalant, the wavelength index tended to be decreased, suggesting that the drug might augment the propensity for AF.