POPDC1 Variants Cause Atrioventricular Node Dysfunction and Arrhythmogenic Changes in Cardiac Electrophysiology and Intracellular Calcium Handling in Zebrafish.

Popeye domain-containing (POPDC) proteins selectively bind cAMP and mediate cellular responses to sympathetic nervous system (SNS) stimulation. The first discovered human genetic variant (POPDC1S201F) is associated with atrioventricular (AV) block, which is exacerbated by increased SNS activity. Zebrafish carrying the homologous mutation (popdc1S191F) display a similar phenotype to humans. To investigate the impact of POPDC1 dysfunction on cardiac electrophysiology and intracellular calcium handling, homozygous popdc1S191F and popdc1 knock-out (popdc1KO) zebrafish larvae and adult isolated popdc1S191F hearts were studied by functional fluorescent analysis. It was found that in popdc1S191F and popdc1KO larvae, heart rate (HR), AV delay, action potential (AP) and calcium transient (CaT) upstroke speed, and AP duration were less than in wild-type larvae, whereas CaT duration was greater. SNS stress by ß-adrenergic receptor stimulation with isoproterenol increased HR, lengthened AV delay, slowed AP and CaT upstroke speed, and shortened AP and CaT duration, yet did not result in arrhythmias. In adult popdc1S191F zebrafish hearts, there was a higher incidence of AV block, slower AP upstroke speed, and longer AP duration compared to wild-type hearts, with no differences in CaT. SNS stress increased AV delay and led to further AV block in popdc1S191F hearts while decreasing AP and CaT duration. Overall, we have revealed that arrhythmogenic effects of POPDC1 dysfunction on cardiac electrophysiology and intracellular calcium handling in zebrafish are varied, but already present in early development, and that AV node dysfunction may underlie SNS-induced arrhythmogenesis associated with popdc1 mutation in adults.

Voltage and propagation mapping: New tools to improve successful ablation of atrioventricular nodal reentry tachycardia.

INTRODUCTION: Mapping system is useful in ablation of atrioventricular nodal reentry tachycardia (AVNRT) and localization of anatomic variances. Voltage mapping identifies a low voltage area in the Koch triangle called low-voltage-bridge (LVB); propagation mapping identifies the collision point (CP) of atrial wavefront convergence. We conducted a prospective study to evaluate the relationship between LVB and CP with successful site of ablation and identify standard value for LVB. MATERIALS AND METHODS: Three-dimensional (3D) maps of the right atria were constructed from intracardiac recordings using the ablation catheter. Cut-off values on voltage map were adjusted until LVB was observed. On propagation map, atrial wavefronts during sinus rhythm collide in the site representing CP, indicating the area of slow pathway conduction. Ablation site was selected targeting LVB and CP site, confirmed by anatomic position on fluoroscopy and atrioventricular ratio. RESULTS: Twenty-seven consecutive patients were included. LVB and CP were present in all patients. Postprocedural evaluation identified standard cut-off of 0.3-1 mV useful for LVB identification. An overlap between LVB and CP was observed in 23 (85%) patients. Procedure success was achieved in all patient with effective site at first application in 22 (81%) patients. There was a significant correlation between LVB, CP, and the site of effective ablation (p = .001). CONCLUSION: We found correlation between LVB and CP with the site of effective ablation, identifying a voltage range useful for standardized LVB identification. These techniques could be useful to identify ablation site and minimize radiation exposure.

Reversible Pulsed Electrical Fields as an In Vivo Tool to Study Cardiac Electrophysiology: The Advent of Pulsed Field Mapping.

BACKGROUND: During electrophysiological mapping of tachycardias, putative target sites are often only truly confirmed to be vital after observing the effect of ablation. This lack of mapping specificity potentiates inadvertent ablation of innocent cardiac tissue not relevant to the arrhythmia. But if myocardial excitability could be transiently suppressed at critical regions, their suitability as targets could be conclusively determined before delivering tissue-destructive ablation lesions. We studied whether reversible pulsed electric fields (PFREV) could transiently suppress electrical conduction, thereby providing a means to dissect tachycardia circuits in vivo. METHODS: PFREV energy was delivered from a 9-mm lattice-tip catheter to the atria of 12 swine and 9 patients, followed by serial electrogram assessments. The effects on electrical conduction were explored in 5 additional animals by applying PFREV to the atrioventricular node: 17 low-dose (PFREV-LOW) and 10 high-dose (PFREV-HIGH) applications. Finally, in 3 patients manifesting spontaneous tachycardias, PFREV was applied at putative critical sites. RESULTS: In animals, the immediate post-PFREV electrogram amplitudes diminished by 74%, followed by 78% recovery by 5 minutes. Similarly, in patients, a 69.9% amplitude reduction was followed by 84% recovery by 3 minutes. Histology revealed only minimal to no focal, superficial fibrosis. PFREV-LOW at the atrioventricular node resulted in transient PR prolongation and transient AV block in 59% and 6%, while PFREV-HIGH caused transient PR prolongation and transient AV block in 30% and 50%, respectively. The 3 tachycardia patients had atypical atrial flutters (n=2) and atrioventricular nodal reentrant tachycardia. PFREV at putative critical sites reproducibly terminated the tachycardias; ablation rendered the tachycardias noninducible and without recurrence during 1-year follow-up. CONCLUSIONS: Reversible electroporation pulses can be applied to myocardial tissue to transiently block electrical conduction. This technique of pulsed field mapping may represent a novel electrophysiological tool to help identify the critical isthmus of tachycardia circuits.

High Dominant Frequencies and Fractionated Potentials Do Not Indicate Focal or Rotational Activation During AF.

BACKGROUND: Dominant frequencies (DFs) or complex fractionated atrial electrograms (CFAEs), indicative of focal sources or rotational activation, are used to identify target sites for atrial fibrillation (AF) ablation in clinical studies, although the relationship among DF, CFAE, and activation patterns remains unclear. OBJECTIVES: This study sought to investigate the relationship between patterns of activation underlying DF and CFAE sites during AF. METHODS: Epicardial high-resolution mapping of the right and left atrium including Bachmann's bundle was performed in 71 participants. We identified the highest dominant frequency (DFmax) and highest degree of CFAE (CFAEmax) with the use of existing clinical criteria and classified patterns of activation as focal or rotational activation and smooth propagation, conduction block (CB), collision and remnant activity, and fibrillation potentials as single, double, or fractionated potentials containing, respectively, 1, 2, or 3 or more negative deflections. Relationships among activation patterns, DFmax, and potential types were investigated. RESULTS: DFmax were primarily located at the left atrioventricular groove and did not harbor focal activation (proportion focal waves: 0% [IQR: 0%-2%]). Compared with non-DFmax sites, DFmax were characterized by more frequent smooth propagation (22% [IQR: 7%-48%] vs 17% [IQR: 11%-24%]; P = 0.001), less frequent conduction block (69% [IQR: 51%-81%] vs 74% [IQR: 69%-78%]; P = 0.006), a higher proportion of single potentials (72% [IQR: 55%-84%] vs 6%1 [IQR: 55%-65%]; P = 0.003), and a lower proportion of fractionated potentials (4% [IQR: 1%-11%] vs 12% [IQR: 9%-15%]; P = 0.004). CFAEmax were mainly found at the pulmonary veins area, and only 1% [IQR: 0%-2%] of all CFAEmax contained focal activation. Compared with non-CFAEmax sites, CFAEmax sites were characterized by less frequent smooth propagation (1% [IQR: 0%-1%] vs 17% [IQR: 12%-24%]; P < 0.001) and more frequent remnant activity (20% [IQR: 12%-29%] vs 8% [IQR: 5%-10%]; P < 0.001), and harbored predominantly fractionated potentials (52% [IQR: 43%-66%] vs 12% [IQR: 9%-14%]; P < 0.001). CONCLUSIONS: Focal or rotational patterns of activation were not consistently detected at DFmax domains and CFAEmax sites. These findings do not support the concept of targeting DFmax or CFAEmax according to existing criteria for AF ablation.

Junctional Tachycardia: A Critical Reassessment.

Junctional tachycardia (JT) is typically considered to have an automatic mechanism originating from the distal atrioventricular node. When there is 1:1 retrograde conduction via the fast pathway, JT would resemble the typical form of atrioventricular nodal re-entrant tachycardia (AVNRT). Atrial pacing maneuvers have been proposed to exclude AVNRT and suggest a diagnosis of JT. However, after excluding AVNRT, one should consider the possibility of an infra-atrial narrow QRS re-entrant tachycardia, which can exhibit features that resemble AVNRT as well as JT. Pacing maneuvers and mapping techniques should be performed to assess for infra-atrial re-entrant tachycardia before concluding that JT is the mechanism of a narrow QRS tachycardia. Distinguishing JT from typical AVNRT or infra-atrial re-entrant tachycardia has notable implications regarding the approach to ablation of the tachycardia. Ultimately, a contemporary review of the evidence on JT raises some questions as to the mechanism and source of what has traditionally been considered JT.

An unusual case of non-reentrant atrioventricular nodal tachycardia.

INTRODUCTION: Although uncommonly encountered, dual atrioventricular nodal non-reentrant tachycardia (DAVNNRT) is a well-described arrhythmia that can manifest in patients with dual atrioventricular nodal pathways physiology. This arrhythmia is characterized on electrocardiogram (ECG) by a single P wave followed by two conducted QRS complexes (so-called "double fire"), and on intracardiac electrograms by a single atrial electrogram followed by two separate His deflections and ventricular electrograms. METHODS/RESULTS: We report a rare case of "triple-fire" atrioventricular non-reentrant tachycardia in which a patient was found to have three distinct atrioventricular nodal pathways and multiple triple fire responses, both on surface ECG and intracardiac electrograms. CONCLUSION: Multiple pathways physiology and it's clinical ramifications are discussed.

Para-Hisian Pacing During Sinus Rhythm: Establishing Threshold Values to Distinguish Nodal From Septal Pathway Conduction.

OBJECTIVES: This study sought to identify minimum threshold values below which conduction over the atrioventricular (AV) node would be unexpected. BACKGROUND: Para-Hisian pacing is used to evaluate for the presence of a septal accessory pathway (AP); however, threshold values to differentiate nodal from AP conduction are unknown. METHODS: The authors performed high- and low-output para-Hisian pacing during sinus rhythm to capture the His and para-Hisian ventricular myocardium (H+V) and para-Hisian ventricular myocardium (V) alone, respectively. The change in stimulation (stim)-to-atrial electrogram interval after loss of His bundle capture in patients with (AP+) and without (AP-) a septal AP was evaluated. Stim-to-proximal coronary sinus (PCS) and stim-to-high right atrium (HRA) intervals were measured and within-patient differences (△) for V and H+V capture were calculated. RESULTS: A total of 23 AP+ and 45 AP- patients were evaluated. The difference in stimulus to earliest atrial signal in the high right atrial catheter seen with the loss of His bundle capture (△-stim-HRA) (21 ms; interquartile range [IQR]: 3 to 43 ms vs. 64 ms; IQR: 56 to 73 ms; p < 0.001) and difference in stimulus to earliest atrial signal in the proximal coronary sinus catheter seen with the loss of His Bundle capture (△-stim-PCS) (11 ms; IQR: 0 to 30 ms vs. 61 ms; IQR: 52 to 72 ms; p < 0.001) were shorter in AP+ patients. The shortest △-stim-PCS and △-stim-HRA in AP- patients were 37 ms and 32 ms, respectively, whereas the longest corresponding intervals in AP+ patients were 51 ms and 75 ms, respectively. CONCLUSIONS: A △-stim-PCS <37 ms or △-stim-HRA <32 ms confirmed the presence of a septal AP, whereas a value >51 ms for △-stim-PCS or >75 ms for △-stim-HRA excluded it. Alternatively, the minimum △-stim-PCS with loss of His capture compatible with AV nodal conduction in isolation was 37 ms, and a △-stim-PCS >51 ms effectively ruled out the presence of a septal AP.

Unique electrophysiological properties of fast-slow atrioventricular nodal reentrant tachycardia characterized by a shortening of retrograde conduction time via a slow pathway manifested during atrial induction.

INTRODUCTION: Electrophysiological properties of reentry circuits of fast-slow atrioventricular nodal reentrant tachycardia (F/S-AVNRT) may contribute to cyclic variability after atrial induction. METHODS: In 156 atrial inductions of 33 patients with F/S-AVNRT, we measured the atrio-His (AH) and His-atrial (HA) intervals in the first cycle after the induction (AH[1] and HA[1], respectively), those in the second cycle (AH [2] and HA [2], respectively), and those during tachycardia that maintained a stable cycle length AH[T] and HA[T], respectively), and calculated the value of AH(1) minus AH(T) [ΔAH] and the value of HA(1) minus HA(T) [ΔHA] in each induction. According to the sum of ΔAH and ΔHA, tachycardia variability was classified as incremental (<-20), balanced (-20 to 20), or decremental (>20). RESULTS: ΔAH and ΔHA were significantly different between the three responses: 6 ± 28 and -67 ± 39 in 55 inductions (35%) with an incremental response, 20 ± 10 and -23 ± 28 in 59 (38%) with a balanced response, and 54 ± 44 and 4 ± 50 in 42 (27%) with a decremental response, respectively. Incremental response was reproducibly and consistently observed in 33% of patients. HA(2) was similar to HA(T) in inductions with an incremental response. These results suggest that incremental response can be manifested only in the first cycle when HA(1) is excessively shortened, approximating a retrograde conduction time over a slow pathway, in contrast, and far superior to a decremental delay of AH(1). CONCLUSION: In specific patients with F/S-AVNRT, poorly recognized, electrophysiological properties of shortening a retrograde conduction time over a slow pathway was manifested during atrial induction.

New-onset intrinsic and paced QRS morphology of right bundle branch block pattern after atrioventricular nodal ablation: Longitudinal dissociation or anatomical bifurcation?

We performed left bundle pacing combined with atrioventricular nodal (AVN) ablation in a patient with persistent atrial fibrillation and refractory symptomatic heart failure. The major findings were new-onset intrinsic and paced QRS morphology of right bundle branch block (RBBB) pattern after AVN ablation which was performed at a more atrial site compared with the pacing site and the paced RBBB pattern could not be corrected regardless of the pacing output. Longitudinal dissociation cannot explain this observation, while anatomical separation could. We also confirm this was proximal left bundle pacing rather than His bundle pacing.

Demonstration of the Anatomical Tachycardia Circuit in Sinoatrial Node Reentrant Tachycardia: Analysis Using the Entrainment Method.

Background The anatomical tachycardia circuit of sinoatrial node reentrant tachycardia (SANRT) has not been well clarified. This study aimed to elucidate the tachycardia circuit of SANRT. Methods and Results Exit and entrance of the intranodal sinoatrial node conduction (I-SANC) of the reentry circuit were identified in 15 SANRT patients. After identifying the earliest atrial activation site (EAAS) during the tachycardia (EAAS-SANRT), rapid atrial pacing was delivered from multiple atrial sites to identify the entrainment pacing site where manifest entrainment and orthodromic capture of the EAAS-SANRT were demonstrated. Radiofrequency energy was then delivered starting at a site 2 cm proximal to the EAAS-SANRT in the direction of the entrainment pacing site and gradually advanced toward the EAAS-SANRT until tachycardia termination to localize the I-SANC entrance. The EAAS-SANRT was orthodromically captured by pacing delivered from the distal coronary sinus (n=7), high posteroseptal right atrium (n=2), low posteroseptal right atrium (n=2), low anterolateral right atrium (n=2), or coronary sinus ostium (n=2). Radiofrequency energy delivery to the entrance of the I-SANC, 10.4±2.8 mm away from the EAAS-SANRT, terminated tachycardia immediately after onset of energy delivery (3.4±2.3 seconds). The successful ablation site was located further from the EAAS during sinus rhythm (EAAS-sinus) than the EAAS-SANRT (12.8±4.5 versus 7.2±3.1 mm; P<0.0001). Conclusions The reentry circuit of SANRT was composed of the entrance and exit of the I-SANC being located at distinctly different anatomical sites. SANRT was eliminated by radiofrequency energy delivered to the I-SANC entrance, which was further from the EAAS-sinus than I-SANC exit.

Para-Hisian Pacing: New Insights of an Old Pacing Maneuver.

More than 2 decades ago, para-Hisian pacing was introduced to assess the pattern of retrograde conduction during electrophysiological studies. Although there is no ideal maneuver for every patient and condition, para-Hisian pacing is a valuable and handy strategy to differentiate between retrograde conduction over the atrioventricular node and the accessory pathways. The dynamic behavior of para-Hisian pacing, in a region with unique anatomical features, can produce various activation patterns and intriguing electrophysiological phenomena. Although the demonstration of a retrograde nodal activation pattern during para-Hisian pacing does not rule out the presence of an accessory pathway, evidence of retrograde conduction over an accessory pathway does not prove its active role in the culprit tachycardia. Multipolar His bundle recordings, detailed atrial mapping, and recognition of the truly captured structures and the impact of temporal changes of autonomic tone or pacing rates, are essential keys for accurate interpretation of this maneuver that may ultimately guide judicious catheter ablation of the arrhythmic substrate. This review aims to summarize the practical usefulness and potential pitfalls of the para-Hisian pacing maneuver, focusing on the interpretation of electrocardiograms and intracardiac recordings.

A safe and simple approach to avoid fast junctional rhythm during ablation in patients with atrioventricular nodal reentrant tachycardia.

INTRODUCTION: Fast junctional rhythm (JR) during slow pathway modification for atrioventricular nodal reentrant tachycardia (AVNRT) is a predictor of serious atrioventricular block. This study investigated the boundary to avoid fast JR during ablation with three-dimensional (3D) electroanatomical mapping in AVNRT patients. METHODS AND RESULTS: Participants were 129 consecutive patients with common AVNRT who received anatomical ablation to an antegrade slow pathway at our institution between August 2013 and March 2019. Successfully ablated sites with JR were evaluated in terms of distances and angles in the left and right anterior oblique views (LAO and RAO, respectively) to the proximal His bundle (His) site using 3D mapping. We divided JR by heart rate: JR1 ≥150 bpm and JR2 <150 bpm. Average age was 61 ± 16 years; 41.1% of patients were male. The distance from the most proximal His to the JR1 and JR2 site was not significantly different (11.9 ± 4.4 vs 10.7 ± 4.5 mm, P = .24). JR1 predominantly appeared closer to the left ventricle than JR2 in LAO (110.5 ± 19.1° vs 77.5 ± 18.6°, P < .01), and was more posterior from the proximal His in RAO (30.8% vs 6.8%, P < .01). The vertical line drawn down from the proximal His in the LAO view was a good indicator of JR1 appearance (sensitivity and specificity 84.6% and 81.6%, respectively). CONCLUSION: The vertical line drawn down from the proximal His in the LAO view can be employed as a boundary to avoid fast JR during ablation in AVNRT.

Should fast pathway ablation be reconsidered in typical atrioventricular nodal re-entrant tachycardia?

INTRODUCTION: Atrioventricular nodal re-entry tachycardia (AVNRT) is the most common, regular narrow-complex tachycardia. The established treatment is catheter ablation of the AV nodal slow pathway (SP). However, in a select group of patients with long PR intervals in sinus rhythm, SP ablation can lead to AV block due to the absence of robust anterograde conduction through the fast pathway (FP). This report aims to demonstrate that AV nodal FP ablation is a reasonable approach in patients with AVNRT and poor or absent anterograde FP conduction. METHODS AND RESULTS: Standard electrophysiology study techniques were used in the electrophysiology laboratory. Catheter ablations were performed using radiofrequency energy. Mapping of intracardiac activation was performed with electroanatomical mapping systems. Outcomes were assessed acutely during the procedure and during routine clinical follow-up. Six patients with first-degree AV block and recurrent AVNRT who underwent ablation of their tachycardia at our institution are presented. One patient underwent ablation of AV nodal SP resulting in high-degree AV block necessitating pacemaker implantation. The remaining five patients underwent ablation of the AV nodal FP guided by electroanatomical mapping of the earliest atrial activation in tachycardia. These five had successful treatment of the tachycardia with preservation of anterograde AV nodal conduction. Mapping and ablation approach to eliminate retrograde FP conduction are described. CONCLUSION: In select patients with AVNRT and poor anterograde FP conduction, retrograde FP ablation is reasonable and is less likely to result in AV block and pacemaker dependency.