Circulation: Arrhythmia and Electrophysiology October 2018 Issue

Dr Paul Wang:   Welcome to the monthly podcast, On The Beat for Circulation: Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor-in-chief, with some of the key highlights from this month's issue.

                                In our first paper, Ruairidh Martin and associates used ultra-high-density mapping to access the ventricular tachycardia circuit dependent upon re-entry, with scar regions in 36 tachycardias in 31 patients. The author has found that 11 of the ventricular tachycardia circuits and isthmuses were single-loop, and 25 were double-loop. Three had two entrances, five had two exits, and fifteen had dead-end activation. Isthmuses were defined by barriers which included anatomical obstacles, lines of block, and slow conduction in 27 out of 36 isthmuses. The barrier to conduction in isthmus appeared to be partially functional in 75% of circuits. Isthmus voltage is often higher in ventricular tachycardia than in sinus or paced rhythms. The authors found that conduction velocity in the VT isthmus slowed at the isthmus entrances and exits when compared with mid-isthmus. The mean conduction velocity was 0.08 meters per second in entrance zones, 0.29 meters per second in isthmus regions, p < 0.0001, and 0.11 meters per second in exit regions. P = 0.002.

                                In our next paper Daniel Duprez and associates found that plasma collagen biomarkers, particularly at elevated levels, were associated with excess risk of atrial fibrillation. In a stratified sample of the Multi-Ethnic Study of Atherosclerosis (MESA), initially age 45 to 84 years, the authors examined in 3,071 participants plasma Procollagen Type III N-Terminal Propeptide, also known as P3NP, which reflects collagen synthesis in degradation in Collagen Type I Carboxy-Terminal Telopeptide, also known as ICTP, which reflects collagen degradation at baseline. The authors aimed to determine if the levels of these biomarkers were associated with incident atrial fibrillation in participants initially free of overt cardiovascular disease. Incident atrial fibrillation in ten-year follow-up was based on a hospital ICD code for atrial fibrillation or atrial flutter, in or outpatient Medicare claims, or ECG ten years after baseline. The authors found that baseline levels of these markers were positively related, both p < 0.0001 to incident atrial fibrillation in a model adjusting for age, race, ethnicity, and sex. These findings were attenuated but remain statistically significant after further adjustment for systolic blood pressure, height, body mass index, smoking, and renal function.

                                In our next paper, Ahmet Adiyaman and associates conducted a randomized controlled trial comparing the safety and efficacy of minimally invasive thoracoscopic pulmonary vein isolation with left atrial appendage ligation versus percutaneous catheter ablation pulmonary vein isolation. In 52 patients with symptomatic paroxysmal or early persistent atrial fibrillation, paroxysmal atrial fibrillation was present in 74% of patients. The authors found that percutaneous pulmonary vein isolation with a 56% single procedure arrhythmia-free survival at two years was not inferior to minimally invasive thoracoscopic pulmonary vein isolation with left atrial appendage ligation, which had a 29% arrhythmia freedom, p = 0.059. Procedure-related major adverse events occurred in 21% of patients undergoing minimally invasive thoracoscopic pulmonary vein isolation, compared to none undergoing percutaneous catheter ablation with p = 0.029.

                                In the next paper, Richard Ang and associates examined whether the glucagon-like peptide-1 receptor agonist exendin 4 has an effect on ventricular action potential duration in susceptibility to ventricular arrhythmia in the rat heart in vivo and ex vivo. Ventricular monophasic action potentials recorded in anesthetized rats in vivo in isolated profused rat hearts in sinus rhythm and/or ventricular pacing. In vivo systemic administration of exendin 4 increased heart rate and this effect was abolished by beta adrenoceptor blockade. Despite causing sympathetic activation, exendin 4 increased axon potential duration at 90% repolarization, APD90, during ventricular pacing by 7% and reversed the effect of beta adrenoceptor agonist Dobutamine on APD90. In isolated profused hearts, 3 nanomolar exendin 4 increased APD90 by 14% with no effect on heart rate. Exendin 4 also reduced ventricular arrhythmia inducibility in conditions of beta adrenoceptor stimulation with Isoproterenol. Exendin 4 effects on action potential duration in ventricular arrhythmia susceptibility were prevented in conditions of muscarinic receptor blockade or inhibition of nitric oxide synthase. The authors concluded that glucagon-like peptide-1 receptor activation effectively reverses the effects of beta adrenoceptor stimulation on cardiac ventricular excitability and reduces ventricular arrhythmic potential. The effect of glucagon-like peptide-1 receptor activation on the ventricular myocardium is indirect, mediated by acetylcholine and nitric oxide, and, therefore, might be explained by stimulation of cardiac parasympathetic neurons.

                                In our next paper, Michael Barkagan and associates examined the role of modulating baseline impedance on ablation lesion dimension. Radiofrequency ablation was performed using an irrigated catheter at a fixed power setting of 30 watts 20 seconds and a multi-step impedance load from 100 to 210Ω ex vivo in 20 swine hearts and in vivo in the right atrium and in thigh preparations. Ablation was performed using similar power settings at three baseline impedances: low, 90 to 130Ω; intermediate, 131 to 180Ω; and high, 181 to 224Ω. The relationship between baseline impedance, current, and lesion dimensions were examined. Baseline impedance had a strong negative correlation with current squared for all of these experimental models with R either -0.93 or -0.94. Lesion dimensions at similar power setting were directly related to current squared with R = 0.853 for width and R = 0.814 for depth. In thigh muscle lesion depth was greatest at low impedance, 8.2 millimeters, compared to 6.5 millimeters and intermediate impedance and 4.2 millimeters at high impedance, p < 0.0001. In right atrial lines, low baseline impedance resulted in wider lines, 7.2 millimeters, relative to intermediate 5.8 millimeters and high impedance, 4.7 millimeters, p < 0.0001.

                                In the next study, Virginie Dubes and David Benoist and associates examined the origin of ventricular arrhythmias in animal model of repair of tetralogy of Fallot. They studied six piglets undergoing tetralogy of Fallot repair-like surgery compared to five sham-operated piglets. Twenty-three weeks post-surgery, the authors found that right ventricular dysfunction was present, while left ventricular function was preserved in tetralogy of Fallot pigs. Optical mapping showed longer action potential duration on the tetralogy of Fallot left ventricular epicardial and endocardium. Epicardial conduction velocity was significantly reduced in the longitudinal direction but not the transverse direction in tetralogy of Fallot ventricles compared to sham. Elevated collagen content was found in left ventricular basal and apical sections from the tetralogy of Fallot pigs. The tetralogy of Fallot left ventricles had a lower threshold for arrhythmia induction using incremental pacing protocols.

                                In our next study, Meera Varshneya and associates sought to understand the individual roles of slow and rapid delayed rectifier potassium currents, IKS and IKR, and quantify how effectively each stabilize the actions potential, protecting cells against arrhythmias across multiple species. The authors compared ten mathematical models describing ventricular myocytes from human, rabbit, canine, and guinea pig. They examined variability within heterogeneous cell population, tested the susceptibility of cells to a pro-rhythmic behavior, and studied how IKS and IKR responded to changes in the action potential. They found, one, models of higher baseline IKS exhibited less cell-to-cell variability in action potential duration; two, models with higher baseline IKS were less susceptible to early afterdepolarizations induced by depolarizing perturbations; three, as action potential durations lengthened, IKS increases more profoundly than IKR, thereby providing negative feedback that resists excessive action potential duration prolongation; and four, the increase in IKS that occurs during β-Adrenergic stimulation is critical for protecting cardiac myocytes from early afterdepolarizations under these conditions. The authors concluded that slow, delayed rectifier current is uniformly protected across a variety of cell types, suggesting that IKS enhancement could be potentially anti-arrhythmic.

                                In our final paper, Piotr Podziemski and Stef Zeemering and associates performed a direct one-to-one comparison between phase and activation time mapping in high-density epicardial direct contact mapping files of human atrial fibrillation. The authors examined 38 unipolar electrum files of ten seconds duration recorded in 20 patients with atrial fibrillation using a 16 x 16 electrode array placed on the epicardial surface of the left atrial posterior wall or right atrial free wall. Using sinusoidal recomposition and Hilbert Transform, 138 phase singularities were detected, with 104 out of 138 phase singularities detected within on electro distance, 1.5 millimeters, from a line of conduction block between non-rotating wave fronts determined by activation mapping. Only 18 rotating wave fronts were detected out of 8,219 detected waves based on wave mapping. Fourteen out of these 18 cases were detected as phase singularities in phase mapping. Phase analysis of filter electrograms produced by simulated wave fronts separated by conduction block also identified phase singularities on the line of conduction block. The authors found that phase singularities identified by phase analysis of filter epicardial electrograms colocalized with conduction block lines identified by activation mapping. The authors concluded that detection of phase singularity using phase analysis has a low specificity for identifying rotating wave fronts using activation mapping of human atrial fibrillation.

                That's it for this month. We hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next time.