Assessing Torque Transfer in Conduction System Pacing: Development and Evaluation of an Ex Vivo Model.

BACKGROUND: Conduction system pacing (CSP) faces challenges in achieving reliable and safe deployments. Complex interactions between tissue and lead tip can result in endocardial entanglement, a drill effect that prevents penetration. No verified ex vivo model exists to quantitatively assess this relationship. OBJECTIVES: The purpose of this study was to quantitatively characterize CSP lead tip to tissue responses for 4 commonly used leads. METHODS: CSP leads (from Medtronic, Biotronik, Boston Scientific, and Abbott) were examined for helix rotation efficiency in ex vivo ovine right ventricular septa. A custom jig was utilized for rotation measurements. Fifteen turns were executed, documenting tissue-interface changes every 90° using high-resolution photography. Response curves (input rotation vs helix rotation) were evaluated using piecewise linear regression, with a focus on output vs input response slopes and torque breakpoint events. RESULTS: We analyzed 3,840 quarter-turn CSP insertions with 4 different lead types. Helix rotations were consistently less than input: Abbott Tendril = 0.21:1, Medtronic 3830 = 0.21:1, Biotronik Solia = 0.47:1, and Boston Scientific Ingevity = 0.56:1. Torque breakpoint events were observed on average 7.22 times per insertion (95% CI: 6.08-8.35; P = NS) across all leads. In 57.8% of insertions (37 of 64), uncontrolled torque breakpoint events occurred, signaling unexpected excess helix rotations. CONCLUSIONS: Using a robust ex vivo model, we revealed a muted helix rotation response compared with input turns on the lead, and frequent torque change events during insertion. This is critical for CSP implanters, emphasizing the potential for unexpected torque breakpoint events, and suggesting the need for novel lead designs or deployment methods to enhance CSP efficiency and safety.

Localized cardiomyocyte lipid accumulation is associated with slowed epicardial conduction in rats.

Transmural action potential duration differences and transmural conduction gradients aid the synchronization of left ventricular repolarization, reducing vulnerability to transmural reentry and arrhythmias. A high-fat diet and the associated accumulation of pericardial adipose tissue are linked with conduction slowing and greater arrhythmia vulnerability. It is predicted that cardiac adiposity may more readily influence epicardial conduction (versus endocardial) and disrupt normal transmural activation/repolarization gradients. The aim of this investigation was to determine whether transmural conduction gradients are modified in a rat model of pericardial adiposity. Adult Sprague-Dawley rats were fed control/high-fat diets for 15 wk. Left ventricular 300 µm tangential slices were generated from the endocardium to the epicardium, and conduction was mapped using microelectrode arrays. Slices were then histologically processed to assess fibrosis and cardiomyocyte lipid status. Conduction velocity was significantly greater in epicardial versus endocardial slices in control rats, supporting the concept of a transmural conduction gradient. High-fat diet feeding increased pericardial adiposity and abolished the transmural conduction gradient. Slowed epicardial conduction in epicardial slices strongly correlated with an increase in cardiomyocyte lipid content, but not fibrosis. The positive transmural conduction gradient reported here represents a physiological property of the ventricular activation sequence that likely protects against reentry. The absence of this gradient, secondary to conduction slowing and cardiomyocyte lipid accumulation, specifically in the epicardium, indicates a novel mechanism by which pericardial adiposity may exacerbate ventricular arrhythmias.

Three-dimensional functional anatomy of the human sinoatrial node for epicardial and endocardial mapping and ablation.

The sinoatrial node (SAN) is the primary pacemaker of the human heart. It is a single, elongated, 3-dimensional (3D) intramural fibrotic structure located at the junction of the superior vena cava intercaval region bordering the crista terminalis (CT). SAN activation originates in the intranodal pacemakers and is conducted to the atria through 1 or more discrete sinoatrial conduction pathways. The complexity of the 3D SAN pacemaker structure and intramural conduction are underappreciated during clinical multielectrode mapping and ablation procedures of SAN and atrial arrhythmias. In fact, defining and targeting SAN is extremely challenging because, even during sinus rhythm, surface-only multielectrode mapping may not define the leading pacemaker sites in intramural SAN but instead misinterpret them as epicardial or endocardial exit sites through sinoatrial conduction pathways. These SAN exit sites may be distributed up to 50 mm along the CT beyond the ∼20-mm-long anatomic SAN structure. Moreover, because SAN reentrant tachycardia beats may exit through the same sinoatrial conduction pathway as during sinus rhythm, many SAN arrhythmias are underdiagnosed. Misinterpretation of arrhythmia sources and/or mechanisms (eg, enhanced automaticity, intranodal vs CT reentry) limits diagnosis and success of catheter ablation treatments for poorly understood SAN arrhythmias. The aim of this review is to provide a state-of-the-art overview of the 3D structure and function of the human SAN complex, mechanisms of SAN arrhythmias and available approaches for electrophysiological mapping, 3D structural imaging, pharmacologic interventions, and ablation to improve diagnosis and mechanistic treatment of SAN and atrial arrhythmias.

Comparison of Propagation Models and Forward Calculation Methods on Cellular, Tissue and Organ Scale Atrial Electrophysiology.

OBJECTIVE: The bidomain model and the finite element method are an established standard to mathematically describe cardiac electrophysiology, but are both suboptimal choices for fast and large-scale simulations due to high computational costs. We investigate to what extent simplified approaches for propagation models (monodomain, reaction-Eikonal and Eikonal) and forward calculation (boundary element and infinite volume conductor) deliver markedly accelerated, yet physiologically accurate simulation results in atrial electrophysiology. METHODS: We compared action potential durations, local activation times (LATs), and electrocardiograms (ECGs) for sinus rhythm simulations on healthy and fibrotically infiltrated atrial models. RESULTS: All simplified model solutions yielded LATs and P waves in accurate accordance with the bidomain results. Only for the Eikonal model with pre-computed action potential templates shifted in time to derive transmembrane voltages, repolarization behavior notably deviated from the bidomain results. ECGs calculated with the boundary element method were characterized by correlation coefficients 0.9 compared to the finite element method. The infinite volume conductor method led to lower correlation coefficients caused predominantly by systematic overestimations of P wave amplitudes in the precordial leads. CONCLUSION: Our results demonstrate that the Eikonal model yields accurate LATs and combined with the boundary element method precise ECGs compared to markedly more expensive full bidomain simulations. However, for an accurate representation of atrial repolarization dynamics, diffusion terms must be accounted for in simplified models. SIGNIFICANCE: Simulations of atrial LATs and ECGs can be notably accelerated to clinically feasible time frames at high accuracy by resorting to the Eikonal and boundary element methods.

Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm.

Comprehensive cis-regulatory landscapes are essential for accurate enhancer prediction and disease variant mapping. Although cis-regulatory element (CRE) resources exist for most tissues and organs, many rare - yet functionally important - cell types remain overlooked. Despite representing only a small fraction of the heart's cellular biomass, the cardiac conduction system (CCS) unfailingly coordinates every life-sustaining heartbeat. To globally profile the mouse CCS cis-regulatory landscape, we genetically tagged CCS component-specific nuclei for comprehensive assay for transposase-accessible chromatin-sequencing (ATAC-Seq) analysis. Thus, we established a global CCS-enriched CRE database, referred to as CCS-ATAC, as a key resource for studying CCS-wide and component-specific regulatory functions. Using transcription factor (TF) motifs to construct CCS component-specific gene regulatory networks (GRNs), we identified and independently confirmed several specific TF sub-networks. Highlighting the functional importance of CCS-ATAC, we also validated numerous CCS-enriched enhancer elements and suggested gene targets based on CCS single-cell RNA-Seq data. Furthermore, we leveraged CCS-ATAC to improve annotation of existing human variants related to cardiac rhythm and nominated a potential enhancer-target pair that was dysregulated by a specific SNP. Collectively, our results established a CCS-regulatory compendium, identified novel CCS enhancer elements, and illuminated potential functional associations between human genomic variants and CCS component-specific CREs.

Remembering the canonical discoverers of the core components of the mammalian cardiac conduction system: Keith and Flack, Aschoff and Tawara, His, and Purkinje.

The mammalian cardiac conduction system (CCS) is a multifaceted continuum of electrically distinct, interconnected constructs within the myocardial mass. The key components are the sinus node (SAN), the atrioventricular node (AVN), the His bundle (HB), and the Purkinje fiber network (PF), the latter serendipitously discovered by Jan Evangelista Purkinje in 1839 in the sheep ventricle. In 1893, Wilhelm His, Jr. described a ventricular muscular tract conveying SAN-generated action potentials from the AVN (discovered by Sunao Tawara and Karl Albert Aschoff in 1906) to the PF. In 1906, Keith and Flack completed these explorations by localizing the SAN, the primum movens of CCS, which functions as a biologic oscillator emitting cadenced impulses that travel via the Bachmann bundle to the atrial myocytes and, via internodal pathways, to the AVN. Here these impulses are briefly delayed, enabling atrial systole before continuing via the AVN and the high-speed His-Purkinje conduction axis to signal ventricular contraction. The CCS canonical discoverers (Keith and Flack, Aschoff and Tawara, His, and Purkinje), historical controversies, fundamental notions of anatomy, physiology, and pathology, and therapeutic interventions pertaining to the CCS are the main themes of this review. Any scientist mentioned or unmentioned in this report who contributed directly or indirectly, with correct or inaccurate hypotheses, to the characterization of the CCS deserves our deepest gratitude for the long and painstaking hours spent microscopically scrutinizing heart specimens from multiple mammalian species, including humans.NEW & NOTEWORTHY This report presents the first comprehensive summary of the factors enabling the discovery of the cardiac conduction system (CCS). Biographical highlights and achievements of the CCS canonical discoverers, hypotheses concerning mechanisms underlying sinus node (SAN) automaticity, use of eponyms to denominate a discovery, famous controversies, possible reproachable behavior (e.g., intellectual support for eugenics in post-World War I Germany) by two of the discoverers, and examples of historical mentor-pupil relationships are discussed.

In vivo and ex vivo electrophysiological study of the mouse heart to characterize the cardiac conduction system, including atrial and ventricular vulnerability.

The mouse is a common and cost-effective animal model for basic research, and the number of genetically engineered mouse models with cardiac phenotype is increasing. In vivo electrophysiological study in mice is similar to that performed in humans. It is indispensable for acquiring intracardiac electrocardiogram recordings and determining baseline cardiac cycle intervals. Furthermore, the use of programmed electrical stimulation enables determination of parameters such as sinoatrial conduction time, sinus node recovery time, atrioventricular-nodal conduction properties, Wenckebach periodicity, refractory periods and arrhythmia vulnerability. This protocol describes specific procedures for determining these parameters that were adapted from analogous human protocols for use in mice. We include details of ex vivo electrophysiological study, which provides detailed insights into intrinsic cardiac electrophysiology without external influences from humoral and neural factors. In addition, we describe a heart preparation with intact innervation by the vagus nerve that can be used as an ex vivo model for vagal control of the cardiac conduction system. Data acquisition for in vivo and ex vivo electrophysiological study takes ~1 h per mouse, depending on the number of stimulation protocols applied during the procedure. The technique yields highly reliable results and can be used for phenotyping of cardiac disease models, elucidating disease mechanisms and confirming functional improvements in gene therapy approaches as well as for drug and toxicity testing.

Modeling the His-Purkinje Effect in Non-invasive Estimation of Endocardial and Epicardial Ventricular Activation.

Inverse electrocardiography (iECG) estimates epi- and endocardial electrical activity from body surface potentials maps (BSPM). In individuals at risk for cardiomyopathy, non-invasive estimation of normal ventricular activation may provide valuable information to aid risk stratification to prevent sudden cardiac death. However, multiple simultaneous activation wavefronts initiated by the His-Purkinje system, severely complicate iECG. To improve the estimation of normal ventricular activation, the iECG method should accurately mimic the effect of the His-Purkinje system, which is not taken into account in the previously published multi-focal iECG. Therefore, we introduce the novel multi-wave iECG method and report on its performance. Multi-wave iECG and multi-focal iECG were tested in four patients undergoing invasive electro-anatomical mapping during normal ventricular activation. In each subject, 67-electrode BSPM were recorded and used as input for both iECG methods. The iECG and invasive local activation timing (LAT) maps were compared. Median epicardial inter-map correlation coefficient (CC) between invasive LAT maps and estimated multi-wave iECG versus multi-focal iECG was 0.61 versus 0.31. Endocardial inter-map CC was 0.54 respectively 0.22. Modeling the His-Purkinje system resulted in a physiologically realistic and robust non-invasive estimation of normal ventricular activation, which might enable the early detection of cardiac disease during normal sinus rhythm.

Gestational Age and Neonatal Electrocardiograms.

OBJECTIVES: Interpretation of the neonatal electrocardiogram (ECG) is challenging due to the profound changes of the cardiovascular system in this period. We aimed to investigate the impact of gestational age (GA) on the neonatal ECG and create GA-specific reference values. METHODS: The Copenhagen Baby Heart Study is a prospective general population study that offered cardiac evaluation of neonates. ECGs and echocardiograms were obtained and systematically analyzed. GA, weight, height, and other baseline variables were registered. RESULTS: We included 16 462 neonates (52% boys) with normal echocardiograms. The median postnatal age was 11 days (range 0 to 30), and the median GA was 281 days (range 238 to 301). Analyzing the ECG parameters as a function of GA, we found an effect of GA on almost all investigated ECG parameters. The largest percentual effect of GA was on heart rate (HR; 147 vs 139 beats per minute), the QRS axis (103° vs 116°), and maximum R-wave amplitude in V1 (R-V1; 0.97 vs 1.19 mV) for GA ≤35 vs ≥42 weeks, respectively. Boys had longer PR and QRS intervals and a more right-shifted QRS axis within multiple GA intervals (all P < .01). The effect of GA generally persisted after multifactorial adjustment. CONCLUSIONS: GA was associated with significant differences in multiple neonatal ECG parameters. The association generally persisted after multifactorial adjustment, indicating a direct effect of GA on the developing neonatal cardiac conduction system. For HR, the QRS axis, and R-V1, the use of GA-specific reference values may optimize clinical handling of neonates.

Pulsed low-energy stimulation initiates electric turbulence in cardiac tissue.

Interruptions in nonlinear wave propagation, commonly referred to as wave breaks, are typical of many complex excitable systems. In the heart they lead to lethal rhythm disorders, the so-called arrhythmias, which are one of the main causes of sudden death in the industrialized world. Progress in the treatment and therapy of cardiac arrhythmias requires a detailed understanding of the triggers and dynamics of these wave breaks. In particular, two very important questions are: 1) What determines the potential of a wave break to initiate re-entry? and 2) How do these breaks evolve such that the system is able to maintain spatiotemporally chaotic electrical activity? Here we approach these questions numerically using optogenetics in an in silico model of human atrial tissue that has undergone chronic atrial fibrillation (cAF) remodelling. In the lesser studied sub-threshold illumination régime, we discover a new mechanism of wave break initiation in cardiac tissue that occurs for gentle slopes of the restitution characteristics. This mechanism involves the creation of conduction blocks through a combination of wavefront-waveback interaction, reshaping of the wave profile and heterogeneous recovery from the excitation of the spatially extended medium, leading to the creation of re-excitable windows for sustained re-entry. This finding is an important contribution to cardiac arrhythmia research as it identifies scenarios in which low-energy perturbations to cardiac rhythm can be potentially life-threatening.

Impact of High-Power Short-Duration Radiofrequency Ablation on Esophageal Temperature Dynamic.

BACKGROUND: High-power short-duration (HP-SD) radiofrequency ablation (RFA) has been proposed as a method for producing rapid and effective lesions for pulmonary vein isolation. The underlying hypothesis assumes an increased resistive heating phase and decreased conductive heating phase, potentially reducing the risk for esophageal thermal injury. The objective of this study was to compare the esophageal temperature dynamic profile between HP-SD and moderate-power moderate-duration (MP-MD) RFA ablation strategies. METHODS: In patients undergoing pulmonary vein isolation, RFA juxtaposed to the esophagus was delivered in an alternate sequence of HP-SD (50 W, 8-10 s) and MP-MD (25 W, 15-20 s) between adjacent applications (distance, ≤4 mm). Esophageal temperature was recorded using a multisensor probe (CIRCA S-CATH). Temperature data included magnitude of temperature rise, maximal temperature, time to maximal temperature, and time return to baseline. In swine, a similar experimental design compared the effect of HP-SD and MP-MD on patterns of esophageal injury. RESULTS: In 20 patients (68.9±5.8 years old; 60% persistent atrial fibrillation), 55 paired HP-SD and MP-MD applications were analyzed. The esophageal temperature dynamic profile was similar between HP-SD and MP-MD ablation strategies. Specifically, the magnitude of temperature rise (2.1 °C [1.4-3] versus 2.0 °C [1.5-3]; P=0.22), maximal temperature (38.4 °C [37.8-39.3] versus 38.5 °C [37.9-39.4]; P=0.17), time to maximal temperature (24.9±7.5 versus 26.3±6.8 s; P=0.1), and time of temperature to return to baseline (110±23.2 versus 111±25.1 s; P=0.86) were similar between HP-SD and MP-MD ablation strategies. In 6 swine, esophageal injury was qualitatively similar between HP-SD and MP-MD strategies. CONCLUSIONS: Esophageal temperature dynamics are similar between HP-SD and MP-MD RFA strategies and result in comparable esophageal tissue injury. Therefore, when using a HP-SD RFA strategy, the shorter application duration should not prompt shorter intervals between applications.

A computationally efficient dynamic model of human epicardial tissue.

We present a new phenomenological model of human ventricular epicardial cells and we test its reentry dynamics. The model is derived from the Rogers-McCulloch formulation of the FitzHugh-Nagumo equations and represents the total ionic current divided into three contributions corresponding to the excitatory, recovery and transient outward currents. Our model reproduces the main characteristics of human epicardial tissue, including action potential amplitude and morphology, upstroke velocity, and action potential duration and conduction velocity restitution curves. The reentry dynamics is stable, and the dominant period is about 270 ms, which is comparable to clinical values. The proposed model is the first phenomenological model able to accurately resemble human experimental data by using only 3 state variables and 17 parameters. Indeed, it is more computationally efficient than existing models (i.e., almost two times faster than the minimal ventricular model). Beyond the computational efficiency, the low number of parameters facilitates the process of fitting the model to the experimental data.

Initiation and termination of reentry-like activity in rat cardiomyocytes cultured in a microelectrode array.

Cardiac reentry is a lethal arrhythmia associated with cardiac diseases. Although arrhythmias are reported to be due to localized propagation abnormalities, little is known about the mechanisms underlying the initiation and termination of reentry. This is primarily because of a lack of an appropriate experimental system in which activity pattern switches between reentry and normal beating can be investigated. In this study, we aimed to develop a culture system for measuring the spatial dynamics of reentry-like activity during its onset and termination. Rat cardiomyocytes were seeded in microelectrode arrays and purified with a glucose-free culture medium to generate a culture with a heterogeneous cell density. Reentry-like activity was recorded in purified cardiomyocytes, but not in the controls. Reentry-like activity occurred by a unidirectional conduction block after shortening of the inter-beat interval. Furthermore, reentry-like activity was terminated after propagation with a conduction delay of less than 300 ms, irrespective of whether the propagation pattern changed or not. These results indicate that a simple purification process is sufficient to induce reentry-like activity. In the future, a more detailed evaluation of spatial dynamics will contribute to the development of effective treatment methods.

Recording an ECG With a Smartwatch in Newborns and Young Children: Feasibility and Perspectives.

Correlating symptoms with arrhythmia in neonates and young children is often difficult because of their sporadic and unpredictable nature. We show that it is possible to register an ECG with a smartwatch in neonates and young children and provide illustrative cases of supraventricular tachycardia and complete atrioventricular block identified with this technology.

A novel transgenic Cre allele to label mouse cardiac conduction system.

The cardiac conduction system is a network of heterogeneous cell population that initiates and propagates electric excitations in the myocardium. Purkinje fibers, a network of specialized myocardial cells, comprise the distal end of the conduction system in the ventricles. The developmental origins of Purkinje fibers and their roles during cardiac physiology and arrhythmia have been reported. However, it is not clear if they play a role during ischemic injury and heart regeneration. Here we introduce a novel tamoxifen-inducible Cre allele that specifically labels a broad range of components in the cardiac conduction system while excludes other cardiac cell types and vital organs. Using this new allele, we investigated the cellular and molecular response of Purkinje fibers to myocardial injury. In a neonatal mouse myocardial infarction model, we observed significant increase in Purkinje cell number in regenerating myocardium. RNA-Seq analysis using laser-captured Purkinje fibers showed a unique transcriptomic response to myocardial infarction. Our finds suggest a novel role of cardiac Purkinje fibers in heart injury.

Identification to cardiac conduction cells in humans and pigs according to their zonal distribution, using histological, immunohistochemical and morphometric study.

Histologically, the cardiac conduction network is formed of electrically isolated subendocardial fibers that comprise specialized cells with fewer myofibrils and mitochondria than cardiomyocytes. Our aim is to uncover regional variations of cardiac conduction fibers through histological and morphometric study in a porcine and human model. We analyzed five male adult human hearts and five male pig hearts. The left ventricles were dissected and sectioned in the axial plane into three parts: basal, middle third and apex regions. Cardiac conduction fibers study was carried out using hematoxylin-eosin and Masson's trichrome staining, and cardiac conduction cells and their junctions were identified using desmin, and a PAS method. Cardiac conduction fibers were difficult to pinpoint in humans, mostly showing a darker color or equal to cardiomyocytes. Cardiac conduction fibers in humans were in the subendocardium and in pigs in the myocardium and subendocardium. Cardiac conduction fibers were located mainly in the septal region in both humans and pigs. In our morphometric analysis, we were able to determine that cardiac conduction cells in humans (18.52 +/- 5.41 µm) and pigs (21.32 +/- 6.45 µm) were large, compared to cardiomyocytes. Conduction fiber-myocardial junctions were present in 10% in humans and 24.2% in pigs. The performance of immunohistochemical methods made it possible to improve the identification of cardiac conduction cells in the species studied. Study of cardiac conduction fibers and cells and their myocardial junctions is vital to gain insight into their normal distribution in the species analyzed, and thus advance the use of pigs in experimental models of the cardiac conduction system in humans.

Effect of preprocedural pharmacologic cardioversion on pulmonary vein isolation in patients with persistent atrial fibrillation.

BACKGROUND: The optimal strategy for catheter ablation of persistent atrial fibrillation (PeAF) remains unknown. A preprocedural additive treatment for patients undergoing pulmonary vein isolation (PVI) alone to optimize catheter ablation should be investigated. OBJECTIVE: The purpose of this study was to determine whether pharmacologic cardioversion with a fixed low-dose antiarrhythmic drug (AAD) before ablation could stratify the long-term outcome of a PVI-alone strategy. METHODS: We conducted a prospective cohort study of PeAF patients who underwent PVI using contact force-sensing catheters. No substrate modification was performed. Fixed low-dose bepridil was administered before ablation for cardioversion and patients were classified into 2 groups based on obtaining sinus rhythm (SR). The rate of recurrence of atrial fibrillation (AF) and/or atrial tachycardia (AT) within 36 months was compared between the 2 groups. RESULTS: Among the 303 PeAF patients who received the AAD, 102 returned to SR (SR group), and the other 201 had persistence of AF (non-SR group). AF persistence duration at baseline and during bepridil administration was similar between the 2 groups. The SR group had a significantly lower 36-month AF/AT recurrence rate than the non-SR group (17 [22.2%] vs 55 [34.0%], log-rank P = .022). AT-type recurrence was observed in 16 patients (2 [3.3%] in the SR group vs 14 [8.9%] in the non-SR group; log-rank P = .051). Nonresponse to AAD was an independent predictor of AF/AT recurrence after adjusting for other risk factors (hazard ratio 1.34; 95% confidence interval 1.01-1.77; P = .040). CONCLUSION: Preprocedural pharmacologic cardioversion could be a useful determinant for patients with treatable PeAF by PVI alone.

Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction.

BACKGROUND: Genetic variants in SCN10A, encoding the neuronal voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5. METHODS: The expression of SCN10A was investigated in mouse and human hearts. With the use of CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by genome-wide association studies single-nucleotide polymorphism mapping and expression quantitative trait loci analysis. RESULTS: We found that cardiomyocytes of the atria, sinoatrial node, and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, whereas full-length Scn10a transcript was undetectable in the human and mouse heart. Expression quantitative trait loci analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, whereas the expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that noncoding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts NaV1.5-mediated sodium current and heart rhythm. CONCLUSIONS: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that noncoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.

Electrocardiographic and electrophysiological characteristics of idiopathic ventricular arrhythmias originating from the vicinity of tricuspid annulus.

Electrocardiographic and electrophysiological characteristics of VAs originating from the vicinity of the TA are not fully understood. Hence, 104 patients (mean age 52.6 ± 17.9 years; 62 male) with VAs originating from the vicinity of the TA were enrolled. After electrophysiological evaluation and ablation, data were compared among those patients. The ECGs and the correction of the ECGs based on the long axis of the heart calculated from the chest X-Ray were also analyzed. VAs originating from the vicinity of TA had distinctive ECG characteristics that were useful for identifying the precise origin. Our localization algorithm adjusted by the angle between the cardiac long axis and the horizon was found to be accurate in predicting the exact ablation site in 92.3% (n = 96) cases. Logistic regression analysis showed fractionated electrograms, the magnitudes of the local atrial electrograms and a/V ratio were critical factors for successful ablation. Among the 104 patients with VAs, complete elimination could be achieved by RFCA in 96 patients (success rate 92.3%) during a follow-up period of 35.2 ± 19.6 months. This study suggests that the ablation site could be localized by ECG analysis adjusted by the angle between the cardiac long axis and the horizon. Fractionated electrograms, the magnitudes of the local atrial electrograms and a/V ratio were demonstrated to be critical factors for successful ablation.

First in situ 3D visualization of the human cardiac conduction system and its transformation associated with heart contour and inclination.

Current advanced imaging modalities with applied tracing and processing techniques provide excellent visualization of almost all human internal structures in situ; however, the actual 3D internal arrangement of the human cardiac conduction system (CCS) is still unknown. This study is the first to document the successful 3D visualization of the CCS from the sinus node to the bundle branches within the human body, based on our specialized physical micro-dissection and its CT imaging. The 3D CCS transformation by cardiac inclination changes from the standing to the lying position is also provided. Both actual dissection and its CT image-based simulation identified that when the cardiac inclination changed from standing to lying, the sinus node shifted from the dorso-superior to the right outer position and the atrioventricular conduction axis changed from a vertical to a leftward horizontal position. In situ localization of the human CCS provides accurate anatomical localization with morphometric data, and it indicates the useful correlation between heart inclination and CCS rotation axes for predicting the variable and invisible human CCS in the living body. Advances in future imaging modalities and methodology are essential for further accurate in situ 3D CCS visualization.