Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics.

Increased cardiac contractility during the fight-or-flight response is caused by ß-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and ß subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of ß-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which ß-adrenergic agonists stimulate voltage-gated calcium channels. We express α1C or ß2B subunits conjugated to ascorbate peroxidase5 in mouse hearts, and use multiplexed quantitative proteomics6,7 to track hundreds of proteins in the proximity of CaV1.2. We observe that the calcium-channel inhibitor Rad8,9, a monomeric G protein, is enriched in the CaV1.2 microenvironment but is depleted during ß-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for ß subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of CaV1.3 and CaV2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.

Catheter ablation of atrioventricular nodal reentrant tachycardia with an irrigated contact-force sensing radiofrequency ablation catheter.

INTRODUCTION: Radiofrequency ablation (RFA) slow pathway modification for catheter ablation of atrioventricular nodal reentrant tachycardia (AVNRT) is traditionally performed using a 4-mm nonirrigated (NI) RF ablation catheter. Slow pathway modification using irrigated, contact-force sensing (ICFS) RFA catheters has been described in case reports, but the outcomes have not been systematically evaluated. METHODS: Acute procedural outcomes of 200 consecutive patients undergoing slow pathway modification for AVNRT were analyzed. A 3.5-mm ICFS RFA catheter (ThermoCool SmartTouch STSF, Biosense Webster, Inc.) was utilized in 134 patients, and a 4-mm NI RFA catheter (EZ Steer, Biosense Webster, Inc.) was utilized in 66 patients. Electroanatomic maps were retrospectively analyzed in a blinded fashion to determine the proximity of ablation lesions to the His region. RESULTS: The baseline characteristics of patients in both groups were similar. Total RF time was significantly lower in the ICFS group compared to the NI group (5.53 ± 4.6 vs. 6.24 ± 4.9 min, p = 0.03). Median procedure time was similar in both groups (ICFS, 108.0 (87.5-131.5) min vs. NI, 100.0 (85.0-125.0) min; p = 0.2). Ablation was required in closer proximity to the His region in the NI group compared to the ICFS group (14.4 ± 5.9 vs. 16.7 ± 6.4 mm, respectively, p = 0.01). AVNRT was rendered noninducible in all patients, and there was no arrhythmia recurrence during follow-up in both groups. Catheter ablation was complicated by AV block in one patient in the NI group. CONCLUSION: Slow pathway modification for catheter ablation of AVNRT using an ICFS RFA catheter is feasible, safe, and may facilitate shorter duration ablation while avoiding ablation in close proximity to the His region.

Temporal trends in atrial fibrillation ablation procedures at an academic medical center: 2011-2021.

INTRODUCTION: Radiofrequency ablation technology for treating atrial fibrillation (AF) has evolved rapidly over the past decade. We investigated the impact of technological and procedural advances on procedure times and ablation outcomes at a major academic medical center over a 10-year period. METHODS: Clinical data was collected from patients who presented to NYU Langone Health between 2011 and 2021 for a first-time AF ablation. Time to redo AF ablation or direct current cardioversion (DCCV) for recurrent AF during a 3-year follow-up period was determined and correlated with ablation technology and practices, antiarrhythmic medications, and patient comorbid conditions. RESULTS: From 2011 to 2021, the cardiac electrophysiology lab adopted irrigated-contact force ablation catheters, high-power short duration ablation lesions, steady-pacing, jet ventilation, and eliminated stepwise linear ablation for AF ablation. During this time the number of first time AF ablations increased from 403 to 1074, the percentage of patients requiring repeat AF-related intervention within 3-years of the index procedure dropped from 22% to 14%, mean procedure time decreased from 271 ± 65 to 135 ± 36 min, and mean annual major adverse event rate remained constant at 1.1 ± 0.5%. Patient comorbid conditions increased during this time period and antiarrhythmic use was unchanged. CONCLUSION: Rates of redo-AF ablation or DCCV following an initial AF ablation at a single center decreased 36% over a 10-year period. Procedural and technological changes likely contributed to this improvement, despite increased AF related comorbidities.

Outcomes and atrial substrate analysis in patients with HIV undergoing atrial fibrillation ablation.

INTRODUCTION: Patients with HIV infection have increased risk of atrial fibrillation, but the pathophysiologic mechanisms and the utility of catheter ablation in this population are not well-studied. We aimed to characterize outcomes of atrial fibrillation ablation and left atrial substrate in patients with HIV. METHODS: The study was a retrospective propensity score-matched analysis of patients with and without HIV undergoing atrial fibrillation ablation. A search was performed in the electronic medical record for all patients with HIV who received initial atrial fibrillation ablation from 2011 to 2020. After calculating propensity scores for HIV, matching was performed with patients without HIV by using nearest-neighbor matching without replacement in a 1:2 ratio. The primary outcome was freedom from atrial arrhythmia and secondary outcomes were freedom from atrial fibrillation, freedom from atrial tachycardia, and freedom from repeat ablation, compared by log-rank analysis. The procedures of patients with HIV who underwent repeat ablation at our institution were further analyzed for etiology of recurrence. To further characterize the left atrial substrate, a subsequent case-control analysis was then performed for a set of randomly chosen 10 patients with HIV matched with 10 without HIV to compare minimum and maximum voltage at nine pre-specified regions of the left atrium. RESULTS: Twenty-seven patients with HIV were identified. All were prescribed antiretroviral therapy at time of ablation. These patients were matched with 54 patients without HIV by propensity score. 86.4% of patients with HIV and 76.9% of controls were free of atrial fibrillation or atrial tachycardia at 1 year (p = .509). Log-rank analysis showed no difference in freedom from atrial arrhythmia (p value .971), atrial fibrillation (p-value .346), atrial tachycardia (p value .306), or repeat ablation (p value .401) after initial atrial fibrillation ablation in patients with HIV compared to patients without HIV. In patients with HIV with recurrent atrial fibrillation, the majority had pulmonary vein reconnection (67%). There were no significant differences in minimum or maximum voltage at any of the nine left atrial regions between the matched patients with and without HIV. CONCLUSIONS: Ablation to treat atrial fibrillation in patients with HIV, but without overt AIDS is frequently successful therapy. The majority of patients with recurrence of atrial fibrillation had pulmonary vein reconnection, suggesting infrequent nonpulmonary vein substrate. In this population, the left atrial voltage in patients with HIV is similar to that of patients without HIV. These findings suggest that the pulmonary veins remain a critical component to the initiation and maintenance of atrial fibrillation in patients with HIV.

Outcomes of posterior wall isolation with pulmonary vein isolation for paroxysmal atrial fibrillation.

INTRODUCTION: Prior studies have shown that addition of posterior wall isolation (PWI) may reduce atrial fibrillation recurrence in patients with persistent atrial fibrillation. No data on PWI in paroxysmal AF (pAF) patients with normal left atrial voltage is available, to date. OBJECTIVE: This study sought to evaluate the efficacy of PWI in addition to pulmonary vein isolation (PVI) in patients presenting with pAF and normal left atrial voltage. METHODS: Consecutive patient registry analysis was performed on all patients with pAF and normal left atrial voltage undergoing initial radiofrequency ablation from November 1, 2018 to November 15, 2019. Primary endpoint was recurrence of atrial arrhythmia including AF, atrial tachycardia (AT), or atrial flutter (AFL). RESULTS: A total of 321 patients were studied, 214 in the PVI group and 107 in the PWI + PVI group. Recurrence of any atrial arrhythmia occurred in 18.2% of patients in the PVI group and 16.8% in the PVI + PWI cohort (p = 0.58). At 1 year, recurrence was 14.0% in the PVI group and 15.0% in the PWI + PVI group (p = 0.96). There was a lower AT/AFL recurrence in the PVI + PWI group, not reaching significance (3.7% in the PWI + PVI group vs. 7.9% in PVI group, p = 0.31). Need for carina lesions predicted recurrence in the PVI-only group. CONCLUSIONS: Addition of PWI to PVI in pAF patients undergoing their first ablation did not reduce the frequency of atrial arrhythmia recurrence. This warrants further study in a prospective trial.

Improving Fluid Output Monitoring in the Intensive Care Unit.

PURPOSE: To assess the potential clinical impact of an automated urine output (UOP) monitoring system in the intensive care unit. METHODS: Frequency of UOP documentation during a 20-month period was assessed in records of inpatients on the medicine floor, cardiac intensive care (CCU), and cardiothoracic-intensive care units (CTICU). Documentation timeliness (time between expected and observed UOP recording) was assessed over a 3-month period. A novel reusable device that monitors UOP based on continuous analysis of the weight of a urine collection container was tested in the CCU/CTICU. RESULTS: A total of 165,363 UOP measurements were recorded for 2,039 CCU/CTICU admissions. Sixty percent of CCU/CTICU admissions had UOP recorded in the electronic medical record (EMR) less than every 2 hours. One-third of CCU/CTICU measurements were documented more than 2 hours late, and only 10% were recorded less than 20 minutes late. Half of these patients had fewer than 2 measurements recorded per nursing shift and recordings were documented an average of 85 minutes late. There was no significant difference between daytime and nighttime shifts. UOP values obtained by the novel electronic monitoring device were within 27 ml (-224 ml, +228 ml) of nurses documented values, across 74 patients over a 24-hour period. CONCLUSIONS: Automating UOP monitoring using a reusable weight-based device is feasible and can improve timeliness of documentation and reduce nursing workload without compromising accuracy.

Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.

INTRODUCTION: Electrocardiographic characteristics in COVID-19-related mortality have not yet been reported, particularly in racial/ethnic minorities. METHODS AND RESULTS: We reviewed demographics, laboratory and cardiac tests, medications, and cardiac rhythm proximate to death or initiation of comfort care for patients hospitalized with a positive SARS-CoV-2 reverse-transcriptase polymerase chain reaction in three New York City hospitals between March 1 and April 3, 2020 who died. We described clinical characteristics and compared factors contributing toward arrhythmic versus nonarrhythmic death. Of 1258 patients screened, 133 died and were enrolled. Of these, 55.6% (74/133) were male, 69.9% (93/133) were racial/ethnic minorities, and 88.0% (117/133) had cardiovascular disease. The last cardiac rhythm recorded was VT or fibrillation in 5.3% (7/133), pulseless electrical activity in 7.5% (10/133), unspecified bradycardia in 0.8% (1/133), and asystole in 26.3% (35/133). Most 74.4% (99/133) died receiving comfort measures only. The most common abnormalities on admission electrocardiogram included abnormal QRS axis (25.8%), atrial fibrillation/flutter (14.3%), atrial ectopy (12.0%), and right bundle branch block (11.9%). During hospitalization, an additional 17.6% developed atrial ectopy, 14.7% ventricular ectopy, 10.1% atrial fibrillation/flutter, and 7.8% a right ventricular abnormality. Arrhythmic death was confirmed or suspected in 8.3% (11/133) associated with age, coronary artery disease, asthma, vasopressor use, longer admission corrected QT interval, and left bundle branch block (LBBB). CONCLUSIONS: Conduction, rhythm, and electrocardiographic abnormalities were common during COVID-19-related hospitalization. Arrhythmic death was associated with age, coronary artery disease, asthma, longer admission corrected QT interval, LBBB, ventricular ectopy, and usage of vasopressors. Most died receiving comfort measures.

Performance of electrophysiology procedures at an academic medical center amidst the 2020 coronavirus (COVID-19) pandemic.

A global coronavirus (COVID-19) pandemic occurred at the start of 2020 and is already responsible for more than 74 000 deaths worldwide, just over 100 years after the influenza pandemic of 1918. At the center of the crisis is the highly infectious and deadly SARS-CoV-2, which has altered everything from individual daily lives to the global economy and our collective consciousness. Aside from the pulmonary manifestations of disease, there are likely to be several electrophysiologic (EP) sequelae of COVID-19 infection and its treatment, due to consequences of myocarditis and the use of QT-prolonging drugs. Most crucially, the surge in COVID-19 positive patients that have already overwhelmed the New York City hospital system requires conservation of hospital resources including personal protective equipment (PPE), reassignment of personnel, and reorganization of institutions, including the EP laboratory. In this proposal, we detail the specific protocol changes that our EP department has adopted during the COVID-19 pandemic, including performance of only urgent/emergent procedures, after hours/7-day per week laboratory operation, single attending-only cases to preserve PPE, appropriate use of PPE, telemedicine and video chat follow-up appointments, and daily conferences to collectively manage the clinical and ethical dilemmas to come. We discuss also discuss how we perform EP procedures on presumed COVID positive and COVID tested positive patients to highlight issues that others in the EP community may soon face in their own institution as the virus continues to spread nationally and internationally.

Intracellular calcium leak as a therapeutic target for RYR1-related myopathies.

RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1-related myopathies (RYR1-RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1-RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1-RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1-RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1-RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.

Cardiac electrophysiology consultative experience at the epicenter of the COVID-19 pandemic in the United States.

BACKGROUND: The COVID-19 pandemic has greatly altered the practice of cardiac electrophysiology around the world for the foreseeable future. Professional organizations have provided guidance for practitioners, but real-world examples of the consults and responsibilities cardiac electrophysiologists face during a surge of COVID-19 patients is lacking. METHODS: In this observational case series we report on 29 consecutive inpatient electrophysiology consultations at a major academic medical center in New York City, the epicenter of the pandemic in the United States, during a 2 week period from March 30-April 12, 2020, when 80% of hospital beds were occupied by COVID-19 patients, and the New York City metropolitan area accounted for 10% of COVID-19 cases worldwide. RESULTS: Reasons for consultation included: Atrial tachyarrhythmia (31%), cardiac implantable electronic device management (28%), bradycardia (14%), QTc prolongation (10%), ventricular arrhythmia (7%), post-transcatheter aortic valve replacement conduction abnormality (3.5%), ventricular pre-excitation (3.5%), and paroxysmal supraventricular tachycardia (3.5%). Twenty-four patients (86%) were positive for COVID-19 by nasopharyngeal swab. All elective procedures were canceled, and only one urgent device implantation was performed. Thirteen patients (45%) required in-person evaluation and the remainder were managed remotely. CONCLUSION: Our experience shows that the application of a massive alteration in workflow and personnel forced by the pandemic allowed our team to efficiently address the intersection of COVID-19 with a range of electrophysiology issues. This experience will prove useful as guidance for emerging hot spots or areas affected by future waves of the pandemic.

Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure.

BACKGROUND: Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca2+ release channels resulting in diastolic sarcoplasmic reticulum Ca2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2+ handling because of leaky RyR channels in CHF. METHODS: Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca2+ leak was assessed using flow cytometry to measure Ca2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca2+ stores within the endoplasmic reticulum. RESULTS: Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca2+ stores, consistent with chronic intracellular Ca2+ leak. This Ca2+ leak correlated with circulating catecholamine levels. The intracellular Ca2+ leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response. CONCLUSIONS: In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca2+ stores consistent with chronic intracellular Ca2+ leak. RyR1-mediated Ca2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.

A case of electromagnetic interference between HeartMate 3 LVAD and implantable cardioverter defibrillator.

Implantable cardioverter defibrillators (ICDs) have been shown to have a significant benefit in reducing sudden cardiac death (SCD) in patients with systolic heart failure. Additionally, cardiac devices as a bridge to transplant or destination therapy are often used in patients with end-stage systolic heart failure. As a result, most patients with left ventricular assist devices (LVADs) also have an ICD. Here, we present an electromagnetic interference (EMI) between HeartMate 3 LVAD and ICD. This issue might be critical for both electrophysiologists and advanced heart failure cardiologists to understand prior to implantation of ICD/LVADs in these patients.

Conduction velocity is reduced in the posterior wall of hypertrophic cardiomyopathy patients with normal bipolar voltage undergoing ablation for paroxysmal atrial fibrillation.

OBJECTIVES: We investigated characteristics of left atrial conduction in patients with HCM, paroxysmal AF and normal bipolar voltage. BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) exhibit abnormal cardiac tissue arrangement. The incidence of atrial fibrillation (AF) is increased fourfold in patients with HCM and confers a fourfold increased risk of death. Catheter ablation is less effective in HCM, with twofold increased risk of AF recurrence. The mechanisms of AF perpetuation in HCM are poorly understood. METHODS: We analyzed 20 patients with HCM and 20 controls presenting for radiofrequency ablation of paroxysmal AF normal left atrial voltage(> 0.5 mV). Intracardiac electrograms were extracted from the CARTO mapping system and analyzed using Matlab/Python code interfacing with Core OpenEP software. Conduction velocity maps were calculated using local activation time gradients. RESULTS: There were no differences in baseline demographics, atrial size, or valvular disease between HCM and control patients. Patients with HCM had significantly reduced atrial conduction velocity compared to controls (0.44 ± 0.17 vs 0.56 ± 0.10 m/s, p = 0.01), despite no significant differences in bipolar voltage amplitude (1.23 ± 0.38 vs 1.20 ± 0.41 mV, p = 0.76). There was a statistically significant reduction in conduction velocity in the posterior left atrium in HCM patients relative to controls (0.43 ± 0.18 vs 0.58 ± 0.10 m/s, p = 0.003), but not in the anterior left atrium (0.46 ± 0.17 vs 0.55 ± 0.10 m/s, p = 0.05). There was a significant association between conduction velocity and interventricular septal thickness (slope = -0.013, R2 = 0.13, p = 0.03). CONCLUSIONS: Atrial conduction velocity is significantly reduced in patients with HCM and paroxysmal AF, possibly contributing to arrhythmia persistence after catheter ablation.

Role of CaMKIIdelta phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure.

The force frequency relationship (FFR), first described by Bowditch 139 years ago as the observation that myocardial contractility increases proportionally with increasing heart rate, is an important mediator of enhanced cardiac output during exercise. Individuals with heart failure have defective positive FFR that impairs their cardiac function in response to stress, and the degree of positive FFR deficiency correlates with heart failure progression. We have identified a mechanism for FFR involving heart rate dependent phosphorylation of the major cardiac sarcoplasmic reticulum calcium release channel/ryanodine receptor (RyR2), at Ser2814, by calcium/calmodulin-dependent serine/threonine kinase-delta (CaMKIIdelta). Mice engineered with an RyR2-S2814A mutation have RyR2 channels that cannot be phosphorylated by CaMKIIdelta, and exhibit a blunted positive FFR. Ex vivo hearts from RyR2-S2814A mice also have blunted positive FFR, and cardiomyocytes isolated from the RyR2-S2814A mice exhibit impaired rate-dependent enhancement of cytosolic calcium levels and fractional shortening. The cardiac RyR2 macromolecular complexes isolated from murine and human failing hearts have reduced CaMKIIdelta levels. These data indicate that CaMKIIdelta phosphorylation of RyR2 plays an important role in mediating positive FFR in the heart, and that defective regulation of RyR2 by CaMKIIdelta-mediated phosphorylation is associated with the loss of positive FFR in failing hearts.

Comparison of combined substrate-based mapping techniques to identify critical sites for ventricular tachycardia ablation.

BACKGROUND: Established electroanatomic mapping techniques for substrate mapping for ventricular tachycardia (VT) ablation includes voltage mapping, isochronal late activation mapping (ILAM), and fractionation mapping. Omnipolar mapping (Abbott Medical, Inc.) is a novel optimized bipolar electrogram creation technique with integrated local conduction velocity annotation. The relative utilities of these mapping techniques are unknown. OBJECTIVE: The purpose of this study was to evaluate the relative utility of various substrate mapping techniques for the identification of critical sites for VT ablation. METHODS: Electroanatomic substrate maps were created and retrospectively analyzed in 27 patients in whom 33 VT critical sites were identified. RESULTS: Both abnormal bipolar voltage and omnipolar voltage encompassed all critical sites and were observed over a median of 66 cm2 (interquartile range [IQR] 41.3-86 cm2) and 52 cm2 (IQR 37.7-65.5 cm2), respectively. ILAM deceleration zones were observed over a median of 9 cm2 (IQR 5.0-11.1 cm2) and encompassed 22 critical sites (67%), while abnormal omnipolar conduction velocity (CV <1 mm/ms) was observed over 10 cm2 (IQR 5.3-16.6 cm2) and identified 22 critical sites (67%), and fractionation mapping was observed over a median of 4 cm2 (IQR 1.5-7.6 cm2) and encompassed 20 critical sites (61%). The mapping yield was the highest for fractionation + CV (2.1 critical sites/cm2) and least for bipolar voltage mapping (0.5 critical sites/cm2). CV identified 100% of critical sites in areas with a local point density of >50 points/cm2. CONCLUSION: ILAM, fractionation, and CV mapping each identified distinct critical sites and provided a smaller area of interest than did voltage mapping alone. The sensitivity of novel mapping modalities improved with greater local point density.

Rebooting atrial fibrillation ablation in the COVID-19 pandemic.

PURPOSE: Catheter ablation procedures for atrial fibrillation (AF) were significantly curtailed during the peak of coronavirus disease 2019 (COVID-19) pandemic to conserve healthcare resources and limit exposure. There is little data regarding peri-procedural outcomes of medical procedures during the COVID-19 pandemic. We enacted protocols to safely reboot AF ablation while limiting healthcare resource utilization. We aimed to evaluate acute and subacute outcomes of protocols instituted for reboot of AF ablation during the COVID-19 pandemic. METHODS: Perioperative healthcare utilization and acute procedural outcomes were analyzed for consecutive patients undergoing AF ablation under COVID-19 protocols (2020 cohort; n=111) and compared to those of patients who underwent AF ablation during the same time period in 2019 (2019 cohort; n=200). Newly implemented practices included preoperative COVID-19 testing, selective transesophageal echocardiography (TEE), utilization of venous closure, and same-day discharge when clinically appropriate. RESULTS: Pre-ablation COVID-19 testing was positive in 1 of 111 patients. There were 0 cases ablation-related COVID-19 transmission and 0 major complications in either cohort. Pre-procedure TEE was performed in significantly fewer 2020 cohort patients compared to the 2019 cohort patients (68.4% vs. 97.5%, p <0.001, respectively) despite greater prevalence of persistent arrhythmia in the 2020 cohort. Same-day discharge was achieved in 68% of patients in the 2020 cohort, compared to 0% of patients in the 2019 cohort. CONCLUSIONS: Our findings demonstrate the feasibility of safe resumption of complex electrophysiology procedures during the COVID-19 pandemic, reducing healthcare utilization and maintaining quality of care. Protocols instituted may be generalizable to other types of procedures and settings.

RyR1-related myopathy mutations in ATP and calcium binding sites impair channel regulation.

The type 1 ryanodine receptor (RyR1) is an intracellular calcium (Ca2+) release channel on the sarcoplasmic/endoplasmic reticulum that is required for skeletal muscle contraction. RyR1 channel activity is modulated by ligands, including the activators Ca2+ and ATP. Patients with inherited mutations in RyR1 may exhibit muscle weakness as part of a heterogeneous, complex disorder known as RYR1-related myopathy (RYR1-RM) or more recently termed RYR1-related disorders (RYR1-RD). Guided by high-resolution structures of skeletal muscle RyR1, obtained using cryogenic electron microscopy, we introduced mutations into putative Ca2+ and ATP binding sites and studied the function of the resulting mutant channels. These mutations confirmed the functional significance of the Ca2+ and ATP binding sites identified by structural studies based on the effects on channel regulation. Under normal conditions, Ca2+ activates RyR1 at low concentrations (µM) and inhibits it at high concentrations (mM). Mutations in the Ca2+-binding site impaired both activating and inhibitory regulation of the channel, suggesting a single site for both high and low affinity Ca2+-dependent regulation of RyR1 function. Mutation of residues that interact with the adenine ring of ATP abrogated ATP binding to the channel, whereas mutating residues that interact with the triphosphate tail only affected the degree of activation. In addition, patients with mutations at the Ca2+ or ATP binding sites suffer from muscle weakness, therefore impaired RyR1 channel regulation by either Ca2+ or ATP may contribute to the pathophysiology of RYR1-RM in some patients.

Time to diagnosis of acute complications after cardiovascular implantable electronic device insertion and optimal timing of discharge within the first 24 hours.

BACKGROUND: More than 3 million cardiovascular implantable electronic devices (CIEDs) are implanted annually. There are minimal data regarding the timing of diagnosis of acute complications after implantation. It remains unclear whether patients can be safely discharged less than 24 hours postimplantation. OBJECTIVE: The purpose of this study was to determine the precise timing of acute complication diagnosis after CIED implantation and optimal timing for same-day discharge. METHODS: A retrospective cohort analysis of adults 18 years or older who underwent CIED implantation at a large urban quaternary care medical center between June 1, 2015, and March 30, 2020, was performed. Standard of care included overnight observation and chest radiography 6 and 24 hours postprocedure. Medical records were reviewed for the timing of diagnosis of acute complications. Acute complications included pneumothorax, hemothorax, pericardial effusion, lead dislodgment, and implant site hematoma requiring surgical intervention. RESULTS: A total of 2421 patients underwent implantation. Pericardial effusion or cardiac tamponade was diagnosed in 13 patients (0.53%), pneumothorax or hemothorax in 19 patients (0.78%), lead dislodgment in 11 patients (0.45%), and hematomas requiring surgical intervention in 5 patients (0.2%). Of the 48 acute complications, 43 (90%) occurred either within 6 hours or more than 24 hours after the procedure. Only 3 acute complications identified between 6 and 24 hours required intervention during the index hospitalization (0.12% of all cases). CONCLUSION: Most acute complications are diagnosed either within the first 6 hours or more than 24 hours after implantation. With rare exception, patients can be considered for discharge after 6 hours of appropriate monitoring.

The combination of coronary sinus ostial atresia/abnormalities and a small persistent left superior vena cava-Opportunity for left ventricular lead implantation and unrecognized source of thromboembolic stroke.

BACKGROUND: Coronary sinus (CS) ostial atresia/abnormalities prevent access to the CS from the right atrium (RA) for left ventricular (LV) lead implantation. Some patients with CS ostial abnormalities also have a small persistent left superior vena cava (sPLSVC). OBJECTIVE: The purpose of this study was to describe CS ostial abnormalities and sPLSVC as an opportunity for LV lead implantation and unrecognized source of stroke. METHODS: Twenty patients with CS ostial abnormalities and sPLSVC were identified. Clinical information, imaging methods, LV lead implantation techniques, and complications were summarized. RESULTS: Forty percent had at least 1 previously unsuccessful LV lead placement. In 70%, sPLSVC was identified by catheter manipulation and contrast injection in the left brachiocephalic vein, and in 30% by levophase CS venography. In 30%, sPLSVC was associated with drainage from the CS into the left atrium (LA). When associated with CS ostial abnormalities, the sPLSVC diameter averaged 5.6 ± 3 mm. sPLSVC was used for successful LV lead implantation in 90% of cases. In 80%, the LV lead was implanted down sPLSVC, and in 20%, sPLSVC was used to access the CS from the RA. Presumably because of unrecognized drainage from the CS to the LA, 1 patient had a stroke during implantation via sPLSVC. CONCLUSION: When CS ostial abnormalities prevent access to the CS from the RA, sPLSVC can be used to successfully implant LV leads. In some, the CS partially drains into the LA and stroke can occur spontaneously or during lead intervention. It is important to distinguish sPLSVC associated with CS ostial abnormalities from isolated PLSVC.

Frequency of Atrial Arrhythmia in Hospitalized Patients With COVID-19.

There is growing evidence that COVID-19 can cause cardiovascular complications. However, there are limited data on the characteristics and importance of atrial arrhythmia (AA) in patients hospitalized with COVID-19. Data from 1,029 patients diagnosed with of COVID-19 and admitted to Columbia University Medical Center between March 1, 2020 and April 15, 2020 were analyzed. The diagnosis of AA was confirmed by 12 lead electrocardiographic recordings, 24-hour telemetry recordings and implantable device interrogations. Patients' history, biomarkers and hospital course were reviewed. Outcomes that were assessed were intubation, discharge and mortality. Of 1,029 patients reviewed, 82 (8%) were diagnosed with AA in whom 46 (56%) were new-onset AA 16 (20%) recurrent paroxysmal and 20 (24%) were chronic persistent AA. Sixty-five percent of the patients diagnosed with AA (n=53) died. Patients diagnosed with AA had significantly higher mortality compared with those without AA (65% vs 21%; p < 0.001). Predictors of mortality were older age (Odds Ratio (OR)=1.12, [95% Confidence Interval (CI), 1.04 to 1.22]); male gender (OR=6.4 [95% CI, 1.3 to 32]); azithromycin use (OR=13.4 [95% CI, 2.14 to 84]); and higher D-dimer levels (OR=2.8 [95% CI, 1.1 to 7.3]). In conclusion, patients diagnosed with AA had 3.1 times significant increase in mortality rate versus patients without diagnosis of AA in COVID-19 patients. Older age, male gender, azithromycin use and higher baseline D-dimer levels were predictors of mortality.