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Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target

Dridi, Haikel; Kushnir, Alexander; Zalk, Ran; Yuan, Qi; Melville, Zephan; Marks, Andrew R
Ca2+ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca2+ ([Ca2+]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca2+-binding proteins. Defective regulation of [Ca2+] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca2+] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca2+-release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca2+ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca2+ leak as a shared Ca2+-dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca2+ leak from the SR, are undergoing investigation in clinical trials.
PMID: 32555383
ISSN: 1759-5010
CID: 4552722

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

Berman, Jeremy P; Abrams, Mark P; Kushnir, Alexander; Rubin, Geoffrey A; Ehlert, Frederick; Biviano, Angelo; Morrow, John P; Dizon, Jose; Wan, Elaine Y; Yarmohammadi, Hirad; Waase, Marc P; Rubin, David A; Garan, Hasan; Saluja, Deepak
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/CONCLUSIONS: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.
PMCID:7450949
PMID: 32861812
ISSN: 0972-6292
CID: 4587672

Repetitive nonreentrant ventriculoatrial synchrony inducing atrial fibrillation in setting of dofetilide [Case Report]

Garber, Leonid; Shulman, Eric; Kushnir, Alexander; Saraon, Tajinderpal; Park, David S; Chinitz, Larry A
PMCID:9123322
PMID: 35607350
ISSN: 2214-0271
CID: 5232852

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

Jankelson, Lior; Garber, Leonid; Shulman, Eric; Cohen, Roi Bar; Peterson, Connor; Wadhwani, Lalit; Nadeau-Routhier, Charles; Xia, Yuhe; Barbhaiya, Chirag; Holmes, Douglas; Knotts, Robert; Bernstein, Scott; Kushnir, Alexander; Spinelli, Michael; Park, David; Aizer, Anthony; Chinitz, Larry
BACKGROUND: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 one 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. This article is protected by copyright. All rights reserved.
PMID: 34911157
ISSN: 1540-8167
CID: 5093072

Rebooting atrial fibrillation ablation in the COVID-19 pandemic

Barbhaiya, Chirag R; Wadhwani, Lalit; Manmadhan, Arun; Selim, Ahmed; Knotts, Robert J; Kushnir, Alexander; Spinelli, Michael; Jankelson, Lior; Bernstein, Scott; Park, David; Holmes, Douglas; Aizer, Anthony; Chinitz, Larry A
PURPOSE/OBJECTIVE: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.
PMID: 33543350
ISSN: 1572-8595
CID: 4776662

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

Wadhwani, Lalit; Occhipinti, Karen; Selim, Ahmed; Manmadhan, Arun; Kushnir, Alexander; Barbhaiya, Chirag; Jankelson, Lior; Holmes, Douglas; Bernstein, Scott; Spinelli, Michael; Knotts, Robert; Park, David S; Chinitz, Larry A; Aizer, Anthony
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/CONCLUSIONS: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.
PMID: 34517119
ISSN: 1556-3871
CID: 5026662

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

Zou, F; Worley, S J; Steen, T; McKillop, M; Padala, S; O'Donoghue, S; Candemir, B; Kanjwal, K; Kaufman, M; Mouram, S; Sellers, M; Strouse, D; Thomaides, A; Nair, D; Hadadi, C A; Kushnir, A
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(s): 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.
Method(s): Twenty patients with CS ostial abnormalities and sPLSVC were identified. Clinical information, imaging methods, LV lead implantation techniques, and complications were summarized.
Result(s): 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(s): 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.
Copyright
EMBASE:2013096698
ISSN: 1547-5271
CID: 4915822

Improving Fluid Output Monitoring in the Intensive Care Unit

Kushnir, Alexander; Palte, Eytan; Morris, Nadia; Shahabuddin, Zoha A; Hammond, Jeffrey; Vukelic, Sinisa; Rabbani, LeRoy E
PURPOSE/UNASSIGNED:To assess the potential clinical impact of an automated urine output (UOP) monitoring system in the intensive care unit. METHODS/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED:Automating UOP monitoring using a reusable weight-based device is feasible and can improve timeliness of documentation and reduce nursing workload without compromising accuracy.
PMID: 33292043
ISSN: 1525-1489
CID: 4726612

Clinical and Cardiac Characteristics of COVID-19 Mortalities in a Diverse New York City Cohort

Abrams, Mark P; Wan, Elaine Y; Waase, Marc P; Morrow, John P; Dizon, Jose M; Yarmohammadi, Hirad; Berman, Jeremy P; Rubin, Geoffrey A; Kushnir, Alexander; Poterucha, Timothy J; Elias, Pierre A; Rubin, David A; Ehlert, Frederick; Biviano, Angelo; Uriel, Nir; Garan, Hasan; Saluja, Deepak
INTRODUCTION/BACKGROUND:Electrocardiographic characteristics in COVID-19 related mortality have not yet been reported, particularly in racial/ethnic minorities. METHODS AND RESULTS/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 RT-PCR in 3 New York City hospitals between March 1 and April 3, 2020 who died. We described clinical characteristics and compared factors contributing toward arrhythmic versus non-arrhythmic 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 (CVD). The last cardiac rhythm recorded was ventricular tachycardia 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. This article is protected by copyright. All rights reserved.
PMID: 33022765
ISSN: 1540-8167
CID: 4631542

High-density substrate and activation mapping of epicardial ventricular tachycardia during left ventricular assist device implant [Case Report]

Kushnir, Alexander; Pallister, Kristin H; Chaudhary, Salma B; Cevasco, Marisa; Naka, Yoshifumi; Saluja, Deepak
PMCID:7573345
PMID: 33101933
ISSN: 2214-0271
CID: 4645672