Faculty Bibliography

Rationale: Fibroblast growth factor homologous factors (FHFs) are key regulators of sodium channel inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced sodium channel availability in Fhf2 knockout mice predisposes to abnormal excitability at the tissue level are not well defined. Objective: Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction. Methods and Results:Fhf2^KO mice were challenged by reducing calcium conductance using verapamil or by reducing gap junctional conductance using carbenoxolone or by backcrossing into a connexin 43 heterozygous (Cx43^+/-) background. All conditions produced conduction block in Fhf2^KO mice, with Fhf2^WT showing normal impulse propagation. To explore the ionic mechanisms of block in Fhf2^KO hearts, multicellular linear strand models incorporating FHF2-deficient sodium channel inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced calcium conductance or gap junction uncoupling are very different. Enhanced sodium channel inactivation due to FHF2 deficiency shifts dependence onto calcium current to sustain electrotonic driving force, axial current flow, and action potential generation from cell-to-cell. In the setting of gap junction uncoupling, slower charging time from upstream cells conspires with accelerated sodium channel inactivation in mutant strands to prevent sufficient downstream cell charging for action potential propagation. Conclusions: FHF2-dependent effects on sodium channel inactivation ensure adequate sodium current reserve to safeguard against numerous threats to reliable cardiac impulse propagation.

OBJECTIVE:To compare multiple-procedure catheter ablation outcomes of a stepwise approach versus left atrial posterior wall isolation (LA PWI) in patients undergoing non-paroxysmal atrial fibrillation (NPAF) ablation. BACKGROUND:Unfavorable outcomes for stepwise ablation of NPAF in large clinical trials may be attributable to pro-arrhythmic effects of incomplete ablation lines. It is unknown if a more extensive initial ablation strategy results in improved outcomes following multiple ablation procedures. METHODS:222 consecutive patients with NPAF underwent first-time ablation using a contact-force sensing ablation catheter utilizing either a stepwise (Group 1, n=111) or LA PWI (Group 2, n=111) approach. The duration of follow-up was 36 months. The primary endpoint was freedom from atrial arrhythmia >30s. Secondary endpoints were freedom from persistent arrhythmia, repeat ablation, and recurrent arrhythmia after repeat ablation. RESULTS:There was similar freedom from atrial arrhythmias after index ablation for both stepwise and LA PWI groups at 36 months (60% vs. 69%, p=0.1). The stepwise group was more likely to present with persistent recurrent arrhythmia (29% vs 14%, p=0.005) and more likely to undergo second catheter ablation (32% vs. 12%, p<0.001) compared to LA PWI patients. Recurrent arrhythmia after repeat ablation was more likely in the stepwise group compared to the LA PWI group (15% vs 4%, p=0.003). CONCLUSIONS:Compared to a stepwise approach, LA PWI for patients with NPAF resulted in a similar incidence of any atrial arrhythmia, lower incidence of persistent arrhythmia, and fewer repeat ablations. Results for repeat ablation were not improved with a more extensive initial approach. This article is protected by copyright. All rights reserved.

BACKGROUND:There is no known effective therapy for patients with COVID-19. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP). OBJECTIVE:to assess the change in QTc interval and arrhythmic events in patients with COVID-19 treated with HY/AZ METHODS: This is a retrospective study of 251 patients from two centers, diagnosed with COVID-19 and treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality. RESULTS:QTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia (VT) suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting extreme QTc prolongation was normal. CONCLUSION/CONCLUSIONS:The combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.

Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity¹ or surgery², alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors^3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well established, whether such events impact cancer pathogenesis is not known. Here we show that myocardial infarction (MI) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6C^hi monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in both the circulation and tumor. In parallel, MI increased circulating Ly6C^hi monocyte levels and recruitment to tumors and depletion of these cells abrogated MI-induced tumor growth. Furthermore, patients with early-stage breast cancer who experienced cardiovascular events after cancer diagnosis had increased risk of recurrence and cancer-specific death. These preclinical and clinical results demonstrate that MI induces alterations in systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

Occult atrial fibrillation (AF) can be the underlying cause for cryptogenic stroke (CS). Implantable loop recorders (ILRs) have become an important tool for long-term arrhythmia monitoring in CS patients. Office-based ILR implantation by nonelectrophysiologist physicians is increasingly common. To report the real world diagnostic yield and accuracy of remote ILR monitoring in high risk CS patients, we retrospectively analyzed 145 consecutive patients with CS who underwent ILR implantation between October 2014 and October 2018 at New York University Langone Health. A certified device technician and an electrophysiologist adjudicated all transmissions. The yield and accuracy of Reveal LINQ Intra Cardiac Monitor (ICM), a fourth generation device, was compared to that of TruRhythm Detection algorithm (fifth generation device). AF was diagnosed in 17 patients (12%) over a mean follow-up of 28 ± 12 months. The median time to diagnosis was 7.4 ± 21.3 months. A total of 1,637 remote transmissions (scheduled- and auto-triggered alerts: 756; patient-triggered: 881) were adjudicated. The positive predictive value for AF episodes in the scheduled interrogations increased from 4% in the Reveal LINQ ICM to 16% in the TruRhythm LINQ. Of 881 patient-triggered transmissions, none were found to be true positive. In the Reveal LINQ ICM, for scheduled transmissions, primary causes of false positive (FP) were atrial ventricular premature complexes (80%). In the TruRhythm LINQ, for scheduled transmissions, primary cause of FP were T-wave over-sensing (87%). In conclusion, the real world diagnostic yield of ILR for patients with CS remains suboptimal, with at least 84% of AF alerts being FP. Patient-riggered events did not correlate with arrhythmia and the necessity of patient triggering in this population should be questioned. Expert interpretation of recordings is critical to assure accurate diagnosis.

Conducted energy weapon (commonly known as TASER) discharge in patients with implantable cardioverter-defibrillators is known to cause electromagnetic interference and inappropriate ventricular fibrillation sensing without delivery of implantable cardioverter-defibrillators therapy during conducted energy weapon application. We report the first known case of conducted energy weapon discharge resulting in inappropriate implantable cardioverter-defibrillators therapy. (Level of Difficulty: Beginner.).

INTRODUCTION/BACKGROUND:Catheter stability during atrial fibrillation ablation is associated with higher ablation success rates. Rapid cardiac pacing and high frequency jet ventilation (HFJV) independently improve catheter stability. Simultaneous modulation of cardiac and respiratory motion has not been previously studied. The objective of this study was to determine the effect of simultaneous heart rate and respiratory rate modulation on catheter stability. METHODS:Forty patients undergoing paroxysmal atrial fibrillation ablation received ablation lesions at 15 pre-specified locations (12 left atria, 3 right atria). Patients were randomly assigned to undergo rapid atrial pacing for either the first or the second half of each lesion. Within each group, half of patients received HFJV and half standard ventilation. Contact force and ablation data for all lesions were compared among the study groups. Standard deviation of contact force was the primary endpoint defined to examine contact force variability. RESULTS:Lesions with no pacing and standard ventilation had the greatest contact force standard deviation (5.86 + 3.08g), compared to lesions with pacing and standard ventilation (5.45+3.28g, p<0.01) or to lesions with no pacing and HFJV (4.92+3.00g, P<0.01). Lesions with both pacing and HFJV had the greatest reduction in contact force standard deviation, (4.35+2.81g, p<0.01), confirming an additive benefit of each maneuver. Pacing and HFJV together was also associated with a reduction in the proportion of lesions with excessive maximum contact force (p<0.001). DISCUSSION/CONCLUSIONS:Rapid pacing and HFJV additively improve catheter stability. Simultaneous pacing with HFJV further improves catheter stability over pacing or HFJV alone to optimize ablation lesions. This article is protected by copyright. All rights reserved.