The identification of a pathogenic SCN5A variant confers an increased risk of conduction defects and ventricular arrhythmias (VA) in Brugada syndrome (BrS). However, specific aspects of sodium channel function that influence clinical phenotype have not been defined. A systematic literature search identified SCN5A variants associated with BrS. Sodium current (INa ) functional parameters (peak current, decay, steady-state activation and inactivation, and recovery from inactivation) and clinical features (conduction abnormalities [CA], spontaneous VA or family history of sudden cardiac death [SCD], and spontaneous BrS electrocardiogram [ECG]) were extracted. A total of 561 SCN5A variants associated with BrS were identified, for which data on channel function and clinical phenotype were available in 142. In the primary analysis, no relationship was found between any aspect of channel function and CA, VA/SCD, or spontaneous BrS ECG pattern. Sensitivity analyses including only variants graded pathogenic or likely pathogenic suggested that reduction in peak current and positive shift in steady-state activation were weakly associated with CA and VA/SCD, although sensitivity and specificity remained low. The relationship between in vitro assessment of channel function and BrS clinical phenotype is weak. The assessment of channel function does not enhance risk stratification. Caution is needed when extrapolating functional testing to the likelihood of variant pathogenicity.
Abstract Funding Acknowledgements British Heart Foundation Project Grant FS/17/54/33126 Background A key consideration when using animals in research is maximising experimental efficiency to minimise the number of animals required. Large animal models have proven an invaluable tool for establishing pathophysiological mechanisms underpinning atrial fibrillation (AF) and testing novel therapeutics, however animals may be resistant to developing the arrhythmias required. While the relationships between atrial refractory periods, conduction velocity, surface area, and vulnerability to fibrillation have been established in clinical practice, these parameters are not regularly used to design animal studies of persistent AF (PsAF). Purpose We investigated whether routinely collected baseline parameters could be used to improve experimental efficiency in an ovine model, by predicting the development of PsAF as opposed to arrhythmia resistance. The aims were to: reduce the number of animals used in future studies, and avoid prolonged experiments in animals likely to be resistant to AF. Methods All procedures were conducted with respect to the Animals [Scientific Procedures] Act, UK, 1986; and were approved by the local ethical review board. The ovine model consisted of healthy adult Welsh mountain sheep that underwent implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 30 second bursts of 50Hz and sheep were monitored over an eight week period for PsAF. Eight variables were collected at time of implant including weight (kg), left atrial diameter (LAD; cm), P wave duration (msec), PR interval (msec), atrial effective refractory period (ERP; msec), atrial conduction velocity (CV; m/s), AF inducibility with 50Hz bursts (secs), and rate threshold of atrial action potential alternans (msec). Analysis of the data was performed using multiple logistic regression and receiver-operator characteristic (ROC) curves. Regression coefficients are presented as natural logarithm of odds ratios (OR) with 95% confidence intervals (CI). Results Seventeen sheep were included in this study. Five (29%) developed PsAF whereas twelve (71%) were resistant (non-sustained or no AF). Univariate analysis found none of the parameters alone could predict PsAF, however ERP (OR -0.05, CI -.01 to 0.01, p = 0.089) and LAD (OR 8.1, CI -1.6 to 17.5, p = 0.095) suggested a combination may be predictive. A multivariate analysis using Fibrillation number (calculated as LAD / [ERP X CV]) was predictive (OR 26.9, CI 1.1 to 52.7; p = 0.04], with an area under ROC curve of 0.85 (p = 0.027). Conclusions Fibrillation number can predict the development of PsAF in healthy sheep. Practically speaking, this means animals with: a larger LAD, shorter ERP and slower CV are more likely to develop PsAF. These findings can be used to optimise the design of future studies, particularly by reducing the number of animals required.
Abstract Introduction Understanding the spatiotemporal location of the spontaneous termination of ventricular tachycardia (VT) may provide new insights for ablation. To test the hypothesis that spontaneous VT termination most frequently occurs at the VT exit due to source‐sink mismatch and to characterize electrophysiological properties of the sites termination during VT and with extra‐stimulus technique. Methods Retrospective analysis of intraoperative mapping studies of nine patients with ischemic cardiopathy or repaired tetralogy of Fallot. Simultaneous endocardial and epicardial mapping was performed in both ventricles using a custom mapping array during VT. Electrogram (EGM) characteristics before and at the moment of termination were analyzed including: cycle length oscillations, EGM heterogeneity and a variation in the systolic/diastolic path. The decrements to extra stimulus were analysed for termination sites and other diastolic sites. Results Nine VTs in seven patients demonstrated spontaneous VT termination. Seven VTs (77.8%) spontaneously terminated in the final third of the systolic interval, one (11.1%) in early diastole and one (11.1%) in mid diastole. Cycle length oscillations (prolongation, shortening, and no change) were seen in equal frequency. Four VTs (44.4%) showed alternans in the local EGM at the site of termination and this was more prevalent than alternans at other sites in the diastolic pathway ( p < .001). Only one‐third of VTs showed a change in activation pattern before termination. There was no difference based on etiology. During substrate characterization with extra‐stimulus pacing, sites of spontaneous termination showed greater decrement than other sites of the VT circuit during pacing (43.5 ± 14.5 ms vs. 31.2 ± 31.2 ms; p = .003). Conclusion The entrance zone rather than the exit is the commonest site for the spontaneous termination of VT in the human heart. These sites tend to demonstrate EGM alternans during VT and greater decrement during extrastimulus pacing. These findings may help guide future studies into improving the success of VT ablation.
Rastelli surgery is used for the correction of several CHDs. Although late-onset cardiac arrhythmias have emerged as a major complication after corrective surgeries, there is a paucity of data on arrhythmias after Rastelli surgery.
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