BackgroundAtrial septal defects (ASD) are associated with an increased incidence of atrial arrhythmias, but their electrophysiological consequences are poorly defined. We hypothesised that conduction and repolarisation would be preferentially altered in the right atrium of ASD patients.ObjectiveTo quantify atrial conduction and repolarisation in ASD patients and determine the impact of structural remodelling on restitution properties.MethodsPatients with an ASD (n = 22) underwent bi-atrial electroanatomic mapping and quantification of effective refractory periods, longitudinal and transverse local conduction. The control group comprised 24 patients without an ASD undergoing ablation for paroxysmal AF.ResultsBipolar voltage was significantly lower in ASD patients (right atrium: 1.53 ± 0.46 mV versus 1.98 ± 0.59 mV, P = 0.017; left atrium: 1.71 ± 0.36 mV versus 2.06 ± 0.63 mV, P = 0.039). There was no significant difference in global conduction velocity in either atrium between ASD and control patients. Effective refractory periods at 600 ms were not significantly different between patient groups (right atrium: 247 ± 34.7 ms versus 224 ± 36.5 ms, P = 0.071; left atrium: 244 ± 23.9 ms versus 232 ± 40.4 ms, P = 0.29). However, both conduction and repolarisation demonstrated greater rate adaptation in ASD patients in both atria.ConclusionRight atrial remodelling, characterised by atrial dilatation and increased low voltage, is present in ASD patients. During fixed rate pacing, conduction and repolarisation properties are similar between ASD and AF patients. However, the restitution properties of both conduction and repolarisation are more pronounced in ASD than AF patients.

BACKGROUND:Voltage mapping is integral to substrate assessment for ventricular tachycardia (VT) ablation; however, the spatial extent of myocardium contributing to a recorded electrogram signal remains poorly defined. Recent preclinical data assessed the relevant field of view (FOV) of 3.5 mm and 0.167 mm2 electrodes using cardiac magnetic resonance to quantify extent of viable myocardium (VM) and found FOVs of 10 millimeters and 8 millimeters, respectively. However, this is yet to be investigated with clinical data. OBJECTIVES:This study sought to assess the FOV of 1-mm and 460-μm electrodes clinically and to evaluate the ability of cardiac magnetic resonance and cardiac computed tomography (CCT) to predict voltage amplitude. METHODS:Patients undergoing VT ablation received preprocedural late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) and CCT with extracellular volume (ECV) estimation. VM was identified using standard LGE-CMR thresholds, ECV maps were computed from CCT, and unipolar voltage was recorded during ablation procedure. VM volume and volume-weighted ECV within multisize spheres around each electrode recording site were correlated with local voltage amplitude. RESULTS:A total of 16 patients were included; 15 had imaging-derived LGE-CMR/CCT-ECV analysis and 13 underwent left ventricular endocardial voltage mapping for FOV assessment. The FOV of both electrode sizes was determined to be 13 millimeters. Of the imaging modalities assessed, LGE-derived volume of VM produced the strongest correlations with voltage (1-mm electrode: r = 0.53; P < 0.001; 460-μm electrode: r = 0.49; P < 0.001). Volume-weighted ECV demonstrated weaker correlations (r = -0.34 and -0.24; P < 0.001). CONCLUSIONS:Clinical evaluation of 1-mm and 460-μm electrodes suggests a larger FOV than preclinical investigations. This quantifies a larger scale across which myocardial viability can influence unipolar electrogram signals observed during ablation procedures and suggests that smaller electrodes can improve spatial sampling density but do not necessarily provide a distinctly more localized characterization of the electrophysiologic properties of the tissue. LGE-CMR best predicted unipolar voltage, whereas CCT-ECV performed less well. Correlations were lower than expected, indicating the need for electrophysiologic assessment alongside comprehensive imaging.

Premature ventricular complexes (PVCs) are early ventricular contractions triggered by an ectopic focus from within the ventricle. They are common in the general population and may cause symptoms at any burden. They become clinically relevant in the context of symptoms or complications such as PVC-induced cardiomyopathy or, more rarely, PVC-triggered malignant ventricular arrhythmias. Investigating for underlying structural heart disease is essential in patients with clinically relevant PVCs as this will inform patient counselling and management options. Treatment is guided by symptoms or left ventricular dysfunction associated with PVCs. Management options include conservative management, medical therapy and catheter ablation. In this review, we discuss the definition of PVCs and how they may present, outline relevant investigations for these patients, and discuss management considerations and treatment options.

BACKGROUND:Catheter ablation of ventricular tachycardia (VT) is characterized by long procedures and frequent recurrence. Personalized image-based computational models may provide noninvasive ablation target guidance but are computationally demanding and cannot localize focal arrhythmias. OBJECTIVE:This study aims to clinically validate our near real-time in silico pace mapping (InSPM) approach, which rapidly localizes both focal and re-entrant arrhythmia site of origins within personalized image-based models. METHODS:Personalized models incorporating scar were reconstructed from imaging data in 18 patients with structural heart disease; 12-lead electrocardiogram (ECGs) were obtained during clinical pace mapping and pacing site locations defined as ground truth. ECG templates of induced monomorphic VT were obtained. Virtual pacing was conducted in models and simulated ECGs correlated with clinical templates to produce high-resolution virtual pace-maps. Distance (d) between clinical ground truth sites and simulation predicted target areas with highest correlation quantitatively assessed InSPM accuracy for localizing focal activations. For re-entrant VT, predicted targets were compared with surrogates of VT site of origin and mapped VT circuits. RESULTS:Intrinsic resolution of clinical pace mapping was approximately 4 mm for similarly correlated ECGs (mean correlation coefficient >0.99). Across 270 clinical pace-mapping locations, d was 8.2 mm (6.9‒12 mm), relatively insensitive to cardiomyopathy, but with increased accuracy in right vs left ventricles. Patient-specific ECG electrodes alongside accurate scar representation, particularly in patients with ischemia, were important for optimizing InSPM accuracy. InSPM created from clinical ECG VT templates reliably identified re-entrant VT exit sites. CONCLUSION:InSPM provides a rapid and validated personalized computational modeling ablation technology to accurately localize both focal and re-entrant VTs, which may be practically integrated into clinical workflows.

Background Extrastimulus pacing may identify ventricular tachycardia substrate by exposing decremental conduction, a proarrhythmic myocardial property. Functional conduction block may also occur during extrastimulus pacing but its relevance as a marker of arrhythmogenicity is unknown. Objectives This study sought to establish the differences in ventricular tachycardia substrate identification between steady-state (S1) and single extrastimulus (S2) pacing using isochronal late activation mapping deceleration zones (DZs). Methods S1 and S2 (ventricular effective refractory period +20 ms) maps were collected during right ventricular pacing. DZs were identified for all maps. Annotation delta (ΔS1S2), the difference in last deflection between S1 and S2, was calculated to identify regions demonstrating decremental conduction and functional conduction block. Changes in DZ location and ΔS1S2 were analyzed to identify altered substrate behavior evoked by the extrastimulus. Results Eleven patients (age 66 ± 10 years, 9 male) were included. DZ location was significantly different between S1 and S2 maps. Extrastimulus pacing revealed 5 DZs not identified during steady-state pacing, but functional conduction block masked 4 DZs on the S2 maps that were present on their corresponding S1 map. Regions of significant ΔS1S2 colocalized to the primary DZ in 19 of 22 maps, with no significant difference between the proportion of positive and negative delta observed (P = 0.898). Conclusions Extrastimulus pacing may change the location of DZs identified on isochronal late activation mapping maps and can reveal additional substrate; functional block can mask DZs on S2 maps. Analysis of both S1 and S2 maps facilitates more comprehensive substrate characterization, and regions demonstrating significant ΔS1S2 may represent important ablation targets.

Background Haemodynamic, hormonal and autonomic changes of pregnancy confer an increased propensity to arrhythmia. A small proportion of arrhythmias are complicated by tachycardia-induced cardiomyopathy (TCM) which can pose a severe threat to maternal and foetal health. Aim To report experience of catheter ablation in pregnant patients with atrial tachycardia (AT) complicated by TCM. Methods A retrospective review of electronic records of patients who had undergone catheter ablation of AT during pregnancy was performed. Results Three gravid patients (Age 40 ± 6, primigravida = 1, gestational age at symptom onset 23 ± 7 weeks) underwent catheter ablation between 2010 and 2023 for AT complicated by TCM. Of the 3 cases, 2 were twin pregnancies, one assisted by IVF. No patients had any prior cardiac history. Presenting rhythm in all patients was AT, resistant to rate +/- rhythm control. DC cardioversion was unsuccessful in 2 patients. Mean LVEF at presentation was 21 ± 14%. Two patients developed significant haemodynamic compromise pre-procedurally with 1 initiated on VA ECMO with Impella and the other retrieved for consideration of ECMO prior to ablation. Electrophysiology study with electroanatomic mapping (Carto: 2; EnSite: 1) revealed focal AT in all cases. Earliest activation was found at the crista terminalis (n=2) or lateral tricuspid annulus (n=1). Acute intra-procedural success was achieved in all patients with termination of AT following catheter ablation with no post procedural complications. Following restoration of sinus rhythm, LVEF rose to 33 ± 12% at a mean of 3 days and 47 ± 10% at a mean of 921 days post procedure. There was no arrhythmia recurrence at mean follow up of 948 days. Cardiac MRI in 1 patient showed no evidence of scar or fibrosis, indicative of non-ischaemic dilated cardiomyopathy and genetic testing was normal. All patients delivered via caesarean section with live births without foetal complications. Conclusions Catheter of maternal AT complicated by TCM is safe and feasible and requires meticulous pre-procedural planning with the support of a multi-disciplinary team. Where possible zero-fluoroscopic procedures are preferable. Conflict of Interest None

BACKGROUND:Peri-atrial adipose tissue is associated with atrial fibrillation (AF). Increased peri-atrial adipose volume and attenuation, detected by cardiac computed tomography angiography (CTA), have been observed in patients with AF. However, the electrophysiological correlates of both peri-atrial adipose tissue volume and attenuation are unknown. OBJECTIVES:This study sought to investigate the spatial relationship between peri-atrial adipose tissue, peri-atrial adipose tissue attenuation, and atrial electrophysiological remodeling. METHODS:Cardiac CTA was performed in 37 control subjects and 44 patients with AF. Left atrial bipolar voltage and conduction velocity were co-registered with cardiac CTA-derived peri-atrial adipose tissue segmentations. Mean adipose tissue volume and attenuation were compared with local voltage and conduction velocity measurements. RESULTS:Peri-atrial adipose tissue volume was greater in patients with AF (20.9 cm3 vs 14.2 cm3; adjusted odds ratio: 1.11; 95% CI: 1.01-1.24), independent of left atrial volume indexed to body mass index, left atrial mass, age, sex, sleep apnea, and coronary heart disease. In patients with AF, areas with the highest burden of peri-atrial adipose tissue had lower voltage (1.75 ± 1.72 mV vs 2.11 ± 2.02 mV; P < 0.001) and conduction velocity (0.627 ± 0.55 ms-1 vs 0.683 ± 0.48 ms-1; P < 0.001), compared with areas with the lowest burden of peri-atrial adipose tissue. Mean peri-atrial adipose tissue attenuation was similar in both groups. In patients with AF, low peri-atrial adipose tissue attenuation was weakly correlated with reduced bipolar voltage (1.69 ± 1.68 mV vs 2.16 ± 2.07 mV; P < 0.001) and conduction velocity (0.615 ± 0.47 ms-1 vs 0.684 ± 0.43 ms-1; P < 0.001). CONCLUSIONS:Peri-atrial adipose tissue volume was greater in patients with AF. Increased peri-atrial adipose tissue burden and reduced attenuation were spatially but weakly correlated with adverse electrophysiological remodeling in patients with AF.

Purpose of review Ventricular arrhythmias, including ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular complexes (PVCs), may occur in structurally normal hearts and in the context of structural heart disease. In those patients with recurrent arrhythmias despite medical therapy, catheter ablation may be considered. To successfully suppress ventricular arrhythmias, an understanding of the substrate for the arrhythmias is crucial. Recent findings Advances in cross-sectional imaging used prior to VT ablation permit accurate localisation of fibrosis that represents the substrate for VT, allowing an operator to focus the electrophysiologic assessment during a procedure and effectively target all relevant parts of the substrate. In addition, the use of imaging during a procedure allows registration of pre-procedural cross-sectional imaging as well as real-time substrate assessment and allows the operator to visualise tissue-catheter contact for the most effective lesion delivery. Summary In this review, the role of pre-procedural cardiac computed tomographic (CCT) imaging and cardiovascular magnetic resonance (CMR) imaging and the peri-procedural use of intra-cardiac echocardiography (ICE) are discussed.

The Human Leukocyte Antigen (HLA) region, located on the short arm of chromosome 6, is the most complex and polymorphic region in the human genome. This region's high structural and genetic diversity is the result of natural selection for the optimized capacity to detect pathogens and has resulted in extensive genetic variation across the human population. This selection of the HLA system for strong immunity has also contributed to human autoimmune disorders.

Ventricular tachycardia (VT) describes rapid heart rhythms originating from the ventricles. Accurate diagnosis of VT is important to allow prompt referral to specialist services for ongoing management. The diagnosis of VT is usually made based on electrocardiographic data, most commonly 12-lead echocardiography (ECG), as well as supportive cardiac telemetric monitoring. Distinguishing between VT and supraventricular arrhythmias on ECG can be difficult. However, the VT diagnosis frequently needs to be made rapidly in the acute setting. In this review, we discuss the definition of VT, review features of wide-complex tachycardia (WCT) on ECG that might be helpful in diagnosing VT, discuss the different substrates in which VT can occur and offer brief comments on management considerations for patients found to have VT.

Varying degrees of atrioventricular block can be associated with old age or a manifestation of an ischemic, metabolic, or infective pathology. In patients with no clear explanation, it is important to investigate secondary causes. Our case describes the first case of an adult with Rosai-Dorfman histiocytosis presenting with complete heart block. (Level of Difficulty: Advanced.).

Background Atrial fibrillation (AF) is associated with atrial septal defects (ASDs), but the mechanism of arrhythmia in these patients is poorly understood. We hypothesised that right-sided atrial ectopy may predominate in this cohort. Here, we aimed to localise the origin of spontaneous and provoked atrial ectopy in ASD patients. Methods Following invasive calibration of P-wave axes, 24-h Holter monitoring was used to determine the chamber of origin of spontaneous atrial ectopy. Simultaneous electrogram recording from multiple intra-cardiac catheters was used to determine the chamber of origin of isoprenaline-provoked ectopy. Comparison was made to a group of non-congenital heart disease AF patients. Results Amongst ASD patients, a right-sided origin for spontaneous atrial ectopy was significantly more prevalent than a left-sided origin (24/30 patients with right-sided ectopy vs. 14/30 with left-sided ectopy, P = 0.015). Amongst AF patients, there was no difference in the prevalence of spontaneous right vs. left-sided ectopy. For isoprenaline-provoked ectopy, there was no significant difference in the proportions of patients with right-sided or left-sided ectopy in either group. Conclusions When spontaneous atrial ectopy occurs in ASD patients, it is significantly more prevalent from a right-sided than left-sided origin. Isoprenaline infusion did not reveal the predilection for right-sided ectopy during electrophysiology study.

Atrial low voltage, measured during electroanatomic mapping, may indicate the presence of atrial fibrosis, has been implicated in atrial fibrillation perpetuation and shows useful associations with clinical outcomes. Low voltage is however a marker of the underlying substrate, but it is the electrophysiological properties of this substrate which are critical to arrhythmogenesis. Nevertheless, the influence of low voltage on in vivo conduction pattern dynamics is uncertain. Here, we develop a novel method for dynamic conduction velocity assessment. A central electrode pair of a multi-spline, multi-electrode catheter was used to apply a series of pacing trains (S1) followed by coupled premature extra stimulus (S2). For each S1S2 interval, two perpendicular electrodes were selected to calculate conduction velocities in longitudinal and transverse directions. Conduction velocity restitution curves were generated by plotting conduction velocity at each S1S2 interval. The slope of the line fitted to the descending part of the conduction velocity restitution curve showed a very good correlation with the percentage of low voltage area underlying the geodesic path connecting electrodes on which conduction velocity was calculated. (R 2 = 0.64). Using this novel method, we could achieve intraprocedural assessment of the effect of low voltage regions on conduction pattern dynamics.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Background Atrial voltage mapping and atrial cardiac magnetic resonance imaging are two contemporary methods for quantification of atrial fibrosis. However, the absence of a gold standard for measuring atrial fibrosis has precluded their direct comparison. Nevertheless, understanding the relative performance of voltage mapping and atrial late gadolinium enhancement for identification of atrial cardiomyopathy remains critical to correctly targeting clinical application of these techniques. Purpose To assess the relative performance of electroanatomic voltage mapping and atrial late gadolinium enhancement imaging using three surrogate markers chosen to distinguish pre-procedural utility (progression to recurrent atrial fibrillation following ablation) from potential utility for providing atrial fibrillation mechanistic insights (paroxysmal vs. persistent status of atrial fibrillation and relationship with co-morbidities associated with atrial fibrillation). Methods 123 patients underwent atrial late gadolinium enhancement imaging and electroanatomic voltage mapping prior to atrial fibrillation ablation. Atrial late gadolinium enhancement imaging was assessed with CEMRG software and electroanatomic voltage mapping processed with OpenEP software using previously published thresholds. Low voltage tissue was defined at (1) <0.5mV, (2) <1.17mV, and (3) <1.3mV. Atrial fibrosis using late gadolinium enhancement was defined using four thresholds (1) signal intensity >3.3 standard deviations above the blood pool mean; (2) image intensity ratio (IIR) 1.2x blood pool mean; (3) IIR 1.32x blood pool mean; and (4) IIR 0.97x blood pool mean. Results Patients with persistent atrial fibrillation and those with CHA2DS2VaSc >2 had increased low voltage area for each of the thresholds tested, but there was no increase in atrial late gadolinium enhancement area at any of the imaging thresholds tested. Increased atrial fibrosis using IIR>0.97 was independently associated with recurrence of atrial fibrillation (OR 1.05 (CI 1.01-1.09), p=0.009) in both univariate and multivariate analysis. Low voltage area <1.13mV and low voltage area <1.17mV were associated with increased risk of recurrence (OR 1.02 (CI 1.01-1.04), p=0.01, and OR 1.03 (CI 1.01-1.04), p=0.009) in univariate analysis but neither voltage threshold remained statistically significant in multivariate analysis controlling for clinical variables. Conclusion Increased fibrosis burden measured with atrial magnetic resonance imaging, but not with low voltage area, is independently associated with recurrence of atrial fibrillation following catheter ablation. However, increased low voltage area measured with electroanatomic mapping is associated with persistent atrial fibrillation status and CHADS2VaSc score. These findings support the use of magnetic resonance imaging for pre-procedure assessment and the use of electroanatomic mapping for intraprocedural mechanism-based assessment of atrial cardiomyopathy.

Aims Atrial septal defects (ASD) are associated with atrial arrhythmias, but the arrhythmia substrate in these patients is poorly defined. We hypothesized that bi-atrial fibrosis is present and that right atrial fibrosis is associated with atrial arrhythmias in ASD patients. We aimed to evaluate the extent of bi-atrial fibrosis in ASD patients and to investigate the relationships between bi-atrial fibrosis, atrial arrhythmias, shunt fraction, and age. Methods and results Patients with uncorrected secundum ASDs (n = 36; 50.4 +/- 13.6 years) underwent cardiac magnetic resonance imaging with atrial late gadolinium enhancement. Comparison was made to non-congenital heart disease patients (n = 36; 60.3 +/- 10.5 years) with paroxysmal atrial fibrillation (AF). Cardiac magnetic resonance parameters associated with atrial arrhythmias were identified and the relationship between bi-atrial structure, age, and shunt fraction studied. Bi-atrial fibrosis burden was greater in ASD patients than paroxysmal AF patients (20.7 +/- 14% vs. 10.1 +/- 8.6% and 14.8 +/- 8.5% vs. 8.6 +/- 6.1% for right and left atria respectively, P = 0.001 for both). In ASD patients, right atrial fibrosis burden was greater in those with than without atrial arrhythmias (33.4 +/- 18.7% vs. 16.8 +/- 10.3%, P = 0.034). On receiver operating characteristic analysis, a right atrial fibrosis burden of 32% had a 92% specificity and 71% sensitivity for predicting the presence of atrial arrhythmias. Neither age nor shunt fraction was associated with bi-atrial fibrosis burden. Conclusion Bi-atrial fibrosis burden is greater in ASD patients than non-congenital heart disease patients with paroxysmal AF. Right atrial fibrosis is associated with the presence of atrial arrhythmias in ASD patients. These findings highlight the importance of right atrial fibrosis to atrial arrhythmogenesis in ASD patients.

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.