Faculty Bibliography

Background: Analysis of the local unipolar electrogram aids premature ventricular contraction (PVC) localization in catheter ablation of idiopathic, outflow tract PVCs. A unipolar electrogram QS complex may be seen in the region of PVC origin, but the specificity of this finding is low. The unipolar anodal electrode utilized for PVC mapping is typically Wilson central terminal (WCT) or an indifferent electrode placed within the inferior vena cava (IVC). The optimal unipolar electrode selection for unipolar PVC mapping is unknown. Objective: To compare unipolar mapping of idiopathic outflow tract PVCs using WCT to unipolar mapping using an IVC electrode. Methods: PVC mapping and ablation was performed in 20 consecutive patients presenting for first-time ablation of idiopathic, outflow tract PVCs. The unipolar electrode utilized for initial mapping was randomly assigned and blinded to the operator. Mapping was performed using the CARTO 3 mapping system and SmartTouch RF ablation catheter (Biosense Webster, Inc.). Activation mapping and pace-mapping was performed at the discretion of the operator. Locations with a QS complex were annotated on the electroanatomic map. After a complete map was created blinded mapping was repeated with the alternate unipolar electrode prior to RF application. Results: PVCs were localized to the right ventricular outflow tract in 18 patients (90%) and to the left ventricular outflow tract in 2 patients (10%). Complete unipolar mapping could not be completed in 4 of 20 (20%) of cases due to infrequency of PVCs. In the 16 remaining patients, QS complex surface area was significantly larger with WCT than with the IVC electrode (3.11 +/- 1.8 cm² vs. 1.3 +/- 0.8 cm², p < 0.001). The IVC electrode QS area was completely within the WCT QS area in all cases, and the ratio of WCT QS area to IVC electrode QS area was 2.6 +/- 0.8 (range 1.8 to 4.4). The area of RF application at which PVCs were durably suppressed was within the IVC electrode QS area in all patients. Conclusion: Utilization of an indifferent IVC electrode may improve precision and specificity of unipolar mapping in catheter ablation of idiopathic, outflow tract PVCs

Background: Unfavorable outcomes observed with stepwise linear ablation of non-paroxysmal AF (NPAF) in large clinical trials utilizing ablation catheters without contact-force sensing (CFS) may be attributable to pro-arrhythmic effects of incomplete ablation lines. The optimal ablation strategy for catheter ablation of NPAF using a contact force sensing radiofrequency (RF) ablation catheter remains unclear. Objective: To compare catheter ablation outcomes of stepwise linear ablation to left atrial (LA) posterior wall isolation in patients undergoing NPAF ablation using a CFS RF ablation catheter. Methods: We performed pulmonary vein antral isolation (PVAI) followed by isolation of the LA posterior wall in 80 consecutive patients undergoing first-time NPAF ablation between November 2015 and March 2016 (Group 1) and compared clinical outcomes to those of 112 consecutive patients who underwent PVAI followed by step-wise linear ablation for NPAF between May 2014 and November 2015 (Group 2). All ablation procedures were performed using the Carto 3 mapping system and SmartTouch RF ablation catheter (Biosense Webster, Inc.). Arrhythmia recurrence was assessed using 2-week event monitors at 3-month intervals. Arrhythmia-free survival at 12 months was estimated using the Kaplan-Meier method. Results: Baseline characteristics of Group 1 and Group 2 were similar. At 12 months follow-up, arrhythmia-free survival was significantly greater in Group 1 patients compared with Group 2 (81.9% vs. 67.5%, respectively; p=0.0318). There was no significant difference in survival free from AF between group 1 and group 2 (89% vs. 84.1%, respectively; p=0.3431), however group 1 patients developed significantly fewer post-ablation atrial tachycardias (AT) than group 2 patients (8.1% vs 30.1%, respectively; p<0.001). Conclusion: Among patients undergoing NPAF ablation using a contact force sensing RF ablation catheter, LA posterior wall isolation resulted in fewer recurrent atrial arrhythmias than a stepwise linear approach. The reduction in recurrent atrial arrhythmias is driven primarily by a reduction in recurrent AT

AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 +/- 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 +/- 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 +/- 15 vs. 94 +/- 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. CONCLUSIONS: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy.

AIMS: Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbor desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown. METHODS AND RESULTS: To determine the role of desmosomes in pacemaker function, we generated a novel mouse model harboring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harboring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbor DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes. CONCLUSIONS: We provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.

Introduction: Large clinical trials have recently demonstrated stepwise linear ablation for non-paroxysmal atrial fibrillation (NPAF) to be inferior to pulmonary vein isolation alone. It is unknown whether the unfavorable outcomes observed in these trials can be attributed to the pro-arrhythmic effects of incomplete ablation lines. We hypothesized that improved lesion quality related to use of contact-force sensing (CFS) ablation catheters would improve procedural outcomes. Methods: We prospectively analyzed procedural outcomes of 74 consecutive patients with NPAF undergoing first-time radiofrequency catheter ablation with a CFS catheter (Smart Touch, Biosense Webster) using a step-wise approach (Group 1). The clinical outcomes of these patients were compared with 74 consecutive patients with NPAF who underwent catheter ablation between September 2013 and June 2014 with a non-contact force sense radiofrequency ablation catheter (Group 2) at a single tertiary care medical center. Arrhythmia recurrence was assessed using 2-week event monitors at 3-month intervals following index ablation. Results: Baseline characteristics of Group 1 and Group 2 were similar, although in Group 1 there was a greater prevalence of patients with persistent NPAF lasting for 6-months or longer prior to initial ablation (43% vs 21%, p=0.071). The recurrence rate at 1 year as estimated by the Kaplan-Meier method was not significantly different between Group 1 and Group 2 (25.7% vs 29.7%, p=0.582). The presenting recurrent arrhythmia was most frequently atrial tachycardia (AT) in both groups (Group 1: n=19, AT 68.4% and AF 31.6% vs Group 2: n=22, AT 59.1% and AF 40.9%). A similar proportion of patients in both groups underwent repeat ablation (Group 1: 17.6% vs Group 2: 13.5%, p=0.496). Conclusions: Utilization of a CFS ablation catheter was not associated with improved clinical outcomes for stepwise catheter ablation for NPAF. The optimal strategy for NPAF ablation using a contact-force sensing catheter remains undefined

Introduction: LA ablation for persistent AF that achieves organization to atrial tachycardia (AT) or sinus rhythm (SR) predicts greater long term ablation success. However, extensive LA ablation increases the risks of recurrent AT, adverse atrial remodeling and procedural complications. Preclinical and observational studies suggest that right atrial ablation may reduce AF risk. We hypothesized that CTI ablation may reduce the extent of LA ablation required to achieve organization of persistent AF. Methods: Persistent AF patients (n=107) were randomized to two arms (CTI-first or CTI-last) in a single center, prospective, single blind study. Excluding the CTI ablation, stepwise linear LA ablation was performed in a prespecified order. The primary endpoint was the percentage of patients who organized to AT or SR. The secondary endpoint was number of steps to organization. Results: CTI ablation first versus last during AF ablation did not significantly alter the percentage of patients who organized (Table). Among those who organized, the number of steps to organization did not differ between the two arms. No significant differences were found when patients were stratified by LA size or AF duration. Conclusions: CTI ablation does not alter the extent of LA ablation needed to achieve organization of AF. The utility of right atrial ablation for persistent AF ablation remains unclear. (Table presented)

Introduction: Transcatheter aortic valve replacement (TAVR) is becoming a widely accepted alternative treatment for patients with symptomatic aortic stenosis who are at high risk for surgical aortic valve replacement. A common complication of the procedure is the development of conduction defects requiring permanent pacemaker (PPM) implantation. It has been noted that in some patients, the conduction block is not permanent. Determine the incidence and predictors of resuming intrinsic conduction in patients that receive PPM implantation after TAVR. Methods: A retrospective chart review of patients undergoing TAVR at New York University Langone Medical Center was undertaken. Extracted data included patient demographics, pre-TAVR electrocardiogram, procedural, echocardiographic, catheterization, and device interrogation data. Evaluation of device interrogations done at one month follow-up or earlier to look for resumption of intrinsic conduction. Results: There were a total number of 451 patients who were status-post TAVR in our registry at NYU. Of the 451, 45 patients received a permanent pacemaker placement for complete heart block; 9.9% 45/451. The majority of patients were implanted within 48hrs post TAVR. Device follow-up information at 1 month or earlier was available for 33 of the 45 patients who received PPM. 5 patients who were recently implanted are still pending follow-up. 3 patients expired after implantation and 4 were lost to follow-up. Of the 33 patients, 14 (42%) patients had resumption of AV nodal conduction at 1 month follow-up. 19 patients (57%) remained dependent. Conclusions: 42% of patients who received a permanent pacemaker for complete heart block after TAVR had resumption of conduction. This suggests that many patients may not require long term PPM post TAVR. Patients that remained dependent had a higher incidence of preexisting RBBB and LAFB, however a lack thereof does not preclude an increased risk. These data suggest that waiting longer than 48 hours for resumption of AV nodal conduction would avoid unnecessary implantation in patients who develop complete heart block post TAVR

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 +/- 0.69 microM) or by extraction from T. iboga (3.53 +/- 0.16 microM); ibogaine's principal metabolite noribogaine (2.86 +/- 0.68 microM); and voacangine (2.25 +/- 0.34 microM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 microM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 microM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.