Faculty Bibliography

BACKGROUND:The prolongation in QT interval typically observed following cardiac arrest is considered to be multifactorial and induced by external triggers such as hypothermia therapy and exposure to antiarrhythmic medications. OBJECTIVE:To evaluate the corrected QT interval (QTc) dynamics in the first 10 days following cardiac arrest with respect to the etiology of arrest, hypothermia and QT prolonging medications. METHODS:We enrolled 104 adult survivors of cardiac arrest, where daily ECG was available for at least 3 days. We followed their QT and QRS intervals for the first 10 days of hospitalization. We used both Bazett and Fridericia formulas to correct for heart rate. For patients with QRS < 120 we analyzed the QTc interval (n = 90) and for patients with QRS > 120 ms we analyzed the JTc (n = 104) vs. including only the narrow QRS samples (n = 89). We stratified patients by 3 groups: (1) presence of ischemic heart disease (IHD) (2) treatment with hypothermia protocol, and (3) treatment with QTc prolonging medications. Additionally, genetic information obtained during hospitalization was analyzed. RESULTS:QTc and JTc intervals were significantly prolonged in the first 6 days. Maximal QTc/JTc prolongation was observed in day 2 (QTcB = 497 ± 55). There were no differences in daily QTc/JTc and QRS intervals in the first 2 days post arrest between patients with or without hypothermia induction but such difference. All subgroups demonstrated significantly prolonged QTc/JTc interval regardless of the presence of IHD, hypothermia protocol or QTc prolonging medication exposure. Our results were consistent for both Bazetts' and Frediricia correction and for any QRS duration. Prolongation of the JTcB beyond 382 ms after day 3 predicted sustained QTc/JTc prolongation beyond day 6 with an ROC of 0.78. CONCLUSIONS:QTc/JTc interval is significantly and independently prolonged post SCA, regardless of known QT prolonging triggers. Normalization of the QTc post cardiac arrest should be expected only after day 6 of hospitalization. Assessment of the QTc for adjudication of the etiology of arrest or for monitoring the effect of QT prolonging medications may be unreliable.

Background: Elevated intracardiac pressure due to heart failure induces electrical and structural remodeling in the left atrium (LA) that begets atrial myopathy and arrhythmias. The underlying molecular pathways that drive atrial remodeling during cardiac pressure overload are poorly defined. The purpose of this study is to characterize the response of the ETV1 signaling axis in the LA during cardiac pressure overload in humans and mouse models and explore the role of ETV1 in atrial electrical and structural remodeling. Methods: We performed gene expression profiling in 265 left atrial samples from patients who underwent cardiac surgery. Comparative gene expression profiling was performed between two murine models of cardiac pressure overload, transverse aortic constriction (TAC) banding and Angiotensin II (AngII) infusion, and a genetic model of Etv1 cardiomyocyte-selective knockout (Etv1^f/fMlc2a^Cre/+). Results: Using the Cleveland Clinic biobank of human LA specimens, we found that ETV1 expression is decreased in patients with reduced ejection fraction. Consistent with its role as an important mediator of the Neuregulin-1 (NRG1) signaling pathway and activator of rapid conduction gene programming, we identified a direct correlation between ETV1 expression level and NRG1, ERBB4, SCN5A, and GJA5 levels in human LA samples. In a similar fashion to heart failure patients, we showed that left atrial ETV1 expression is downregulated at the RNA and protein levels in murine pressure overload models. Comparative analysis of LA RNA-seq datasets from TAC and AngII treated mice showed a high Pearson correlation, reflecting a highly ordered process by which the LA undergoes electrical and structural remodeling. Cardiac pressure overload produced a consistent downregulation of ErbB4, Etv1, Scn5a, and Gja5 and upregulation of profibrotic gene programming, which includes Tgfbr1/2, Igf1, and numerous collagen genes. Etv1^f/fMlc2a^Cre/+ mice displayed atrial conduction disease and arrhythmias. Correspondingly, the LA from Etv1^f/fMlc2a^Cre/+ mice showed downregulation of rapid conduction genes and upregulation of profibrotic gene programming, whereas analysis of a gain-of-function ETV1 RNA-seq dataset from neonatal rat ventricular myocytes transduced with Etv1 showed reciprocal changes. Conclusions: ETV1 is downregulated in the LA during cardiac pressure overload, contributing to both electrical and structural remodeling.

Background: The COVID-19 pandemic has resulted in worldwide morbidity at unprecedented scale. Troponin elevation is a frequent laboratory finding in hospitalized patients with the disease, and may reflect direct vascular injury or non-specific supply-demand imbalance. In this work, we assessed the correlation between different ranges of Troponin elevation, Electrocardiographic (ECG) abnormalities, and mortality. Methods: We retrospectively studied 204 consecutive patients hospitalized at NYU Langone Health with COVID-19. Serial ECG tracings were evaluated in conjunction with laboratory data including Troponin. Mortality was analyzed in respect to the degree of Troponin elevation and the presence of ECG changes including ST elevation, ST depression or T wave inversion. Results: Mortality increased in parallel with increase in Troponin elevation groups and reached 60% when Troponin was >1 ng/ml. In patients with mild Troponin rise (0.05-1.00 ng/ml) the presence of ECG abnormality and particularly T wave inversions resulted in significantly greater mortality. Conclusion: ECG repolarization abnormalities may represent a marker of clinical severity in patients with mild elevation in Troponin values. This finding can be used to enhance risk stratification in patients hospitalized with COVID-19.

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.