Normal Cardiac Conduction Research Articles

Abstract Mo061: The major voltage-gated sodium channel accessory subunit in working ventricular myocytes may be β1B, not β1

Voltage-gated sodium channels, crucial for the action potential upstroke in cardiomyocytes, consist primarily of a single pore-forming α-subunit and 1 or 2 accessory β-subunits. SCN1B encodes two variants: β1, a transmembrane cell adhesion molecule, and β1B, typically described as a soluble secreted protein. While β1 and β1B share identical sequences in the amino-terminal (NT) extracellular Ig domain, they differ in their carboxy-terminal (CT) sequence. The Ig domain of β1/β1B has been deemed critical in maintaining normal cardiac conduction by various groups. Traditionally, effects on cardiac conduction have been attributed to β1, despite difficulties in detecting it at the protein level in the heart. We hypothesized that β1B, rather than β1, plays a significant role in electrical activity propagation in the heart. Utilizing an NT antibody (detects both variants), a β1-specific CT antibody, and a custom β1B-specific CT antibody, we examined SCN1B gene product profiles in various cardiac cell types, including neonatal rat ventricular myocytes and fibroblasts (NRVMs and NFs), isolated adult mouse cardiomyocytes (MCMs), and tissue slices from isolated adult rat hearts. The β1-specific CT antibody failed to label any bands in Western Blots (WB) of these cells and tissues, whereas the NT antibody detected a 37 kD band in all cell types and showed high levels of localization at cell-cell contacts using immunofluorescence (IF) with NRVMs. Conversely, the CT antibody showed minimal immunolabeling evidence. Moreover, an inhibitor of β1 Regulated Intramembrane Proteolysis failed to generate the expected 19 kD fragment if β1 were present in NRVMs. In adult rat hearts, the NT antibody labeled intercalated discs, while the CT showed minimal signal. Conversely, in WBs of NRVMs using our custom β1B antibody, we observed a 37 kD band consistent with the presence of β1B, and in heart sections, we found labeling of intercalated discs. These findings suggest that the major β subunit in working ventricular myocytes may be β1B, not β1. Further investigation is warranted, as these results could significantly impact our understanding of the roles and functional effects of β1 and β1B on cardiac conduction.

Hippo Signaling: Advances in Potential Therapeutic Targets for Sinoatrial Node Disorders

Review Hippo Signaling: Advances in Potential Therapeutic Targets for Sinoatrial Node Disorders Julianna N. Quinn 1,2, and Jun Wang 1,2, * 1 Department of Pediatrics, McGovern Medical School at UTHealth, The University of Texas Health Science Center at HoustonHoustonTX77030USA 2 McGovern Medical School at UTHealth, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas Health Science Center at HoustonHoustonTX77030USA * Correspondence: jun.wang@uth.tmc.edu Received: 16 June 2023 Accepted: 31 July 2023 Published: 27 December 2023 Abstract: The cardiac conduction system (CCS) propagates electrical impulses, generates cardiac contractions, and ultimately ensures regular heartbeats. Disruptions within the CCS lead to cardiac arrhythmias, which are known to be the leading cause of cardiac-related mortalities in humans. The sinoatrial node (SAN) is a key component of the CCS and functions as the natural cardiac pacemaker to initiate normal cardiac impulse and conduction. The SAN is characterized by significant heterogeneity and contains various cell types, including pacemaker cells that spontaneously generate action potentials to maintain a constant beating rhythm. The fundamental Hippo signaling pathway plays a key role in heart development and regeneration. Recently, the Hippo signaling pathway is indicated as a critical pathway for maintaining SAN homeostasis, suggesting therapeutic targets for SAN disorders. This mini-review focuses on the recent molecular and mechanistic findings of Hippo’s involvement in regulating SAN homeostasis and discusses potential new therapeutic targets for SAN pathologies.

Emerging Technologies in Cardiac Pacing.

Cardiac pacing to treat bradyarrhythmias has evolved in recent decades. Recognition that a substantial proportion of pacemaker-dependent patients can develop heart failure due to electrical and mechanical dyssynchrony from traditional right ventricular apical pacing has led to development of more physiologic pacing methods that better mimic normal cardiac conduction and provide synchronized ventricular contraction. Conventional biventricular pacing has been shown to benefit patients with heart failure and conduction system disease but can be limited by scarring and fibrosis. His bundle pacing and left bundle branch area pacing are novel techniques that can provide more physiologic ventricular activation as an alternative to conventional or biventricular pacing. Leadless pacing has emerged as another alternative pacing technique to overcome limitations in conventional transvenous pacemaker systems. Our objective is to review the evolution of cardiac pacing and explore these new advances in pacing strategies.

THE CHATTERJEE PHENOMENON: A DEMONSTRATION OF CARDIAC MEMORY IN PACED RHYTHMS.

While T-wave inversions (TWI) are associated with various pathologies, they are rarely associated with cardiac memory, termed the Chatterjee phenomenon. A 76-year-old man with sick sinus syndrome with a pacemaker presented with chest tightness and new onset TWI in his precordial leads. On admission, he tested positive for COVID-19, but remained stable and only required minimal supplemental oxygen. His troponin was only slightly elevated, and EKG showed TWI throughout his precordial leads. A previous EKG had shown normal sinus rhythm without a paced rhythm or ST wave abnormalities. Interrogation of his pacemaker revealed an AV-paced rhythm. Given his chest tightness without dynamic changes in his troponin or EKG, the symptoms were considered more likely related to his COVID-19 infection, and he was discharged home. Aberrancies in normal cardiac conduction can result in altered electrical activation, especially for those with AV pacemakers, leading some patients to develop cardiac memory, manifesting as TWI. AV-paced rhythm and narrow QRS complexes with TWI localized to precordial leads without evidence of active cardiac ischaemia may suggest cardiac memory, termed the Chatterjee phenomenon, requiring no invasive interventions. In patients with T-wave inversions, various conditions should considered in the differential diagnosis, including left bundle branch block and sick sinus syndrome, although T-wave inversions in V1-V3 are non-specific and benign.Cardiac memory, termed the Chatterjee Phenomenon, is one of the causes of T-wave inversions which is sometimes ignored.No invasive interventions are needed for T-wave inversions with the Chatterjee phenomenon.

Predictors and long-term outcomes of heart block after transcatheter device closure of perimembranous ventricular septal defect.

Heart block is the most common and concerning complication associated with transcatheter device closure of perimembranous ventricular septal defect (pmVSD) and its occurrence remains a great challenge for device closure. Between June 2002 and June 2020, 1076 pediatric patients with pmVSD, who successfully underwent transcatheter device closure in our center, were enrolled in this cohort study, with a median follow-up of 64 months (range: 1 to 19 years). Of 1076 patients, 234 (21.8%) developed postprocedural heart block, with right bundle branch block being the most common (74.8%), followed by left bundle branch block (16.2%), and atrioventricular block (5.6%). Complete atrioventricular block occurred in 5 cases, including 3 cases with permanent pacemaker implantation, 1 case with recovery to normal sinus rhythm, and 1 case with sudden cardiac death. Most patients (97.9%) developed heart block within 1 week of procedure. Finally, 138 cases returned to normal cardiac conduction. Multivariate logistic regression revealed that thin-waist occluders (odds ratio [OR]: 1.759; 95% confidence interval [CI]: 1.023 to 3.022; P = 0.041), and oversized devices (OR: 1.809; 95% CI: 1.322 to 2.476; P < 0.001) were independently associated with occurrence of postprocedural heart block. Moreover, heart block was less likely to occur when the left disk of occluder was placed within the aneurysmal tissue (OR: 0.568; 95% CI: 0.348 to 0.928; P = 0.024). The outcome of postprocedural heart block is favorable in most cases. Oversized devices and thin-waist occluders should be avoided. Placement of the left disk of the device should into the aneurysmal tissue is highly recommended.

Low Prevalence of Cardiomyopathy in Patients with Mitochondrial Disease and Neurological Manifestations

Patients with mitochondrial diseases can develop cardiomyopathy but with variable expressivity and penetrance. Our prospective study enrolled and evaluated a cohort of 53 patients diagnosed with chronic progressive ophthalmoplegia (CPEO, n = 34), Kearns–Sayre syndrome (KSS, n = 3), neuropathy ataxia and retinitis pigmentosa (NARP, n = 1), myoclonic epilepsy with ragged red fibers (MERRF, n = 1), Harel–Yoon Syndrome (HYS, n = 1) and 13 patients with undefined mitochondrial diseases, presenting primarily with neurological symptoms. Over a 4-year period, six patients in our study cohort were diagnosed with heart disease (11.3%), with only three patients having defined cardiomyopathy (5.7%). Cardiomyopathy was present in a 21-year-old patient with HYS and two CPEO patients having mild cardiomyopathy at an older age. Two CPEO patients had congenital heart disease, and a third CPEO had LV hypertrophy secondary to hypertension. In three patients, traditional risk factors for heart disease, including dyslipidemia, hypertension, and respiratory disease, were present. The majority of our adult cohort of patients have normal cardiac investigations with a median left ventricular (LV) ejection fraction of 59.0%, indexed LV mass of 67.0 g/m2, and normal diastolic and valvular function at baseline. A 12-lead electrocardiogram showed normal cardiac conduction across the study cohort. Importantly, follow-up assessments showed consistent cardiac structure and function. Our study shows a low prevalence of cardiomyopathy and highlights the breadth of phenotypic variability in patients with mitochondrial disorders. The presence of cardiovascular risk factors and aging are important comorbidities in our cohort.

Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development.

SummaryRequirements for vesicle fusion within the heart remain poorly understood, despite the multitude of processes that necessitate proper intracellular trafficking within cardiomyocytes. Here, we show that Syntaxin 4 (STX4), a target-Soluble N-ethylmaleimide sensitive factor attachment receptor (t-SNARE) protein, is required for normal vertebrate cardiac conduction and vesicular transport. Two patients were identified with damaging variants in STX4. A patient with a homozygous R240W missense variant displayed biventricular dilated cardiomyopathy, ectopy, and runs of non-sustained ventricular tachycardia, sensorineural hearing loss, global developmental delay, and hypotonia, while a second patient displayed severe pleiotropic abnormalities and perinatal lethality. CRISPR/Cas9-generated stx4 mutant zebrafish exhibited defects reminiscent of these patients’ clinical presentations, including linearized hearts, bradycardia, otic vesicle dysgenesis, neuronal atrophy, and touch insensitivity by 3 days post fertilization. Imaging of Vamp2+ vesicles within stx4 mutant zebrafish hearts showed reduced docking to the cardiomyocyte sarcolemma. Optical mapping of the embryonic hearts coupled with pharmacological modulation of Ca2+ handling together support that zebrafish stx4 mutants have a reduction in L-type Ca2+ channel modulation. Transgenic overexpression of zebrafish Stx4R241W, analogous to the first patient’s STX4R240W variant, indicated that the variant is hypomorphic. Thus, these data show an in vivo requirement for SNAREs in regulating normal embryonic cardiac function and that variants in STX4 are associated with pleiotropic human disease, including cardiomyopathy.

Left Bundle Branch Pacing: Current Knowledge and Future Prospects.

Cardiac pacing is an effective therapy for treating patients with bradycardia due to sinus node dysfunction or atrioventricular block. However, traditional right ventricular apical pacing (RVAP) causes electric and mechanical dyssynchrony, which is associated with increased risk for atrial arrhythmias and heart failure. Therefore, there is a need to develop a physiological pacing approach that activates the normal cardiac conduction and provides synchronized contraction of ventricles. Although His bundle pacing (HBP) has been widely used as a physiological pacing modality, it is limited by challenging implantation technique, unsatisfactory success rate in patients with wide QRS wave, high pacing capture threshold, and early battery depletion. Recently, the left bundle branch pacing (LBBP), defined as the capture of left bundle branch (LBB) via transventricular septal approach, has emerged as a newly physiological pacing modality. Results from early clinical studies have demonstrated LBBP's feasibility and safety, with rare complications and high success rate. Overall, this approach has been found to provide physiological pacing that guarantees electrical synchrony of the left ventricle with low pacing threshold. This was previously specifically characterized by narrow paced QRS duration, large R waves, fast synchronized left ventricular activation, and correction of left bundle branch block. Therefore, LBBP may be a potential alternative pacing modality for both RVAP and cardiac resynchronization therapy with HBP or biventricular pacing (BVP). However, the technique's widespread adaptation needs further validation to ascertain its safety and efficacy in randomized clinical trials. In this review, we discuss the current knowledge of LBBP.

An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs

BackgroundPopeye domain-containing proteins 1 and 2 (POPDC1 and POPDC2) are transmembrane proteins involved in cyclic AMP-mediated signalling processes and are required for normal cardiac pacemaking and conduction. In order to identify novel protein interaction partners, POPDC1 and 2 proteins were attached to beads and compared by proteomic analysis with control beads in the pull-down of proteins from cultured human skeletal myotubes.ResultsThere were highly-significant interactions of both POPDC1 and POPDC2 with XIRP1 (Xin actin binding repeat-containing protein 1), actin and, to a lesser degree, annexin A5. In adult human skeletal muscle, both XIRP1 and POPDC1/2 were present at the sarcolemma and in T-tubules. The interaction of POPDC1 with XIRP1 was confirmed in adult rat heart extracts. Using new monoclonal antibodies specific for POPDC1 and POPDC2, both proteins, together with XIRP1, were found mainly at intercalated discs but also at T-tubules in adult rat and human heart.ConclusionsMutations in human POPDC1, POPDC2 and in human XIRP1, all cause pathological cardiac arrhythmias, suggesting a possible role for POPDC1/2 and XIRP1 interaction in normal cardiac conduction.

Prevalence and incidence of adverse events with catheter ablation for adults with Wolff-Parkinson-White syndrome: a systematic review protocol.

The objective of this review is to synthesize the best available evidence to determine the prevalence and incidence of adverse events in patients with Wolff-Parkinson-White syndrome who have undergone catheter ablation. Wolff-Parkinson-White syndrome is a rare congenital heart disease affecting the normal cardiac conduction system that predisposes an individual to tachyarrhythmias. Patients with Wolf-Parkinson-White syndrome can experience a wide range of life-threatening symptoms and frequently undergo catheter ablation procedures to treat this disease. These patients are at risk of developing a variety of adverse events, including pericardial effusion, cardiac tamponade, atrial fibrillation, stroke, cerebral hemorrhage, major bleeding or hematoma, deep vein thrombosis, atrioventricular-block, cardiac perforation, coronary artery injury, pulmonary emboli, and death. This review will include adults aged 18 or older with a diagnosis of Wolff-Parkinson-White syndrome who have undergone catheter ablation, including radiofrequency ablation and cryoablation. MEDLINE, CINAHL, Scopus, Embase, and Web of Science databases will be searched from 1980 to the present for English-language studies only. Prevalence and incidence data, experimental, quasi-experimental, observational, and descriptive studies will be included and critically appraised by two independent reviewers. Data will be extracted using the standardized data extraction tool for prevalence data. If sufficient data is available, a meta-analysis will be conducted; otherwise, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. PROSPERO CRD42020180391.

Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure\u2013response analysis

PurposeThis study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors.MethodsPatients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis.ResultsA total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern.ConclusionsECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.

Radiofrequency Catheter Ablation: How to Manage and Prevent Collateral Damage?

Radiofrequency catheter ablation has become the standard of care for the management of various arrhythmias and, in fact, the first-line therapy for many tachyarrhythmias. It entails creating scar tissue in the heart in regions where abnormal impulses form or propagate to restore normal cardiac conduction. As the heart is a complex organ and is surrounded by and related to many other anatomical structures, it is important to avoid the collateral damage that can happen from radiofrequency (RF) ablation on the endocardium as well as on the epicardium. This review explores methods for mitigating or limiting collateral damage during catheter ablation.

Left bundle branch pacing: A comprehensive review.

Cardiac pacing is the only effective therapy for patients with symptomatic bradyarrhythmia. Traditional right ventricular apical pacing causes electrical and mechanical dyssynchrony resulting in left ventricular dysfunction, recurrent heart failure, and atrial arrhythmias. Physiological pacing activates the normal cardiac conduction, thereby providing synchronized contraction of ventricles. Though His bundle pacing (HBP) acts as an ideal physiological pacing modality, it is technically challenging and associated with troubleshooting issues during follow-up. Left bundle branch pacing (LBBP) has been suggested as an effective alternative to overcome the limitations of HBP as it provides low and stable pacing threshold, lead stability, and correction of distal conduction system disease. This paper will focus on the implantation technique, troubleshooting, clinical implications, and a review of published literature of LBBP.

Speckle tracking echocardiographically-based analysis of ventricular strain in children: an intervendor comparison

BackgroundStrain and synchrony can be calculated from a variety of software packages, but there is a paucity of data with inter-vendor comparisons in children. To test the hypothesis that different packages may affect results, independent of acquisition, we compared values obtained using two commercially available analysis tool (QLAB and TomTec), with several different settings.MethodsThe study population included 108 children; patients were divided into three groups: (1) normal cardiac structure and conduction; (2) ventricular paced rhythm; and (3) flattened ventricular septum (reflecting right ventricular pressure or volume load lesions). We analyzed the same image acquired from the apical 4-chamber (AP4) and short-axis at the mid-papillary level (SAXM) views in both QLAB (versions 10.5 and 10.8) and TomTec (version 1.2). In QLAB version 10.8, low, medium, and high quantification smoothness settings were employed. In TomTec, images were analyzed with both low and high frame rates. Tracking quality for each package was graded. AP4 and SAXM strain and synchrony values were recorded. A mixed-effects linear regression model was used, with main effect considered significant if the p-value was < 0.05.ResultsTracking scores were high for all packages except QLAB 10.5 in the SAXM view. AP4 and SAXM strain values varied significantly between QLAB 10.5 and the other packages. Synchrony values varied widely for all strain values (p < 0.001 for both) in all packages. Quantification smoothness changes in QLAB 10.8 did not impact strain significantly in any patient group; temporal resolution changes in TomTec resulted in strain differences in children with flat ventricular septums, but not those with normal or ventricular paced hearts.ConclusionSynchrony values varied substantially among all packages in children. Strain values varied widely between QLAB 10.5 and all other software packages, recommending avoidance of QLAB 10.5 for future studies. Quantification smoothness settings in QLAB 10.8 resulted in minimal strain differences. In TomTec, low and high frame rate strain values differed only in a subset of patients (flattened septum). These data suggest that reliable comparisons between strain values derived from QLAB and TomTec is possible in certain cases, but that caution should be used especially in different hemodynamics conditions.

Cardiomyocyte Expression of ZO-1 Is Essential for Normal Atrioventricular Conduction but Does Not Alter Ventricular Function.

ZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown. To determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function. We generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL. ZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.

Optimization of Dual Pathway AV Nodal Conduction Model

In this work we tested our previously proposed heterogeneous oscillator model of atrioventricular node with respect to dual pathway physiology in order to optimize the model parameters. For this purpose we compared three model variants with different number of pathway node elements represented by nonlinear Aliev-Panfilov equations. The parameters controlling coupling between the pathway elements and the refractoriness of the fast pathway were selected for each model variant to obtain qualitative correspondence to the all range of functional atrioventricular node behavior. The results demonstrate that all considered model variants are able to reproduce normal cardiac signals conduction, AV node reentry, automaticity (pacemaking) and filtering function. However, the model variant with smallest number of the pathway elements better correspond to human electrophysiology, in particular to filtering high atrial rates by AV node. In addition, it is preferred for use in low-power systems with real-time simulations, such as ICD and pacemaker validation and testing hardware, as well as for educational and research purposes.

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo

Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.

Abstract 16713: Defining the Tbx5-Dependent miRNA Regulatory Networks of Atrial Fibrillation

Atrial fibrillation (AF) is the most commonly diagnosed arrhythmic disorder, characterized by random electrical activity in the heart. Complications of AF include stroke and heart failure, which makes understanding the molecular mechanism underlying this conduction defect imperative. The Tbx5 locus has been implicated by genome wide association studies (GWAS) to have an increased risk for AF. Our lab has previously demonstrated the absence of this transcription factor leads to spontaneous and sustained AF, which corroborates the importance of Tbx5 in the maintenance of cardiac rhythm. While Tbx5 is known to drive the network for cardiac rhythm, the downstream regulatory components need to be further characterized, including the downstream miRNAs. The components involved in cardiac rhythm are dose sensitive, therefore small perturbations in gene expression can lead to arrhythmias. Maintaining stable levels of gene expression can be regulated with miRNAs, which provide a negative feedback in dose sensitive pathways. Tbx5 -deficient mice developed spontaneous, sustained AF; in order to further interrogate the TBX5-dependent pathway that led to AF, we transcriptionally profiled small RNAs from the left atrium of Tbx5 -deficient mice. The most downregulated TBX5-dependent miRNA was miR10b. In concordance with previous publications, our miR10b mimic and inhibitor experiments in HL-1 cardiomyocytes demonstrate that miR10b negatively regulates Tbx5 expression. Therefore, we hypothesized that miR10b was crucial in the maintenance of atrial rhythm. Cellular electrophysiology studies with the overexpression of miR10b in HL-1 cardiomyocytes led to the elongation of atrial action potentials, similar to the phenotype we saw in the Tbx5 -deficient atrial tissue. Using whole mouse electrophysiology, we found that the mir10b removal in the hearts leads to increased AF susceptibility. Thus, providing evidence that mirR10b is crucial for the maintenance of normal cardiac conduction. In order to identify other miRNAs essential for cardiac conduction, we examined the other TBX5-dependent miRNAs in a high-throughput calcium screen. Further defining the miRNAs can provide a better understanding of the regulatory mechanisms crucial for cardiac conduction.

Heart rate: when macrophages hit the note

Macrophages regulate cardiac homeostasis under pathological and physiological conditions. Recent studies have elegantly substantiated the presence of specific subset of macrophages residing within the distal atrioventricular node in mice and humans. These macrophages directly couple with cardiomyocytes via connexin-43-containing gap junctions and increase atrioventricular conduction by accelerating cardiomyocyte repolarization. Conditional deletion of connexin-43 in macrophages or congenital lack of macrophages delay nodal conduction and foster progressive atrioventricular block. Exhaustive understanding of the role of tissue-resident macrophages in normal and aberrant cardiac conduction could initiate the development of therapeutic strategies focused on the modulation of macrophage functions in heart arrhythmia.

Bradycardia and Syncope Associated with Swallowing ‘Yokan’ Japanese Sticky Sweets

Case: An 89-year-old woman was transferred to the emergency department after a syncopal episode that occurred while she was eating the Japanese confectionery called ‘Yokan’. She was cyanotic and her breathing stopped. Upon arrival, she developed bradycardia of 48 beats/min (Figure 1). An initial CT scan showed that the second narrowed part of the esophagus contained ‘Yokan’ (Figures 2 and 3). Two days later, her bradycardia improved, and she no longer had impaired consciousness. In a followup CT scan, there was no ‘Yokan’ present in the esophagus. ‘Yokan’ is a sticky Japanese sweet made of red bean paste, agar, and sugar. The pathogenic mechanism is thought to occur via a vagal reflex resulting in inhibition of the normal cardiac conduction system. In this case, ‘Yokan’ filling the esophagus results in stretching of the mechanical receptors of the esophagus. This signal is transmitted from the afferent fibers of the vagal plexus of the esophagus to the brainstem, which then stimulates efferent fibers and cardiovascular depression. The consistency and temperature of food products are thought to play vital roles in the pathogenic mechanism of swallowing syncope. It is important to be aware that ‘Yokan’, when not masticated, may cause swallowing syncope.