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Abstract Aims Response to cardiac resynchronization therapy (CRT) is known to be associated with a number of clinical characteristics, including QRS duration and morphology, gender, height, and the aetiology of heart failure (HF). We assessed the relation of gender and baseline characteristics with QRS duration and Kansas City Cardiomyopathy Questionnaire. Methods and results AdaptResponse is a global randomized trial. The trial enrolled CRT‐indicated patients with New York Heart Association classes II–IV HF, left bundle branch block (QRS ≥ 140 ms in men, ≥130 ms in women), and baseline PR interval ≤200 ms. In total, 3620 patients were randomized, including 1569 women (43.3%) approaching the actual proportion of women in the HF population. Women were older and more often New York Heart Association class III or IV than men (55.6% vs. 48.7%), had less frequent ischaemic cardiomyopathy (21.2% vs. 39.5%), and had a 5.1 ms shorter QRS duration than men. Women were more often depressed (18.5% vs. 9.7%), had a significantly lower Kansas City Cardiomyopathy Questionnaire score, and had differences in medication prescriptions. Conclusions AdaptResponse is the largest randomized CRT trial and enrolled more women than any other landmark CRT trial. Women differed from men with regard to baseline characteristics and quality of life. Whether these differences translate into clinical outcome differences will be examined further in the AdaptResponse trial.

Although cardiac resynchronization therapy (CRT) has proven beneficial in several randomized trials, a subset of patients have limited clinical improvement. The AdaptivCRT algorithm provides automated selection between synchronized left ventricular or biventricular pacing with optimization of atrioventricular delays. The rationale and design of the economic analysis of the AdaptResponse clinical trial are described. The costs associated with HF hospitalization are substantial and are compounded by a high rate of readmission. HF hospitalization payments range from $1,001 for Greece to $12,235 for US private insurance. When examining the breakdown of HF-related costs, it is clear that approximately 55% of the hospitalization costs are directly attributable to length of stay. Notably, the mean costs of a CRT patient in need of a HF-related hospitalization are currently estimated to be an average of $10,679. The economic analysis of the AdaptResponse trial has two main objectives. The hospital provider objective seeks to test the hypothesis that AdaptivCRT reduces the incidence of all-cause re-admissions after a heart failure admission within 30 days of the index event. A negative binomial regression model will be used to estimate and compare the number of readmissions after an index HF hospitalization. The payer economic objective will assess cost-effectiveness of CRT devices with the AdaptivCRT algorithm relative to traditional CRT programming. This analysis will be conducted from a U.S. payer perspective. A decision analytic model comprised of a 6-month decision tree and a Markov model for long term extrapolation will be used to evaluate lifetime costs and benefits. AdaptivCRT may offer improvements over traditional device programming in patient outcomes. How the data from AdaptResponse will be used to demonstrate if these clinical benefits translate into substantial economic gains is herein described. [ABSTRACT FROM AUTHOR]

This review discusses the electrophysiological causes of AV conduction disorders, evolution of the classifications of AV blocks, epidemiology, clinical manifestations, diagnosis and management of patients with AV conduction disorders. Indications for electrotherapy are considered. Typical mistakes in ECG interpretation related to AV blocks are analyzed.

Aims: Response to cardiac resynchronization therapy (CRT) is known to be associated with a number of clinical characteristics, including QRS duration and morphology, gender, height, and the aetiology of heart failure (HF). We assessed the relation of gender and baseline characteristics with QRS duration and Kansas City Cardiomyopathy Questionnaire. Methods and results: AdaptResponse is a global randomized trial. The trial enrolled CRT‐indicated patients with New York Heart Association classes II–IV HF, left bundle branch block (QRS ≥ 140 ms in men, ≥130 ms in women), and baseline PR interval ≤200 ms. In total, 3620 patients were randomized, including 1569 women (43.3%) approaching the actual proportion of women in the HF population. Women were older and more often New York Heart Association class III or IV than men (55.6% vs. 48.7%), had less frequent ischaemic cardiomyopathy (21.2% vs. 39.5%), and had a 5.1 ms shorter QRS duration than men. Women were more often depressed (18.5% vs. 9.7%), had a significantly lower Kansas City Cardiomyopathy Questionnaire score, and had differences in medication prescriptions. Conclusions: AdaptResponse is the largest randomized CRT trial and enrolled more women than any other landmark CRT trial. Women differed from men with regard to baseline characteristics and quality of life. Whether these differences translate into clinical outcome differences will be examined further in the AdaptResponse trial. [ABSTRACT FROM AUTHOR]

Background: The AdaptivCRT (aCRT) algorithm continuously adjusts cardiac resynchronization therapy (CRT) according to intrinsic atrioventricular conduction, providing synchronized left ventricular pacing in patients with normal PR interval and adaptive BiV pacing in patients with prolonged PR interval. Previous analyses demonstrated an association between aCRT and clinical benefit. We evaluated the incidence of patient mortality and atrial fibrillation (AF) with aCRT compared with standard CRT in a real‐world population. Methods and Results: Patients enrolled in the Medtronic Personalized CRT Registry and implanted with a CRT from 2013‐2018 were divided into aCRT ON or standard CRT groups based upon device‐stored data. A Frailty survival model was used to evaluate the potential survival benefit of aCRT, accounting for patient heterogeneity and center variability. Daily AF burden and first device‐detected AF episodes of various durations were recorded by the device during follow‐up. A total of 1814 CRT patients with no reported long‐standing AF history at implant were included. Mean follow‐up time was 26.1 ± 16.5 months and 1162 patients (64.1%) had aCRT ON. Patient survival probability at 36 months was 88.3% for aCRT ON and 83.7% for standard CRT (covariate‐adjusted hazard ratio [HR] = 0.71, 95% CI: 0.53‐0.96, P =.028). Mean AF burden during follow‐up was consistently lower in aCRT ON patients compared with standard CRT. At 36 months, the probability of AF was lower in patients with aCRT ON, regardless of which AF definition threshold was applied (6 minutes‐30 days, all P <.001). Conclusion: Use of the AdaptivCRT algorithm was associated with improved patient survival and lower incidence of AF in a real‐world, prospective, nonrandomized registry. [ABSTRACT FROM AUTHOR]

The atrioventricular node (AV) is considered the electrical connection between the atria and ventricles. There is an electrical pause between activation of the atria and the ventricles (PR segment), but to date the mechanism responsible for this interruption remains unclear. The present communication focuses on the hypothesis that magnetic field dynamics could provide the answer. Proof of this hypothesis is that in Wolff-Parkinson-White syndrome, where there is physical connection between the atria and ventricles (bundle of Kent), there is electrical AV continuity, no PR segment is detected, and catheter ablation of the abnormal bundle restores AV discontinuity. Spontaneous initiation of the heart at the level of the sinus node, the pacemaker of the heart, could also be explained via field dynamics. The known transmembrane pacemaker protein CHN4, present in both sinoatrial and AV nodal cells, could interact with field information to provide specificity in an electronic key-to-lock mechanism interaction. [ABSTRACT FROM AUTHOR]

The Pacsin proteins (Pacsin 1, 2 and 3) play an important role in intracellular trafficking and thereby signal transduction in many cells types. This study was designed to examine the role of Pacsin 2 in cardiac development and function. We investigated the development and electrophysiological properties of Pacsin 2 knockout (P2KO) hearts and single cardiomyocytes isolated from 11.5 and 15.5 days old fetal mice. Immunofluorescence experiments confirmed the lack of Pacsin 2 protein expression in P2KO cardiac myocytes in comparison to wildtype (WT). Western blotting demonstrates low expression levels of connexin 43 and T-box 3 proteins in P2KO compared to wildtype (WT). Electrophysiology measurements including online Multi-Electrode Array (MEA) based field potential (FP) recordings on isolated whole heart of P2KO mice showed a prolonged AV-conduction time. Patch clamp measurements of P2KO cardiomyocytes revealed differences in action potential (AP) parameters and decreased pacemaker funny channel ( I f ), as well as L-type Ca 2+ channel ( I CaL ), and sodium channel ( I Na ). These findings demonstrate that Pacsin 2 is necessary for cardiac development and function in mouse embryos, which will enhance our knowledge to better understand the genesis of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Data from randomized trials have suggested a modest or no effect of conventional cardiac resynchronization therapy (convCRT) on the incidence of atrial fibrillation (AF). AdaptivCRT (aCRT, Medtronic, Mounds View, MN) is a recently described algorithm for synchronized left ventricular (LV) pacing and continuous optimization of cardiac resynchronization therapy (CRT).Objective: We compared the long-term effects of aCRT with convCRT pacing on the incidence of AF.Methods: The Adaptive CRT trial randomized CRT-defibrillator (CRT-D)-indicated patients (2:1) to receive either aCRT or convCRT pacing. The aCRT algorithm evaluates intrinsic conduction every minute, providing LV-only pacing during normal atrioventricular (AV) conduction and AV and ventriculoventricular timing adjustments during prolonged AV conduction. The primary outcome of this subanalysis was an episode of AF >48 consecutive hours as detected by device diagnostics.Results: Over a follow-up period with a mean and standard deviation of 20.2 ± 5.9 months, 8.7% of patients with aCRT and 16.2% with convCRT experienced the primary outcome (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.31-0.93; P = .03). In patients with prolonged baseline AV, the incidence of the primary outcome was 12.8% in patients randomized to aCRT compared with 27.4% in convCRT patients (HR = 0.45; 95% CI = 0.24-0.85; P = .01). Also, patients with AF episodes adjudicated as clinical adverse events were less common with aCRT (4.3%) than with convCRT (12.7%) (HR = 0.39; 95% CI = 0.19-0.79; P = .01).Conclusion: Patients receiving aCRT had a reduced risk of AF compared with those receiving convCRT. Most of the reduction in AF occurred in subgroups with prolonged AV conduction at baseline and with significant left atrial reverse remodeling. [ABSTRACT FROM AUTHOR]

Background: Electrocardiographic conduction abnormalities following transcatheter aortic valve replacement (TAVR) with the Edwards-Sapien valve (ESV) are not uncommon and may be transient. We sought to examine the clinical time-course of conduction abnormalities after TAVR with ESV and determine risk factors for persistent abnormalities.Methods: In this single-center prospective study, 116 consecutive patients underwent implantation of the ESV after approval by the Food and Drug Administration (FDA). Demographic, clinical, and intra-procedural variables were collected in a registry, including ECGs before, immediately after, and at discharge from hospital. Conduction abnormalities were analyzed including PR interval lengthening, QRS widening, left bundle branch block (LBBB), and high-grade AV block.Results: There were 92 patients included in the analysis. A total of 41 new conduction abnormalities were observed in 31 (34 %) patients: 7 new PR prolongation, 14 QRS widening, 14 new LBBB, and 5 high-grade AV block requiring permanent pacemaker. Of the 41 new CAs, 11 (27 %) were transient; of the transient abnormalities, 9 (82 %) resolved within 24 h of the index procedure. Chronic kidney disease was a risk factor for the development of a persistent abnormality and for need for PPM. Antegrade approach was associated with the development of persistent LBBB and persistent QRS widening.Conclusions: A significant proportion of conduction abnormalities after ESV implantation improved prior to discharge from the hospital, usually within 24 h. CKD is associated with persistence of abnormalities and with need for PPM. Antegrade approach increases risk for new intraventricular conduction delays, including LBBB. [ABSTRACT FROM AUTHOR]

Background: In Boston Scientific dual-chamber devices, the RYTHMIQ algorithm aims to minimize right ventricular pacing.Objective: We evaluated the performance of this algorithm determining (1) the appropriateness of the switch from the AAI(R) mode with backup VVI pacing to the DDD(R) mode in case of suspected loss of atrioventricular (AV) conduction and (2) the rate of recorded pacemaker-mediated tachycardia (PMT) when AV hysteresis searches for restored AV conduction.Methods: In this multicenter study, we included 157 patients with a Boston Scientific dual-chamber device (40 pacemakers and 117 implantable cardioverter-defibrillators) without permanent AV conduction disorder and with the RYTHMIQ algorithm activated. We reviewed the last 10 remote monitoring-transmitted RYTHMIQ and PMT episodes.Results: We analyzed 1266 episodes of switch in 142 patients (90%): 207 (16%) were appropriate and corresponded to loss of AV conduction, and 1059 (84%) were inappropriate, of which 701 (66%) were related to compensatory pause (premature atrial contraction, 7%; premature ventricular contraction, 597 (56%); or both, 27 (3%)) or to a premature ventricular contraction falling in the post-atrial pacing ventricular refractory period interval (219, 21%) and 94 (10%) were related to pacemaker dysfunction. One hundred fifty-four PMT episodes were diagnosed in 27 patients (17%). In 85 (69%) of correctly diagnosed episodes, the onset of PMT was directly related to the algorithm-related prolongation of the AV delay, promoting AV dissociation and retrograde conduction.Conclusion: This study highlights some of the limitations of the RYTHMIQ algorithm: high rate of inappropriate switch and high rate of induction of PMT. This may have clinical implications in terms of selection of patients and may suggest required changes in the algorithm architecture. [ABSTRACT FROM AUTHOR]

Abstract: The generation of ventricular response during atrial arrhythmias and its dependence on atrial activity is poorly understood. This paper introduces the atrioventricular (AV) synchrogram, a novel method for the beat-to-beat assessment of AV coupling during atrial arrhythmias, based on the stroboscopic observation of the ventricular phase at times triggered by atrial activation. The method was applied on a database of 120 atrial electrograms and ECG signals recorded in patients during typical atrial flutter (AFL), rapid atrial flutter (rAFL), and atrial fibrillation (AF). Synchronized epochs of different n:m order were automatically detected in the AV synchrogram and characterized in terms of percentage of significantly coupled beats (p lb ), maximal length of coupling segments (l max ), average conduction ratio (CR). Synchrogram analysis demonstrated that AV coupling and degree of conduction were significantly affected by the rate and regularity of atrial activity. The occurrence and stability of AV coupled epochs was maximal during regular atrial activation in AFL (median (interquartile range) of p lb =100 (100–100)%, l max =29.0 (28.5–29.4)s), and significantly (p <0.001) decreased at faster atrial rates in rAFL (p lb =74.3 (57.6–100)%, l max =7.4 (3.9–28.7)s). A further decrease of coupling indexes occurred at higher irregularity of atrial activity in AF (p lb =25.7 (19.9–30.2)%, l max =2.1 (1.8–2.6)s). The increase of atrial rate led to a significant (p <0.001) reduction of CRs from 0.50 (0.29–0.50) in AFL to 0.25 (0.22–0.25) in rAFL and 0.30 (0.24–0.35) in AF. Application of the analysis to the time course of AF showed the presence of a Farey sequence structure in n:m coupling patterns at increasing atrial rate, which was consistent with the scaling effect of nodal recovery on atrial beats. In conclusion, AV synchrogram analysis enables beat-to-beat assessment of AV coupling and dynamical tracking of AV response during atrial arrhythmias, which may favor mechanistic insight about the genesis of ventricular rhythms and potentially the development of efficacious rate control strategies. [Copyright &y& Elsevier]

Background: The performance of the Reverse Mode Switch (RMS) algorithm, aimed at minimizing right ventricular pacing by operating in the AAI(R) mode with switch to the DDD(R) mode if atrioventricular (AV) conduction loss is detected, is not well known. Objective: To determine the appropriateness of the RMS episodes available from patient follow-up data at our center. Methods: Patients with the TELIGEN dual-chamber implantable cardioverter-defibrillator and the RMS algorithm activated were identified. The RMS episodes with available electrograms were analyzed and classified as appropriate (AV conduction loss) or inappropriate (non-AV conduction loss) events. Cumulative percentage of ventricular pacing and amount of premature ventricular complexes (PVCs) were recorded. Results: Of 21 patients, RMS episodes had occurred in 19 of them, with a mean of 527 episodes per month. Of the 172 RMS episodes available for analysis, 27 (16%) were classified as appropriate and 145 (84%) as inappropriate. Almost all (91%) inappropriate RMS episodes were due to PVC, and there was a positive correlation between the number of total RMS episodes per month and the number of PVCs per month (P < .0005). Considering patients with only inappropriate RMS episodes (n = 11), there was a positive correlation between the percentage of ventricular pacing and the number of RMS episodes per month (P < .05). Conclusions: A large majority of the RMS episodes available for analysis inappropriately triggered switch from the AAI(R) mode to the DDD(R) mode owing to PVCs. Patients with the RMS algorithm and elevated PVC burden are probably at risk of a high percentage of unnecessary right ventricular pacing. [Copyright &y& Elsevier]

Abstract: Introduction: Anaesthetised guinea pigs are commonly used within Safety Pharmacology to evaluate drug effects on cardiac electrophysiology. However, anesthesia compromises the ability to thermoregulate, which can be further challenged when more invasive surgery is required. As anaesthetised animals are often used when screening for cardiotoxicity, thereby influencing go/no–go decisions, we wanted to quantify the impact of small temperature changes on the recorded electrophysiological parameters. Methods: Male guinea pigs were anaesthetised by pentobarbital, placed on a pre-heated table and a rectal thermistor inserted for monitoring of body temperature. After intubation animals were vagotomised and β-blocked, and lead II ECG needle electrodes attached. Following thoracotomy an atrial pacing electrode was attached and a suction MAP electrode positioned on the ventricular epicardium. In control animals temperature was kept constant (38.1±0.1°C) over the duration of the experiment. Animals in one group were slowly warmed to 41.9°C by a heating plate and a heating lamp, and in another group slowly cooled to 34.4°C by turning off all heating equipment. MAP duration at 90% repolarisation (MAPD90), AV conduction, ECG and body temperature were recorded during cardiac pacing every 5min up to 50min. Results: No time-dependent changes were seen in the control group. In contrast, a linear correlation was found between changes in body temperature and MAPD90, AV conduction, QTc and QRS intervals. For each degree temperature fell below 38°C MAPD90 was prolonged by 6.1ms, and for each degree above 38°C MAPD90 was shortened by 5.3ms. Corresponding changes were seen for QTc interval and AV conduction time, while effects on the QRS interval were smaller. Discussion: The data highlights the importance of carefully controlling body temperature when performing electrophysiological recordings in laboratory animals. A change by a single degree can affect electrophysiological parameters by 5–10%, thus increasing the risk for a false positive or negative interpretation of cardiotoxicity. [Copyright &y& Elsevier]

Aims: To compare patients with atrial flutter (AFl) and 1:1 atrioventricular conduction (AVC) with patients with AFl and higher AVC. Methods: The characteristics of 19 patients with AFl and 1:1 AVC (group A) were compared with those of 116 consecutive patients with AFl and 2:1 AVC or higher degree AV block (group B). Results: Age, gender, and left ventricular function were similar in the two groups. In group A versus group B, more patients had no structural heart disease (42% vs 17%, P < 0.05) and syncope/presyncope (90% vs 12%, P < 0.05). The AFl cycle length (CL) in group A was longer than in group B (265 ± 24 ms vs 241 ± 26 ms, P < 0.01). The transition from AFl with 1:1 to 2:1 AVC or vice versa was associated with small but definite changes in AFl CL, which showed larger variations in response to sympathetic stimulation. In group A patients who were studied off drugs, the atrial-His interval was not different from group B, but maximal atrial pacing rate with 1:1 AVC was faster. In group A, five patients were misdiagnosed as ventricular tachyarrhythmias, and three with a defibrillator received inappropriate shocks. Four patients had ablation of AVC and six had ablation of AFl circuit. Conclusions: The main difference between groups A and B may be an inherent capacity of the AV node for faster conduction, especially in response to increased sympathetic tone. The latter affects not only AVC but also the AFl CL. One should be aware of the different presentations of AFl with 1:1 AVC to avoid misdiagnosis/mismanagement and to consider the diagnosis in patients with narrow or wide QRS tachycardia and rates above 220/min. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: While the dog in vivo model is commonly employed in the later phase of discovery for assessing drug-induced QT prolongation, an early screening assay is valuable when selecting compounds for further development and when compound availability usually is low. One such screening assay is the anaesthetised guinea pig monophasic action potential (MAP) model. The aim of the present study was to evaluate the ability of this model to detect proarrhythmic properties by testing a set of reference compounds with known clinical profile. Moreover, these results were compared to data previously obtained using in vivo canine QT assays (QT PRODACT study). Methods: Anaesthetised and ventilated male guinea pigs were vagotomised and pretreated with propranolol. After thoracotomy, a pacing electrode was clipped to the left atrial appendage and a suction MAP electrode positioned on the left ventricular epicardium. The drug or corresponding vehicle was injected intravenously in cumulative doses and MAP duration at 90% repolarisation (MAPD90) was recorded during cardiac pacing. Results: The 8 drugs known to be proarrhythmic in the clinic all displayed dose-dependent prolongation of MAPD90, while the 4 drugs devoid of dysrhythmia in man had no effect. When comparing doses producing a 10% MAPD90 increase with doses reported to increase QTc by 10% in dogs a strong correlation was seen (R2 0.94 and 0.58 for anaesthetised and conscious dogs, respectively). Discussion: The guinea pig MAP assay identified all clinically positive drugs while negative drugs were without effect on ventricular repolarisation. Furthermore, a good concurrence is shown between the guinea pig and dog models in identifying compounds with proarrhythmic properties. Overall, the study reinforces the anaesthetised guinea pig MAP model as a reliable assay predicting QT liability of new chemical entities and as a highly sensitive early screening model for cardiovascular risk. [Copyright &y& Elsevier]

Abstract: Aim: To provide tools for predicting the course of AV conduction disturbances after ethanol-induced septal ablation (PTSMA) for hypertrophic obstructive cardiomyopathy (HOCM). Methods and Results: Based on a scoring system developed 1996–1998 and including parameters from baseline ECG, heart rate profile, severity of outflow obstruction (LVOTO), peri-interventional enzyme kinetics, and peri-interventional conduction problems, the risk of permanent AV block following PTSMA was assessed in 155 consecutive HOCM patients (pts.; mean age: 53±13 years) between 1999 and 2004. During PTSMA with 2.1±0.5 ml of ethanol, transient complete AV block occurred in 71 pts. (46%). Pts. were grouped into a low, intermediate, and high risk group for permanent conduction damage, and treated accordingly (early discharge from monitoring, prolonged monitoring, early DDD-PM implantation). Permanent pacing was necessary in 11 cases (7%), 0/116 of these (0%) in the low, 4/31 (13%) in the intermediate, and 7/8 (87%) in the high-risk group. While a new right bundle branch block was the most frequent ECG finding after PTSMA, a left bundle branch block at baseline was associated with 4 of the 11 DDD-PM implantations (p <0.0001). In-hospital mortality was 0%, short-term (3-months) follow up was complete. During follow-up, AV conduction recovered in 4 pts. (46%) with a DDD-PM. New onset AV blocks did not occur. Significant improvement of symptoms was reported by 141 pts. (91%). Conclusions: Catheter-based septal ablation is an effective non-surgical technique for reducing symptoms and outflow gradients in HOCM. The proposed scoring system appears to reliably discriminate pts. with a high risk for permanent PM dependency from those with stable AV conduction after PTSMA. Pts. with left bundle branch block at baseline should undergo DDD-PM implantation prior to ablation. [Copyright &y& Elsevier]

We propose a unified atrial fibrillation (AF)-ventricular pacing (VP) (AF-VP) model to demonstrate the effects of VP on the ventricular rhythm during atrial fibrillation AF. In this model, the AV junction (AVJ) is treated as a lumped structure characterized by refractoriness and automaticity. Bombarded by random AF impulses, the AVJ can also be invaded by the VP-induced retrograde wave. The model includes bidirectional conduction delays in the AVJ and ventricle. Both refractory period and conduction delay of the AVJ are dependent upon its recovery time. The electrotonic modulation by blocked impulses is also considered in the model. Our simulations show that, with proper parameter settings, the present model can account for most principal statistical properties of the RR intervals during AF. We further demonstrate that the AV conduction property and the ventricular rate in AF depend on both AF rate and the degree of electrotonic modulation in the AVJ. Finally, we show that multilevel interactions between AF and VP can generate various patterns of ventricular rhythm that are consistent with previous experimental observations. [ABSTRACT FROM AUTHOR]

Abstract: In cat, distinct populations of vagal preganglionic and postganglionic neurons selectively modulate heart rate, atrioventricular conduction and left ventricular contractility, respectively. Vagal preganglionic neurons to the heart originate in the ventrolateral part of nucleus ambiguus and project to postganglionic neurons in intracardiac ganglia, including the sinoatrial (SA), atrioventricular (AV) and cranioventricular (CV) ganglia, which selectively modulate heart rate, AV conduction and left ventricular contractility, respectively. These ganglia receive projections from separate populations of vagal preganglionic neurons. The neurochemical anatomy and synaptic interactions of afferent neurons which mediate central control of these preganglionic neurons is incompletely understood. Enkephalins cause bradycardia when microinjected into nucleus ambiguus. It is not known if this effect is mediated by direct synapses of enkephalinergic terminals upon vagal preganglionic neurons to the heart. The effects of opioids in nucleus ambiguus upon AV conduction and cardiac contractility have also not been studied. We have tested the hypothesis that enkephalinergic nerve terminals synapse upon vagal preganglionic neurons projecting to the SA, AV and CV ganglia. Electron microscopy was used combining retrograde labeling from the SA, AV or CV ganglion with immunocytochemistry for enkephalins in ventrolateral nucleus ambiguus. Eight percent of axodendritic synapses upon negative chronotropic, and 12% of axodendritic synapses upon negative dromotropic vagal preganglionic neurons were enkephalinergic. Enkephalinergic axodendritic synapses were also present upon negative inotropic vagal preganglionic neurons. Thus enkephalinergic terminals in ventrolateral nucleus ambiguus can modulate not only heart rate but also atrioventricular conduction and left ventricular contractility by directly synapsing upon cardioinhibitory vagal preganglionic neurons. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to demonstrate that adverse but reversible effects on AV conduction may be observed during cryoablation despite no evidence of deleterious effects evident during cryomapping.Background: Transcatheter cryoablation has recently been introduced for treatment of supraventricular tachycardia. Potential advantages compared with radiofrequency ablation include decreased risk of thromboembolism and perforation, less patient discomfort, more sharply demarcated lesions, and decreased risk of inadvertent damage to adjacent structures due to the ability to observe the electrophysiologic effects of lesion generation prior to permanent tissue damage. Occasionally, however, adverse electrophysiologic effects may be observed during cryoablation when prior cryomapping suggests a safe location.Methods: We reviewed the experience with our first 32 consecutive patients who underwent cryoablation for supraventricular tachycardia. Patients who experienced transient heart block during cryoablation following uneventful cryomapping were identified.Results: Five patients in whom cryomapping was performed with no evidence for deleterious effects on AV conduction were identified. However, application of cryoablation at these mapped sites resulted in transient complete heart block. This experience demonstrates that the cryolesion created during cryoablation may expand relative to that suggested by cryomapping.Conclusions: It is important to maintain vigilance in monitoring for AV nodal conduction abnormalities during cryoablation, even when cryomapping suggests a safe location for cryoablation. [ABSTRACT FROM AUTHOR]

AV conduction with atrial rate adaptive pacing (AAIR) during exercise was investigated in 43 patients (28 men, 15 female, mean age 68 ± 7 years) who were paced and medicated with antiarrhythmic drugs for the bradycardia tachycardia syndrome (BTS). Patients were included if they had no second- or third-degree AV block, no complete bundle branch or bifascicular block, and a PQ interval ≤ 240 ms during sinus rhythm at rest. The interval between the atrial spike and the following Q wave (SQ) was measured in the supine position at rest (R) with maximum AAI pacing rate (Fmax achieved below the Wencke-bach point (SQ-R-Fmax). Bicycle ergometry was performed using the Chronotropic Assessment Exercise Protocol, and AAI pacing rate was increased stepwise by programming load-adapted increments. Seven patients showed intrinsic rhythm during exercise. In those 36 patients who were atrially paced throughout ergometry (E), SQ was measured with 70 beats/min on the lowest CAEP stage (SQ-E-70) and with Fmax at maximum work load (SQ-E-Fmax). During exercise, no second-degree AV block was observed, but 28 of 36 patients (78%) showed a nonphysiological increase of the SQ interval, and the average SQ-E-Fmax significantly longer than SQ-E-70 (250 ± 31 versus 228 ± 32 ms, P < 0.01). There was only a weak correlation between SQ-R-Fmax and SQ-E-Fmax (f = 0.35824, P < 0.05). When Fmax obtained during exercise was kept during recovery, 14 patients (39%) developed a second-degree AV block between 15 and 240 seconds after ergometry, 8 patients within 90 seconds. Patients who had exhibited a P on T wave in the ECG with Fmax at the end of exercise (11 of 36 patients) were reevaluated by Doppler echocardiographv. Using the same exercise protocol and identical, load-adapted rate increments, only 3 of 11 patients showed premature mitral valve closure. It is concluded... [ABSTRACT FROM AUTHOR]

In 42 patients (26 men, 16 women; mean age 69 ± 10 years), who were paced and medicated with antiarrhythmic drugs for the bradycardia tachycardia syndrome, chronotropic response and AV conduction with rapid atrial pacing during exercise were studied. Patients were included if they had no second- or third-degree AV block, no complete bundle branch or bifascicular block, and a PQ interval ⩽ 240 ms during sinus rhythm at rest. The interval between the atrial spike and the following Q wave (SQ) was measured in the supine position at rest with an AAI pacing rate of 5 beats/min above the sinus rate (SQ-R+5), and at the end of exercise with 110 beats/min (SQ-E110). Bicycle ergometry was performed using the Chronotropic Assessment Exercise Protocol with the pacemakers being programmed to AAI with a fixed rate of 60 beats/min. Chronotropic incompetence was defined as peak exercise heart rate: (1) < 100 beats/min: (2) < 75% of the maximum predicted heart rate; or (3) the heart rate at half the maximum workload < 60 + 2 beats/min per mL O2/kg per minute (calculated O2 consumption). During exercise, one patient developed atrial fibrillation. Chronotropic incompetence was present in 71% (29/41) of the patients according to definition 2, and in 76% (31/41) according to definition 1 or 3. Ten out of 41 patients (24%) exhibited a second-degree AV block with atrial pacing at 110 beats/min at the end of exercise. Only 9 out of the remaining 31 patients (29%) showed a physiological adaptation of the SQ-E110, and 21 patients (68%) exhibited a paradoxical increase of the SQ interval with rapid atrial pacing at the end of exercise as compared to the SQ-R+5. These observations indicate that the pacing system to be used in most patients paced and medicated for the bradycardia tachycardia syndrome should be dual chamber, and the option of rate adaptation should be considered. [ABSTRACT FROM AUTHOR]

Cardiac and coronary vasodilator effects of pimobendan (UD-CG 115 BS) were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. Pimobendan was administered intra-arterially. In paced papillary muscle preparations, the drug increased the force of contraction in a dose-dependent manner. In SA node preparations, the drug produced an increase in sinus rate. When the drug was injected into the artery supplying the AV node, the drug produced a decrease in AV conduction time by accelerating AV nodal conduction in AV node preparations. In spontaneously beating papillary muscle preparations, the drug increased the rate of ventricular automaticity. No ventricular arrhythmias were produced by the drug. In all preparations, the drug increased (coronary) blood flow. The order of effectiveness of pimobendan on the above cardiovascular variables was as follows: ventricular muscle contraction ≫ coronary blood flow > SA nodal automaticity > AV nodal conduction > ventricular automaticity. The results indicate that pimobendan is relatively specific for force and its cardiovascular profile is very similar to those of phosphodiesterase inhibitors. Therefore, it is likely that this cardiovascular profile would be determined by its inhibitory action on phosphodiesterase. [ABSTRACT FROM AUTHOR]

The cardiac and coronary vasodilator effects of milrinone and amrinone were compared in isolated, blood-perfused papillary muscle and sinoatrial (SA) node and atrioventricular (AV) node preparations of dogs. Milrinone (0.3-100 nmol) and amrinone (0.01-3 µmol) were administered intraarterially. Both drugs increased the force of contraction of paced and unpaced papillary muscles and the rate of automaticity of the latter; they increased sinus rate and accelerated AV nodal conduction. However, both drugs were not homogeneously effective on cardiac variables but affected them in the following order: The force of contraction of the ventricular muscle > SA nodal automaticity ÷ AV nodal conduction>ventricular automaticity. In producing these cardiac effects, milrinone was 30-60 times more potent than amrinone. Both drugs increased (coronary) blood flow in all preparations. In this respect milrinone was about ten times more potent than amrinone. As a result, milrinone can be characterized as having almost equal cardiotonic and coronary vasodilatory effects, whereas amrinone is more coronary vasodilatory than cardiotonic. These differences in cardiovascular profile may contribute to their differential salutary mechanisms in the treatment of heart failure. Both drugs induced neither AV nodal tachycardia nor ventricular arrhythmia. [ABSTRACT FROM AUTHOR]

Introduction: Evidence from animal experiments indicates that the autonomic nervous system may influence the sinus (SA) and atrioventricular (AV) nodes differently. We investigated, therefore, whether there are spontaneous functional differences in the innervation of the SA and AV nodes in man. Methods and Results: This study was performed in 10 healthy males (ages 21 to 26 years) during strict bed rest from 10 pm to 6 am. Three ECG leads were digitized on-line. PR and PP intervals were determined on a beat-to-beat basis off-line using a correlation algorithm with an accuracy of ± 2 msec and were verified visually. During major body movements, there were sudden decreases in PP intervals of 36 to 827 msec (mean 335) for periods of 6 to 265 seconds (mean 24). During these phases of heart rate (HR) acceleration, PR intervals showed either concomitant shortening (9 to 30 msec), no change, or lengthening (6 to 25 msec). Furthermore, tonic changes in the PR interval occurred over 15-minute periods during which the range of PP intervals was constant. Additionally, recovery-adjusted PR interval (PR b2/RP) and cycle length were negatively correlated for some periods, which confirmed independent autonomic effects on SA node and AV node. Conclusion: Beat-to-beat measurement of PR intervals allows for evaluation of autonomic effects on the human AV node. The different patterns in PR intervals during sudden spontaneous increases in HR and the tonic changes in PR interval indicate that the autonomic inputs to the SA and AV nodes are, in principle, independent of each other. [ABSTRACT FROM AUTHOR]