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The cardiac conduction system was examined histologically in 13 canine cases of atrioventricular (AV) valve endocardiosis with third-degree AV block. In all cases, gross examination revealed marked thickening and distortion of the base of the central fibrous body (CFB) and varying degrees of endocardial thickening of the upper portion of the ventricular septum (VS) as well as marked thickening of the mitral and tricuspid valve leaflets due to myxomatous degeneration. Microscopically, the thickened and distorted CFB had encased or trapped, either partly or totally, the underlying penetrating and branching portions of the AV bundle. The myxomatous and/or fibrofatty tissue, which had proliferated at the base of the extensive CFB, protruded into or encroached on the AV bundle, causing severe (51-75%) to very severe (76% or more) reduction of the conduction fibres. The upper portions of the left and right bundle branches were involved in the endocardial thickening due to degenerative and fibrotic changes at the uppermost VS; however, both bundle branches were much less severely affected than the AV bundle, the degree of reduction of the conduction fibres ranging from mild (25% or less) to moderate (26-50%). These observations suggest that the sites most vulnerable to lesions in the AV conduction system are the penetrating and branching portions of the AV bundle, which would represent the anatomical basis for third-degree AV block in canine cases of AV valve endocardiosis., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Limited studies are available regarding the pathophysiological mechanism of acquired atrioventricular block (AVB). Matrix metalloproteinases (MMPs) and angiotensin-converting enzyme (ACE) have been implicated in the pathogenesis of arrhythmia. However, the relationship between these molecules and acquired AVB is still unclear. One hundred and two patients with documented acquired AVB and 100 controls were studied. Gene polymorphisms of the MMP1 and ACE encoding genes were screened by the gene sequencing method or polymerase chain reaction-fragment length polymorphism assay, followed by an association study. The frequencies of the MMP1 -1607 2G2G genotype and MMP1 -1607 2 G allele were significantly higher in the AVB group than that in the controls (OR = 1.933, P = 0.027 and OR = 1.684, P = 0.012, respectively). Consistently, the level of serum MMP1 was significantly greater in acquired AVB patients than that in controls (6568.9 ± 5748.6 pg/ml vs. 4730.5 ± 3377.1 pg/ml, P = 0.019). In addition, the MMP1 2G2G genotype showed a higher MMP-1 serum level than the other genotypes (1G1G/1G2G) (7048.1 ± 5683.0 pg/ml vs. 5072.4 ± 4267.6 pg/ml, P = 0.042). MMP1 1 G/2 G gene polymorphism may contribute to determining the disease susceptibility of acquired AVB by linking the MMP serum protein level.

Competing Interests: Competing interests: None declared.

Introduction: Immune Checkpoint Inhibitor (ICI) therapy is now a standard of care in numerous cancers with very promising results. Nevertheless, adverse events, and especially immune-related adverse events (irAEs) not reported during clinical trials, are emerging and can be life-threatening., Observation: We report here a teachable case of a 80 year-old man, of third-degree atrioventricular block consecutive to myocarditis associated with the administration of nivolumab (anti-PD1) monotherapy., Conclusion: Myocarditis occurring during ICI treatment is a rare but potentially lethal event. Daily serum troponin level seems to predict ICI-related myocarditis but interpretation could be difficult in the context of associated myositis. Echocardiography and cardiac MRI are also useful but can remain negative. Electrocardiogram is a cornerstone of myocarditis diagnosis. In case of cardiac involvement, continuous heart rhythm monitoring should be performed in addition to the administration of high-dose corticosteroids therapy and the cessation of ICI therapy. Add-on treatments should be discussed with a well-trained multidisciplinary team., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

The cardiac conduction system was examined histologically in 12 canine cases of lymphocytic myocarditis with complete atrioventricular (AV) block. Histological analysis showed active myocarditis characterized by intense infiltration of mononuclear cells, primarily lymphoid, associated with degeneration and necrosis of the adjacent cardiomyocytes. Additionally, there was healing or healed myocarditis manifested by disappearance of cardiomyocytes and replacement fibrosis. This destructive inflammatory process of lymphocytic myocarditis involved the whole of the AV conduction system, resulting in loss and deletion of the conduction fibres, as well as the myocardium of all chambers. Such total or subtotal destruction of the AV conduction system caused by the inflammatory changes was thought to have set the stage for blocking AV conduction of cardiac impulses, but the aetiology of the lymphocytic myocarditis was not elucidated., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Purpose: K v 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of K v 11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model., Experimental Approach: LUF7244 was tested in vitro for (a) increasing human I Kv11.1 and canine I Kr and (b) decreasing dofetilide-induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block., Key Results: LUF7244 (0.5-10 μM) concentration dependently increased I Kv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on I KIR2.1 , I Nav1.5 , I Ca-L , and I Ks , doubled I Kr , shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide-induced early afterdepolarizations. LUF7244 (2.5 mg·kg -1 ·15 min -1 ) in dogs with sinus rhythm was not proarrhythmic and shortened, non-significantly, repolarization parameters (QTc: -6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide-induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block., Conclusions and Implications: LUF7244 counteracted dofetilide-induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of K v 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

A 0.5 kg, 5-yr-old male bearded dragon ( Pogona vitticeps ) presented with a 2-mo history of lethargy, anorexia, and impaired locomotion. Upon physical examination, bradyarrhythmia (heart rate: 20 beats/min) and balance disorders were noted. Electrocardiography revealed a first-degree atrioventricular block (P-R interval: 360 ms). On echocardiography, all cardiac chambers were slightly above normal ranges. Complete blood count, blood biochemistry, and T4 were unremarkable except for mildly elevated aspartate aminotransferase. Adenovirus testing was negative by polymerase chain reaction. Following euthanasia, necropsy revealed marked thickening of the arterial trunks and histopathology confirmed multifocal atherosclerosis of efferent heart vessels, arteriosclerosis of cerebral arterioles, and multifocal spongiosis of brain tissue, more pronounced in the optic chiasma. Owing to its severity, atherosclerosis may have contributed to chronic arterial hypertension with damages to the heart, brain vessels, and brain tissue-optic chiasma., (Copyright 2019 by American Association of Zoo Veterinarians.)

Background: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life., Methods: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model., Results: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( I KACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of I KACh channel function by increasing the basal current, even in the absence of m 2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective I KACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish., Conclusions: The I KACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant I KACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective I KACh channel blocker. Thus, the I KACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the I KACh channel.

In patients with unexplained cardiomyopathy, electroanatomical mapping can identify abnormal tissue to target during electrophysiology-guided endomyocardial biopsy (EP-guided EMB). The objective of this study is to determine whether catheter ablation performed in the same setting as EP-guided EMB increases procedural risk. Sixty-seven patients (mean age 54.4 ± 13.8, 57% male) undergoing EP-guided EMB were included. Radiofrequency catheter ablation was performed in 17 patients (25%) for ventricular arrhythmias and in 2 (3%) for typical atrial flutter. Femoral arterial access was obtained in 90% ablation patients and 40% biopsy-only patients; vascular access complications were more common in the ablation group than in the EMB-only group (p = 0.02). There were no significant differences in rate of tricuspid regurgitation, thromboembolism, or pericardial effusion, whether procedural anticoagulation was used. In conclusion, catheter ablation and procedural anticoagulation can be combined with EP-guided EMB with an increased risk of vascular access complications, but no significant increase in intracardiac complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Atrioventricular (AV) block has been extensively studied. However, conduction inside the myocardium in patients with AV block has not been reported. In this study, we aimed to demonstrate the presence of intramyocardial block in patients with AV block. Five consecutive patients with spontaneous high-grade AV block and Torsades de pointes (TdP) were prospectively studied with standard United States Catheter Instruments (USCI) endocardial temporary catheter located at the right ventricle (RV) apex. The morphology of endocardial potentials observed in the basic QRS complexes as well as during episodes of TdP was studied. The electrogram (EGM) of the basic rhythm showed a sharp deflection of high amplitude preceded and/or followed by a smooth potential of low amplitude interpreted as far-field potentials in all patients. The sharp potential can be observed at the beginning, in the middle or at the end of the smooth potential. All these potentials were reproduced from beat to beat and were falling inside the QRS complex of the surface ECG. Therefore, these aspects are zones of electrically depressed or silent myocardium larger than the interelectrode distance of 12 mm. This situation is in agreement with recent genetic factors. In this study, we demonstrated for the first time that patients with spontaneous AV block also have trouble in ventricular activation located on the AV conduction system and inside the myocardium. It is then possible to speculate that the presence of diffuse non-conducting myocardium explains why most TdPs do not degenerate into ventricular fibrillation (VF) and generally stop spontaneously., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Progressive cardiac conduction disease (PCCD) is a common pediatric heart conduction disorder. It is an autosomal inheritance of rare mutations, which leads to familial cases of PCCD. In these cases, the His-Purkinje system's conductive capacity is progressively deranged, involving either right or left bundle branch block. Also, QRS complexes display widening is an important characteristic that culminates in complete AV block, syncope, and sudden death. Mutations in TRPM4 gene that encodes for transient receptor potential melastatin 4 have recently been reported to cause familial cases of PCCD and heart block. TRPM4 conducts a Ca2+-activated non-selective monovalent cationic current leading to a negative plasma membrane potential. TRPM4 channels let Na+ ion influx, causing membrane depolarization, whereas, at positive membrane potentials, TRPM4 channels repolarize the membrane by facilitating K+ ion efflux from the cell. TRPM4 protein contains many regulatory motifs that confer voltage dependence, ATP/ADP sensitivity, and Ca2+ responsiveness. Mutational studies revealed the significance of the two-calmodulin binding sites at the N-terminus of for Ca2+ dependent activation of this channel. Mutations that reduce deSUMOylation increase the steady-state levels of active TRPM4 channels on the membrane without alteration of its sensitivity to Ca2+ or ATP or its voltage dependence of activation. Increased TRPM4 function interferes with cardiac conduction and eventually contributes to heart block. Both gain and loss of function mutations of TRPM4 are implicated in the cardiac block. Currently, the major therapeutic management of cardiac block due to TRPM4 mutations is implantation of a pacemaker to reinstate normal current propagation through AV node.

Objective: To elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block., Patient: A long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33years. He then survived another 2.5years after the onset of paroxysmal AV block and pacemaker implantation., Methods and Results: His cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches., Conclusion: HS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Case Description: A 13-year-old neutered male Border Collie was presented with acute onset syncope, weakness and anorexia 10 months after transvenous pacemaker implantation. The patient was laterally recumbent, bradycardic (36 beats/min) and febrile (40.7°C) on presentation. An electrocardiogram (ECG) revealed recurrence of third-degree atrioventricular block with a ventricular escape rhythm. Fluoroscopy identified migration of the pacemaker tip through the apex of the right ventricle. Echocardiography failed to reveal any evidence of pericardial effusion or cardiac tamponade. Full postmortem was performed after euthanasia. The pacemaker lead had perforated the apex of the right ventricle and lodged in the right pleural space. Culture of blood (taken antemortem), pericardial sac, right ventricular wall (surrounding pacemaker lead), pacemaker lead tip and pericardial fluid revealed a pure growth of Moraxella phenylpyruvica., Conclusion: Bacteraemia associated with M. phenylpyruvica has never been reported in the dog, but sporadic cases are reported in humans. Infection could have resulted from either pre-existing myocarditis or opportunistic infection and bacteraemia post pacemaker implantation. Evaluation of the pacemaker function at regular intervals would allow early detection of poor pacemaker-to-myocardium contact, which would prompt further investigation of pacemaker lead abnormalities such as perforation., (© 2016 Australian Veterinary Association.)

Background: Atrioventricular block (AVB) is a conduction abnormality along the atrioventricular node that, depending on etiology, may lead to different outcomes., Objectives: To evaluate variations of intrinsic rhythm (IR) in dogs that underwent pacemaker implantation (PMI)., Animals: Medical records of 92 dogs affected by 3rd degree atrioventricular block (3AVB), advanced 2nd degree AVB (2AVB), paroxysmal 3AVB, 2:1 2AVB, or 3AVB with atrial fibrillation (AF) were retrospectively reviewed., Method: The patient IR was documented with telemetry on the day of 1--(95% CI, 1-2), 33--(95% CI, 28-35), 105--(95%CI, 98-156), and 275 days (95%CI, 221-380) after PMI. According to AVB grade at different examinations, AVB was defined as progressed, regressed, or unchanged., Results: In 48 dogs, 3AVB remained unchanged, whereas in 7 it regressed. Eight cases of 2AVB progressed, 3 regressed and 2 remained unchanged. Eight cases of paroxysmal 3AVB progressed and 3 remained unchanged. Four dogs affected by 2:1 2AVB progressed, 2 regressed, and 1 remained unchanged. All cases with 3AVB with AF remained unchanged. Regression occurred within 30 days after PMI, whereas progression was documented at any time. Variations in IR were associated with type of AVB (P < .03) and time of follow-up (P < .0001)., Conclusions and Clinical Importance: The degree of AVB assessed at the time of PMI should not be considered definitive because more than one-third of the cases in this study either progressed or regressed. Additional studies would be necessary to elucidate possible causes for transient AVB in dogs., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Temporary atrioventricular (AV) conduction disturbances are a common complication following cardiac surgery, especially involving the aortic valve. Permanent complete AV block is a serious and rare complication. Its prevalence has been estimated at 3-6% of all patients undergoing aortic valve replacement. Identification of factors that affect the occurrence of complete AV block requiring permanent pacemaker implantation might help reduce the risk of this problem in the future., Aim: To evaluate clinical, anatomical and surgical factors that might affect occurrence of complete AV, resulting in the need for permanent pacemaker implantation., Methods: In our prospective study, we analysed clinical data of consecutive 159 patients operated due to isolated aortic valve disease between February 2011 and March 2012. Patients with a pacemaker implanted before that time were excluded from the study. The main indication for surgery was aortic stenosis (n = 114, 71.7%). Infectious endocarditis was an indication in 6 (3.8%) cases. Mean patient age was 65.3 ± 11.4 years, and the proportion of males to females was 56.6%/43.4%. Overall, 135 (84.9%) patients had sinus rhythm preoperatively. All operations were performed using median sternotomy, cardiopulmonary bypass, and hypothermia at 30-32°C. A biological prosthesis was implanted in 120 (70.4%) patients. Patients who needed an additional procedure such as another valve surgery, aortic surgery or coronary artery bypass grafting were excluded from the study., Results: Permanent pacemaker implantation was required in 11 (6.9%) patients. The pacemaker was implanted after at least 7 days of complete AV block which was then considered permanent. Univariate analysis showed that permanent pacemaker implantation was associated with prolonged cardiopulmonary bypass time, prolonged aortic cross-clamp time, and the occurrence of electrolyte disturbances. Univariate logistic regression revealed that the need for permanent pacemaker implantation depended on 5 factors including prolonged cardiopulmonary bypass time, prolonged aortic cross-clamp time, larger size of the implanted valve prosthesis, endocarditis as the indication for surgery, and electrolyte disturbances. In both backward and forward stepwise multivariate regression models, two parameters, prolonged aortic cross-clamp time and the presence of electrolyte disturbances, correlated with the occurrence of complete AV block., Conclusions: Permanent complete AV block is a serious complication after aortic valve surgery. Of all analysed clinical, anatomical and surgical factors, prolonged cardiopulmonary bypass time, prolonged aortic cross-clamp time, larger size of the implanted valve prosthesis, endocarditis as the indication for surgery, and electrolyte disturbances were found to be statistically significant predictors of permanent pacemaker implantation.

An asymptomatic 40-year-old woman with a first-degree atrioventricular block presented a right atrial mass in transthoracic echocardiograms. Transesophageal echocardiograms showed abnormally thickened tissue on the interatrial septum, which extended around the aortic annulus. Multimodality examinations demonstrated lesions in the heart, lungs, liver, and spleen, suggesting sarcoidosis. She was diagnosed with cardiac sarcoidosis after we detected granulomas in a lung specimen. A right atrial mass shrunk following steroid therapy. We should therefore consider the possibility of cardiac sarcoidosis when we see wall thickening and a mass echo in the atrium. These signs may point to an early-phase lesion of cardiac sarcoidosis.

Background: Congenital atrioventricular block is a well-established immunologic complication of maternal systemic lupus erythematosus. We sought to further characterize the electrophysiological manifestations of maternal systemic lupus erythematosus on neonatal atria., Methods and Results: Cases of isolated congenital atrioventricular block treated at our center over the past 41 years were identified. Data were extracted from clinical charts, pacemaker interrogations, ECGs, echocardiograms, and histopathological reports, when available. Of 31 patients with isolated congenital atrioventricular block, 18 were negative for maternal antibodies and had normal epicardial atrial sensing and pacing thresholds. In contrast, 12 of 13 patients with positive maternal antibodies had epicardial pacemakers, 5 (42%) of whom had left atrial (LA) inexcitability and/or atrial conduction delay. In 3 patients, the LA could not be captured despite high-output pacing. The fourth patient had acutely successful LA appendage and left ventricular lead placement. At early follow-up, an increased delay between the surface P-wave and intracardiac atrial depolarization was observed, indicative of atrial conduction delay. The fifth patient exhibited LA lead dysfunction, with atrial under-sensing and an increased capture threshold, 2 weeks after implantation. Biopsies of LA appendages performed in 2 patients showed no evidence of atrial fibrosis or loss of atrial myocytes., Conclusions: Herein, we report previously undescribed yet prevalent electrophysiological ramifications of maternal systemic lupus erythematosus, which extend beyond congenital atrioventricular block to encompass alterations in LA conduction, including LA inexcitability. These manifestations can complicate epicardial pacemaker implantation in newborns. In the absence of histological evidence of extensive atrial fibrosis, immune-mediated functional impairment of electrical activity is suspected., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Cardiac electrical conduction delays and blocks cause rhythm disturbances such as complete heart block, which can be fatal. Standard of care relies on electronic devices to artificially restore synchrony. We sought to create a new modality for treating these disorders by engineering electrical conduction tracts designed to propagate electrical impulses., Objectives: This study sought to create a new approach for treating cardiac conduction disorders by using engineered electrical conduction tracts (EECTs)., Methods: Paramagnetic beads were conjugated with an antibody to gamma-sarcoglycan, a cardiomyocyte cell surface antigen, and mixed with freshly isolated neonatal rat ventricular cardiomyocytes. A magnetic field was used to pattern a linear EECT., Results: In an in vitro model of conduction block, the EECT was patterned so that it connected 2 independently beating neonatal rat ventricular cardiomyocyte monolayers; it achieved coordinated electrical activity, with action potentials propagating from 1 region to the other via EECT. Spiking the EECT with heart-derived stromal cells yielded stable structures with highly reproducible conduction velocities. Transplantation of EECTs in vivo restored atrioventricular conduction in a rat model of complete heart block., Conclusions: An EECT can re-establish electrical conduction in the heart. This novel approach could, in principle, be used not only to treat cardiac arrhythmias but also to repair other organs., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Primary cardiac lymphoma is very rare, and usually manifests after the fifth decade of life. The lack of typical manifestations makes it difficult to diagnose at an early stage that can be discovered only by echocardiography. The location of the tumour often results in cardiac compromise, which prevents the delivery of potentially curative therapies. Clinical presentations may depend on flow obstruction, infiltration of adjacent tissues, tumour embolisation, and atrioventricular (AV) disturbances. We report a rare case of primary cardiac lymphoma that presented with clinical signs of shock from two distinct mechanisms. The first mechanism was intermittent complete AV block that was caused by disruption of the electrical conduction system from tumour infiltration in addition to direct mechanical compression of the atrioventricular node by the tumour. The second mechanism, subtotal RV inflow obstruction from the bulky mass contributed to compromising venous return, which played a major role of refractory shock in this case., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background:  Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation., Methods and Results:  Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents., Conclusions:  The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.

Background: Dynamic left ventricular outflow tract obstruction with or without mitral regurgitation is typically observed in hypertrophic cardiomyopathy, but is also occasionally seen without left ventricular hypertrophy. In this report, we present a case of cardiogenic shock that mimics ST-elevation myocardial infarction, due to dynamic left ventricular outflow tract obstruction with transient mitral regurgitation and myocardial bridging after transient complete atrioventricular block., Case Presentation: A 65-year-old man with hypertension presented himself at the emergency department with syncope after chest pain. His initial electrocardiography showed inferior ST elevation with profound precordial ST depression and transient complete atrioventricular block. Due to sustained hypotension, an intra-aortic balloon pump was applied. His coronary angiography revealed almost normal right coronary artery and left circumflex artery and only a severe myocardial bridge in the mid-segment of his left anterior descending artery. Instead, severe mitral regurgitation was found without regional wall motion abnormality both in the left ventriculography and the portable echocardiography. However the severe mitral regurgitation completely disappeared in follow up echocardiography the day after. The pressure gradient across the left ventricular outflow tract was measured at 8.95 mmHg during the resting state, and was increased to 38.95 mmHg during the Valsalva state., Conclusions: The patient presented with a case of cardiogenic shock that mimicked ST-elevation myocardial infarction due to dynamic left ventricular outflow tract obstruction combined with myocardial bridging in the mid-left anterior descending artery.

Background: We evaluated the effects of the site of ventricular pacing on left ventricular (LV) synchrony and function in children requiring permanent pacing., Methods and Results: One hundred seventy-eight children (aged <18 years) from 21 centers with atrioventricular block and a structurally normal heart undergoing permanent pacing were studied cross-sectionally. Median age at evaluation was 11.2 (interquartile range, 6.3-15.0) years. Median pacing duration was 5.4 (interquartile range, 3.1-8.8) years. Pacing sites were the free wall of the right ventricular (RV) outflow tract (n=8), lateral RV (n=44), RV apex (n=61), RV septum (n=29), LV apex (n=12), LV midlateral wall (n=17), and LV base (n=7). LV synchrony, pump function, and contraction efficiency were significantly affected by pacing site and were superior in children paced at the LV apex/LV midlateral wall. LV dyssynchrony correlated inversely with LV ejection fraction (R=0.80, P=0.031). Pacing from the RV outflow tract/lateral RV predicted significantly decreased LV function (LV ejection fraction <45%; odds ratio, 10.72; confidence interval, 2.07-55.60; P=0.005), whereas LV apex/LV midlateral wall pacing was associated with preserved LV function (LV ejection fraction ≥55%; odds ratio, 8.26; confidence interval, 1.46-47.62; P=0.018). Presence of maternal autoantibodies, gender, age at implantation, duration of pacing, DDD mode, and QRS duration had no significant impact on LV ejection fraction., Conclusions: The site of ventricular pacing has a major impact on LV mechanical synchrony, efficiency, and pump function in children who require lifelong pacing. Of the sites studied, LV apex/LV midlateral wall pacing has the greatest potential to prevent pacing-induced reduction of cardiac pump function.

Defects in the desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by sarcoplasmic accumulation of desmin-positive deposits and electron dense granulofilamentous aggregates. We describe a desminopathy family with unusual clinical features of complete atrioventricular block and mild myopathy. The atrioventricular block can be found in each of the affected members sparing of the detectable cardiac structural abnormalities through echocardiogram. A novel heterozygous deletion-insertion mutation (c.1045-1063 del/G ins), deleting 7 amino acid (Met349-Arg355) and inserting 1 amino acid (Gly349) in a highly conserved alpha-helical 2B domain of desmin, has been identified. The results of this study indicate that atrioventricular conduction block without cardiac structural abnormalities may be an intrinsic feature of disease associated with specific desmin mutation. Furthermore atrioventricular conduction block may be an exclusive clinical manifestation and a major cause of disability and death in some patients with desmiopathy.

Pharmacological ion-channel blockers were used to investigate the spontaneous heart rates in Pacific hagfish, Eptatretus stoutii. Zatebradine, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, vastly reduced atrial and ventricular contraction rates in a similar concentration-dependent manner, indicating a major role for HCN in setting intrinsic heart rate. When voltage-gated Na(+) channels were blocked with tetrodotoxin (TTX), atrial contraction rate declined in a dose-dependent manner, but remained faster than ventricular rate even at very high TTX concentrations. This TTX resistance compared with other fish suggests an important role for a TTX-sensitive inactivation-resistant Na(+) current in atrioventricular conduction and chamber synchrony, and a lesser role in setting intrinsic heart rate. T and L-type calcium channel blockers, nickel and nifedipine respectively, also reduced atrial and ventricular contraction rates, nickel having a larger effect on the atrium. These novel results for hagfish are consistent with intrinsic atrial and ventricular rates being set mostly by HCN, with lesser contributions from other ion channels. We suggest that future electrophysiological studies will reveal that hagfishes, with their ancestral position in the evolution of the vertebrate-type chambered heart, share some but not all features of vertebrate intrinsic heart rate control., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Primary cardiac lymphoma (PCL) is very rare, and is extremely challenging to diagnose due to nonspecific symptoms. When discovered, the right atrium and ventricle are most commonly affected, while diffuse cardiac involvement is uncommon. PCL is fatal unless promptly diagnosed and treated. Herein, we present the case of a 36-year-old immunocompetent male who presented with a 5-year history of non-specific chest symptoms and was diagnosed with primary diffuse cardiac large B-cell lymphoma involving the entire heart.

TBX3 is critical for human development: mutations in TBX3 cause congenital anomalies in patients with ulnar-mammary syndrome. Data from mice and humans suggest multiple roles for Tbx3 in development and function of the cardiac conduction system. The mechanisms underlying the functional development, maturation, and maintenance of the conduction system are not well understood. We tested the requirements for Tbx3 in these processes. We generated a unique series of Tbx3 hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of Tbx3 function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving Tbx3 mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of Tbx3 in adults reveal its requirement for conduction system homeostasis. Arrhythmias in Tbx3-deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner. TBX3 and its regulatory targets merit investigation as candidates for human arrhythmias.

Generally, restrictive cardiomyopathy due to desmin deposition is characterized by restriction to ventricular diastolic filling and different degrees of atrioventricular block (AVB). In this report, we describe the pathological changes of the cardiac conduction system related to AVB. The sinus node, the compact node, and the penetrating bundle (bundle of His) had no abnormalities, however, there was extensive fibrosis of the terminal portions of the branching bundle and the beginning of the left and right bundles at the top of the ventricular septum. The pathogenesis of this fibrous replacement is probably the same that leads to extensive fibrosis of the working ventricular myocardium, and remains to be elucidated.

Numerous studies have revealed that Rap1 (Ras-proximate-1 or Ras-related protein 1), a small GTPase protein, plays a crucial role in mediating cAMP signaling in isolated cardiac tissues and cell lines. However, the involvement of Rap1 in the cardiac development in vivo is largely unknown. By injecting anti-sense morpholino oligonucleotides to knock down Rap1a and Rap1b in zebrafish embryos, and in combination with time-lapsed imaging, in situ hybridization, immunohistochemistry and transmission electron microscope techniques, we seek to understand the role of Rap1 in cardiac development and functions. At an optimized low dose of mixed rap1a and rap1b morpholino oligonucleotides, the heart developed essentially normally until cardiac contraction occurred. Morphant hearts showed the myocardium defect phenotypes, most likely due to disrupted myofibril assembly and alignment. In vivo heart electrocardiography revealed prolonged P-R interval and QRS duration, consistent with an adherens junction defect and reduced Connexons in cardiac myocytes of morphants. We conclude that a proper level of Rap1 is crucial for heart morphogenesis and function, and suggest that Rap1 and/or their downstream factor genes are potential candidates for genetic screening for human heart diseases.

The novel antiarrhythmic drug K201 (4-[3-{1-(4-benzyl)piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride) is currently in development for treatment of atrial fibrillation. K201 not only controls intracellular calcium release by the ryanodine receptors, but also possesses a ventricular action that might predispose to torsade de pointes arrhythmias. The anti- and proarrhythmic effects of K201 were investigated in the anesthetized canine chronic atrioventricular block model. Two doses of K201 (0.1 and 0.3mg/kg/2 min followed by 0.01 and 0.03 mg/kg/30 min i.v.) were tested in 4 serial experiments in dogs with normally conducted sinus rhythm (n=10) and in torsade de pointes-susceptible dogs with chronic atrioventricular block. Susceptibility was assessed with dofetilide (0.025 mg/kg/5 min i.v.). Beat-to-beat variability of repolarization was quantified as short-term variability of left ventricular monophasic action potential duration. In dogs with normally conducted sinus rhythm, both doses of K201 prolonged ventricular repolarization whereas only the higher dose prolonged atrial repolarization. At chronic atrioventricular block, dofetilide induced torsade de pointes in 9 of 10 dogs. K201 did neither suppress nor prevent dofetilide-induced torsade de pointes. K201 dose-dependently prolonged ventricular repolarization. In contrary to the lower dose, the higher dose did increase beat-to-beat variability of repolarization (from 1.2 ± 0.3 to 2.9 ± 0.8 ms, P<0.05) and resulted in spontaneous, repetitive torsade de pointes arrhythmias in 1 of 7 dogs; Programmed electrical stimulation resulted in torsade de pointes in 2 more dogs. In conclusion, both doses of K201 showed a class III effect. No relevant antiarrhythmic effects against dofetilide-induced torsade de pointes were seen. Only at the higher dose a proarrhythmic signal was observed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to investigate the incidence and type of ECG changes in patients with leptospirosis regardless of clinical evidence of cardiac involvement., Material/methods: A total of 97 patients with serologically confirmed leptospirosis treated at the University Hospital for Infectious Diseases "Dr. Fran Mihaljević" in Zagreb, Croatia, were included in this retrospective study. A 12-lead resting ECG was routinely performed in the first 2 days after hospital admission. Thorough past and current medical history was obtained, and careful physical examination and laboratory tests were performed., Results: Abnormal ECG findings were found in 56 of 97 (58%) patients. Patients with abnormal ECG had significantly elevated values of bilirubin and alanine aminotransferase, lower values of potassium and lower number of platelets, as well as more frequently recorded abnormal chest x-ray. Non-specific ventricular repolarization disturbances were the most common abnormal ECG finding. Other recorded ECG abnormalities were sinus tachycardia, right branch conduction disturbances, low voltage of the QRS complex in standard limb leads, supraventricular and ventricular extrasystoles, intraventricular conduction disturbances, atrioventricular block first-degree and atrial fibrillation. Myopericarditis was identified in 4 patients. Regardless of ECG changes, the most commonly detected infection was with Leptospira interrogans serovar Australis, Leptospira interrogans serovar Saxkoebing and Leptospira kirschneri serovar Grippotyphosa., Conclusions: The ECG abnormalities are common at the beginning of disease and are possibly caused by the direct effect of leptospires or are the non-specific result of a febrile infection and metabolic and electrolyte abnormalities. New studies are required for better understanding of the mechanism of ECG alterations in leptospirosis.

Using 24-h ambulatory electrocardiography, the RR intervals of all beats were determined in a West Highland white terrier with sick sinus syndrome characterized by long sinus pauses, bradycardia, supraventricular tachycardia (SVT) and varying degrees of atrioventricular (AV) heart block. Distinctive patterns of bradycardia and 1:1, 2:1, 3:1, 4:1 and 5:1 AV block associated with SVT were evident in the tachogram (RR interval distribution over time) and Poincaré plots (short-term heart rate variability plots of RRn versus RRn+1). These patterns differed from those of abrupt alteration in cycle length during long sinus pauses or bursts of supraventricular tachycardia. Recognition of such patterns may direct attention to time points for which close attention to the cardiac rhythm should be evaluated in the full-disclosure of the 24-h ECG recording., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A 1 year old intact female Labrador retriever dog presented for evaluation of syncope caused by severe bradycardia. Advanced atrioventricular block was diagnosed. A mass infiltrating the interventricular septum and the tricuspid annulus was identified with echocardiography. Histopathological evaluation of the mass was consistent with cardiac leiomyoma, and immunohistochemical staining for smooth muscle actin confirmed the diagnosis. To the authors' knowledge, this is the first report of cardiac leiomyoma in the canine species., (Copyright © 2011 Elsevier B.V. All rights reserved.)

'Neonatal' lupus erythematosus (NLE) describes a clinical spectrum of cardiac and non-cardiac abnormalities observed in neonates and foetuses whose mothers have the auto-antibodies anti-SSA/Ro (anti-Ro) and anti-SSB/La (anti-La). Of the cardiac abnormalities, congenital AVB is the most common cardiovascular abnormality found in affected foetuses and infants. Many other cardiovascular manifestations of NLE have been more recently recognized including atrial and ventricular arrhythmias and other conduction abnormalities, myocarditis, cardiomyopathy often with endocardiofibroelastosis and structural heart disease, particularly valvar lesions. In this report, the spectrum of cardiovascular manifestations observed in foetuses and infants with NLE are reviewed and the pathogenesis, diagnosis and clinical outcomes are briefly discussed.

Background: Previous studies of patients with long QT syndrome (LQTS) and 2:1 atrioventricular block (AVB) have reported a mortality rate greater than 50% during infancy., Objective: The purpose of this study was to determine the outcome of this high-risk population in the current era., Methods: A retrospective study from four tertiary care pediatric centers assessed patients with congenital LQTS and 2:1 AVB from January 2000 to January 2009. All neonates who presented with 2:1 AVB and prolonged QTc unrelated to medication were included in the study. Statistical analysis was performed using a paired t-test. Medical records were reviewed for ECG findings, genotype, medications, and device therapy., Results: Twelve patients that met the inclusion criteria were identified. All patients underwent diagnostic ECG in the first 24 hours of life. The average QTc interval prior to therapy was 616 +/- 99 ms (range 531-840 ms). Over a follow-up period of 71 +/- 45 months (range 15-158 months), 11 of 12 patients received devices (8 permanent pacemaker, 3 implantable cardioverter-defibrillator). Average age of device placement was 48 months (median 2 months, range 3 days to 10.5 years). All patients were treated with beta-blockers; mexiletine was added in three patients, and mexiletine and flecainide were added in one patient. Three (25%) patients experienced torsades de pointes while receiving beta-blockers, one of which was refractory to medical therapy. This patient underwent left cardiac sympathetic denervation and implantable cardioverter-defibrillator placement. Genotyping was available for 6 (50%) patients (2 SCN5A mutation, 4 KCNH2 mutation). At last follow-up, no mortality was observed. Follow-up QTc intervals had decreased (mean 480 +/- 20 ms, range 450-507 ms, P <.002)., Conclusion: Management of patients with LQTS and 2:1 AVB presents unique challenges. Despite historical data indicating poor prognosis, our study represents a cohort of high-risk LQTS patients with a relatively optimistic outcome. This finding reflects early diagnosis and intervention, coupled with improved management strategies, in the current era., (Copyright (c) 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Seizure-induced syncope is uncommon and is usually due to peri-ictal bradycardia and asystole. In contrast, peri-ictal atrioventricular conduction block (AV block) has been reported only rarely. Here, we review the literature on peri-ictal AV block and describe a patient with recurrent episodes of epigastric auras that were occasionally followed by a sensation of dizziness and syncope because of transient third-degree AV block. After installation of a cardiac pacemaker, epigastric auras persisted, whereas the sensation of dizziness and syncope stopped. MRI revealed a lesion in the left insula, leading to the notion that recurrent syncope was most likely due to ictal activity in central autonomic networks.

We describe the case of a 47-year-old man presenting with inferior acute myocardial infarction complicated by complete atrioventricular block and cardiogenic shock, who underwent primary angioplasty and rheolytic thrombectomy with AngioJet and subsequent evaluation by optical coherence tomography. Optical coherence tomography is a rather novel technique in the management of coronary disease, and as far as we know, this is the first report about optical coherence tomography imaging after AngioJet thrombectomy. Moreover, we provide a brief discussion on advantages and disadvantages of this imaging modality on the basis of current practice.

The incidence of arrhythmias after acute myocardial infarction of the inferior wall varies with the affected segment and increases when there is right ventricular involvement. This paper provides a clear review of the blood supply to the conduction system and gives an anatomic explanation of that supply.We dissected 20 human hearts after anterograde and retrograde injection of latex. In every heart, we dissected the conduction system and its blood supply. Retrograde perfusion enabled proper injection of the atrial vessels that originate at the beginning of the coronary trunks.We describe the 4 main arteries that supply blood to the conduction system. The classic concept included the atrioventricular node artery and the 1st septal artery. To that we add Kugel's artery and the right superior descending artery.The incidence of arrhythmias after acute myocardial infarction of the inferior wall is greater when the occlusion of the coronary trunk is at or near the origin. This is due to the existence of the right superior descending artery, which is given off by the right coronary trunk less than 1 cm from the origin. The arrhythmias caused by the occlusion of the circumflex artery are due to the existence of Kugel's artery, which displays a peculiar anastomotic pattern.

A 79-year-old woman with systemic sclerosis was admitted to our hospital because of syncope. On admission, electrocardiogram showed progression of intraventricular conduction defect. Chest radiograph showed marked cardiomegaly. Echocardiogram revealed deterioration of left ventricular systolic function. We suspected progressive myocardial disease with Stokes-Adams attack. When we were preparing a temporary pacemaker, paroxysmal atrioventricular block with asystole for 15 seconds and convulsion occurred. Electrophysiological study showed His-ventricular block and sinus node dysfunction. A permanent pacemaker was implanted. In systemic sclerosis, progression of ventricular conduction defect may warrant prompt electrophysiological study and prophylactic pacemaker implantation.

We hypothesized that a nonviral gene delivery of the hyperpolarization-activated HCN2 channel combined with the beta(2)-adrenergic receptor (ADRB2) would generate a functional pacemaker in a mouse model of complete atrioventricular block (CAVB) induced by radiofrequency ablation of the His bundle. Plasmids encoding HCN2 and ADRB2 mixed with tetronic 304, a poloxamine block copolymer, were injected in the left ventricular free wall (HCN2-ADRB2 mice). Sham mice received a noncoding plasmid. CAVB was induced 5 days later. Ventricular escape rhythms in HCN2-ADRB2 mice were significantly faster than in sham mice at day 15 after ablation and later. In HCN2-ADRB2 mice, QRS complexes were larger than in sham mice and characterized by abnormal axes. Immunostaining of GFP-HCN2 fusion protein showed an expression of HCN2 channel in left ventricular myocardium for at least 45 days after injection. In the mouse, CAVB induces progressive hypertrophy and heart failure leading to 50% mortality after 110 days. HCN2-ADRB2 mice survived 3 weeks longer than sham mice. Finally, beta-adrenergic input increased ventricular escape rhythms significantly more in HCN2-ADRB2 mice than in sham mice. In conclusion, nonviral gene transfer can produce a functional cardiac biological pacemaker regulated by sympathetic input, which improves life expectancy in a mouse model of CAVB.

Electrophysiological properties of the pulmonary vein myocardium were assessed in a canine chronic atrioventricular block model resulting in left atrial volume overload. Five chronic atrioventricular block dogs and five sham-operated dogs were used. The heart was removed two months after a surgical procedure causing atrioventricular block, when atrial structural remodeling was established. Standard microelectrode penetrations were made with glass microelectrodes to obtain action potential signals of left atrium and pulmonary vein myocardia. The resting membrane potential in the pulmonary vein was more positive than that in the left atrium (-69 mV vs -74 mV) in both animal groups. The action potential duration at 50% repolarization of the pulmonary vein was shorter in the chronic atrioventricular block dogs than in the sham-operated dogs (38 ms vs 63 ms), whereas no significant difference was detected in the action potential duration of the left atrium between the two animal groups (67 ms vs 61 ms). The action potential duration of the pulmonary vein in the chronic atrioventricular block dogs was prolonged by charybdotoxin but not by iberiotoxin. Such prolongation was not observed in the normal pulmonary vein. These results suggest that long-term left atrial dilatation shortened the action potential duration of pulmonary vein myocardium, which may be associated with activation of the intermediate conductance Ca2+-activated K+ channel (IK channel).