Search

BACKGROUND: Left ventricular (LV) remodeling following a myocardial infarction (MI) is associated with new onset atrial fibrillation (AF). LV remodeling post-MI is characterized by regional changes in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), causing extracellular matrix (ECM) remodeling. OBJECTIVE: This study tested the hypothesis that a shift in regional atrial MMP activity, MMP/TIMP expression, and ECM remodeling occurs post-MI, which cause increased vulnerability to AF. METHODS: MI was induced in pigs (25 kg; coronary ligation; n=9), and at approximately 14 days post-MI, an atrial electrical stimulation protocol was performed. Following which, an MMP radiotracer was infused, MMP/TIMP mRNA profiling performed, and ECM collagen assessed by histochemistry. An additional 7 non-MI pigs served as controls. RESULTS: AF could be induced in 89% (8/9) of the post-MI pigs but none of the controls. MMP activity (MMP radiotracer uptake) increased by approximately 2-fold in most atrial regions post-MI, whereas fibrillar collagen content was unchanged or actually reduced in right atrial regions and increased in left atrial regions. MMP/TIMP profiles revealed a heterogeneous pattern from the left atrial appendage to right atrial regions. CONCLUSION: AF vulnerability early post-MI was associated with a heterogeneous pattern of atrial ECM remodeling, detectable by non-invasive molecular imaging. Detection of early atrial MMP activation post-MI may help define the myocardial substrate underlying AF.

Aims No prior study has been adequately powered to evaluate real-world safety outcomes in those receiving adjunctive ablation lesions beyond pulmonary vein isolation (PVI). We sought to evaluate characteristics and in-hospital complications among patients undergoing PVI with and without adjunctive lesions. Methods and results Patients in the National Cardiovascular Data Registry AFib Ablation Registry undergoing first-time atrial fibrillation (AF) ablation between 2016 and 2020 were identified and stratified into paroxysmal (PAF) and persistent AF, and separated into PVI only, PVI + cavotricuspid isthmus (CTI) ablation, and PVI + adjunctive (superior vena cava isolation, coronary sinus, vein of Marshall, atypical atrial flutter lines, other). Adjusted odds of adverse events were calculated using multivariable logistic regression. A total of 50 937 patients [PAF: 30 551 (60%), persistent AF: 20 386 (40%)] were included. Among those with PAF, there were no differences in the adjusted odds of complications between PVI + CTI or PVI + adjunctive when compared with PVI only. Among persistent AF, PVI + adjunctive was associated with a higher risk of any complication [3.0 vs. 4.5%, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.07–1.58] and major complication (0.8 vs. 1.4%, OR 1.56, 95% CI 1.10–2.21), while no differences were observed in PVI + CTI compared with PVI only. Overall, there was high heterogeneity in adjunctive lesion type, and those receiving adjunctive lesions had a higher comorbidity burden. Conclusion Additional CTI ablation was common without an increased risk of complications. Adjunctive lesions other than CTI are commonly performed in those with more comorbidities and were associated with an increased risk of complications in persistent AF, although the current analysis is limited by high heterogeneity in adjunctive lesion set type.

BackgroundAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility.MethodsRight atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation.In vitrostudies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies.ResultsIn human patients with AF, PPP1R12C expression was increased two-fold versus SR controls (P=2.0×10−2, n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation (P=1.4×10−6, n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10−2and 6.7×10−3respectively, n=8,8 in each group).In vitrostudies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls (P=5.0×10−6, n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls (P=1.8×10−2and 4.1×10−2respectively, n= 6,6,5).ConclusionsAF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Aims Atrial fibrillation (AF) is associated with atrial enlargement, mitral annulus (MA) and tricuspid annulus (TA) dilation, and atrial functional regurgitation (AFR). However, less is known about the impact of AF on both atrioventricular valves in those with normal and abnormal ventricular function. We aimed to compare the remodelling of the TA and MA in patients with non-valvular AF without significant AFR. Methods and results Ninety-two patients referred for transoesophageal echocardiography were included and categorized into three groups: (i) AF with normal left ventricular (LV) function (Normal LV-AF), n = 36; (ii) AF with LV systolic dysfunction (LVSD-AF), n = 29; and (iii) Controls in sinus rhythm, n = 27. Three-dimensional MA and TA geometry were analysed using automated software. In patients with AF regardless of LV function, the MA and TA areas were larger compared with controls (LVSD-AF vs. Normal LV-AF vs. Controls, end-systolic MA: 5.2 ± 1.1 vs. 4.5 ± 0.7 vs. 3.9 ± 0.7 cm2/m2; end-systolic TA: 5.6 ± 1.3 vs. 5.3 ± 1.3 vs. 4.1 ± 0.7 cm2/m2; P < 0.05 for each comparison with Controls). TA and MA areas were not statistically different between the two AF groups. The TA increase over controls was greater than that of the MA in the Normal LV-AF group (27.7% vs. 15.6%, P = 0.041). Conversely, in the LVSD-AF group, MA and TA increased similarly (35.9% vs. 32.4%, P = 0.660). Conclusion Patients with AF showed dilation of both TA and MA compared with patients in sinus rhythm. In patients with normal LV function, AF was associated with greater TA dilation than MA dilation whereas in patients with LVSD the TA and MA were equally dilated.

The subcutaneous (S-) implantable cardioverter-defibrillator (ICD) is an alternative to the transvenous (TV-) ICD that is increasingly implanted in younger patients; data on the safety and effectiveness of the S-ICD in older patients are lacking.The purpose of this study was to compare outcomes among older patients who received an S- or TV-ICD.The authors compared S-ICD and single-chamber TV-ICD implants in Fee-For-Service Medicare beneficiaries using the National Cardiovascular Data Registry ICD Registry. Outcomes were ascertained from Medicare claims data. Cox regression or competing-risk models (with TV-ICD as reference) with overlap weights were used to compare death and nonfatal outcomes (device reoperation, device removal for infection, device reoperation without infection, and cardiovascular admission), respectively. Recurrent all-cause readmissions were compared using Anderson-Gill models.A total of 16,063 patients were studied (age 72.6 ± 5.9 years, 28.4% women, ejection fraction 28.3 ± 8.9%). Compared with TV-ICD patients (n = 15,072), S-ICD patients (n = 991, 6.2% overall) were more often Black, younger, and dialysis dependent and less likely to have history of atrial fibrillation or flutter. In adjusted analyses, there were no differences between device type and risk of all-cause mortality (HR: 1.020; 95% CI: 0.819-1.270), device reoperation (subdistribution [s] HR: 0.976; 95% CI: 0.645-1.479), device removal for infection (sHR: 0.614; 95% CI: 0.138-2.736), device reoperation without infection (sHR: 0.975; 95% CI: 0.632-1.506), cardiovascular readmission (sHR: 1.087; 95% CI: 0.912-1.295), or recurrent all-cause readmission (HR: 1.072; 95% CI: 0.990-1.161).In a large representative national cohort of older patients undergoing ICD implantation, risk of death, device reoperation, device removal for infection, device reoperation without infection, and cardiovascular and all-cause readmission were similar among S- and TV-ICD recipients.

Purpose: Percutaneous left atrial appendage (LAA) occlusion is increasingly performed in patients with atrial fibrillation and long-term contraindications for anticoagulation. Our aim was to evaluate the effects of LAA occlusion with the Watchman device on the geometry of the LAA orifice and assess its impact on the adjacent left upper pulmonary vein (LUPV) hemodynamics.Methods: We included 50 consecutive patients who underwent percutaneous LAA occlusion with the Watchman device. Three-dimensional images of LAA pre- and post-device placement were analyzed offline. We measured the LAA orifice diameters in the long axis, and the minimum and maximum diameters, circumference, and area in the short axis view. Eccentricity index was calculated as maximum/minimum diameter ratio. The LUPV peak S and D velocities pre- and post-procedure were also measured.Results: Patients were elderly (mean age 76±8 years years), 30 (60%) were men. There was a significant increase of all LAA orifice dimensions following LAA occlusion: diameter 1 (pre-device 18.1±3.2 vs. post-device 21.5±3.4 mm, p2, pConclusion: LAA orifice stretches significantly and it becomes more circular following LAA occlusion without causing a significant impact on the LUPV hemodynamics.

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early onset AF, heart block and incompletely penetrant non-ischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early onset AF, heart block and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIP(A123T) in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.

Atrial cardiomyopathy has been recognized as having important consequences for cardiac performance and clinical outcomes. The pathophysiological role of the left atrial (LA) appendage and the effect of percutaneous left atrial appendage occlusion (LAAO) upon LA mechanics is incompletely understood. We evaluated if changes in LA stiffness due to endocardial LAAO can be detected by LA pressure-volume (PV) analysis and whether stiffness parameters are associated with baseline characteristics. Patients undergoing percutaneous endocardial LAAO (

Background During the COVID-19 pandemic, attempts to conserve resources and limit virus spread have resulted in delay of nonemergent procedures across all medical specialties including cardiac electrophysiology. Many patients have delayed care and continue to express concerns about potential nosocomial spread of coronavirus. Objective To quantify risk of development of COVID19 due to in-hospital transmission related to an electrophysiology procedure, in the setting of preventive measures instituted in our laboratory areas. Methods We contacted patients by telephone who underwent emergent procedures in the electrophysiology lab during the COVID19 surge at our hospital (3/16/2020 to 5/15/2020, reaching daily census 450 COVID19 patients,) > two weeks after the procedure, to assess for symptoms of and/or testing for COVID-19, and assessed outcomes from medical record review. Results Of the 124 patients undergoing EP procedures in this period, none had developed documented or suspected coronavirus infection. 7 patients described symptoms of chest pain, dyspnea, or fever; 3 were tested for coronavirus and found to be negative. Of the remaining 4, 2 had a more plausible alternative explanation for the symptoms, and 2 had transient symptoms not meeting published criteria for probable COVID19 infection. Conclusion Despite a high hospital census of COVID-19 patients during the period of hospital stay for an electrophysiology procedure, there were no likely COVID-19 infections occurring in follow up of at least two weeks. With proper use of preventive measures as recommended by published guidelines, the risk of nosocomial spread of COVID-19 to patients in the electrophysiology lab is low., Graphical abstract

Background Many of the drugs being used in the treatment of the ongoing pandemic coronavirus disease 2019 (COVID-19) are associated with QT prolongation. Expert guidance supports electrocardiographic (ECG) monitoring to optimize patient safety. Objective The purpose of this study was to establish an enhanced process for ECG monitoring of patients being treated for COVID-19. Methods We created a Situation Background Assessment Recommendation tool identifying the indication for ECGs in patients with COVID-19 and tagged these ECGs to ensure prompt over reading and identification of those with QT prolongation (corrected QT interval > 470 ms for QRS duration ≤ 120 ms; corrected QT interval > 500 ms for QRS duration > 120 ms). This triggered a phone call from the electrophysiology service to the primary team to provide management guidance and a formal consultation if requested. Results During a 2-week period, we reviewed 2006 ECGs, corresponding to 524 unique patients, of whom 103 (19.7%) met the Situation Background Assessment Recommendation tool–defined criteria for QT prolongation. Compared with those without QT prolongation, these patients were more often in the intensive care unit (60 [58.3%] vs 149 [35.4%]) and more likely to be intubated (32 [31.1%] vs 76 [18.1%]). Fifty patients with QT prolongation (48.5%) had electrolyte abnormalities, 98 (95.1%) were on COVID-19–related QT-prolonging medications, and 62 (60.2%) were on 1–4 additional non-COVID-19–related QT-prolonging drugs. Electrophysiology recommendations were given to limit modifiable risk factors. No patient developed torsades de pointes. Conclusion This process functioned efficiently, identified a high percentage of patients with QT prolongation, and led to relevant interventions. Arrhythmias were rare. No patient developed torsades de pointes.

This study identified factors associated with risk for cardiac perforation in the setting of atrial fibrillation (AF) ablation in contemporary clinical practice.Cardiac perforation is an uncommon but potentially fatal complication of AF ablation. An improved understanding of factors associated with cardiac perforation could facilitate improvements in procedural safety.Logistic regression models were used to assess predictors of cardiac perforation among Medicare beneficiaries who underwent AF ablation from July 1, 2013 and December 31, 2017. Cardiac perforation was defined as a diagnosis of hemopericardium, cardiac tamponade, or pericardiocentesis, within 30 days of AF ablation.Of 102,398 patients who underwent AF ablation, 0.61% (n = 623) experienced cardiac perforation as a procedural complication. Rates of cardiac perforation decreased over time. In adjusted analyses of the overall population, female sex (odds ratio [OR]: 1.34; 95% confidence interval [CI]: 1.14 to 1.58; p = 0.0004), obesity (OR: 1.35; 95% CI: 1.09 to 1.68; p = 0.0050), and absence of intracardiac echocardiography (ICE) (OR: 4.85; 95% CI: 4.11 to 5.71; p 0.0001) were associated with increased risk for cardiac perforation, whereas previous cardiac surgery (OR: 0.14; 95% CI: 0.07 to 0.26; p 0.0001) was associated with a lower risk for perforation. Patient risk factors for cardiac perforation were identical in the subset of patients in whom ICE was used (n = 76,134). A risk score was generated with the following point assignments: female sex (1 point); obesity (1 point); nonuse of ICE (5 points); and previous cardiac surgery (-6 points).Cardiac perforation is a rare complication of AF ablation; incidence has decreased over time. One of the strongest predictors of cardiac perforation in the contemporary era is a modifiable factor, use of intraprocedural ICE.

Objectives This study sought to define electrographic characteristics of the fossa ovalis (FO) and use these findings in developing a 3-dimensional (3D) transseptal puncture (TSP) technique that does not rely on fluoroscopy or echocardiography. Background Traditional TSP method based on fluoroscopy or echocardiography is basically a 2-dimensional (2D) technique. A valid 3D method of TSP has not been sufficiently clarified. Methods The shape of the FO and its center were “electrographically” defined by comparing their potential characteristics to those of the surrounding limbus. After validation by intracardiac echocardiography, this FO mapping was incorporated into 3D electroanatomical reconstruction of the right atrium. Using a new catheter connection, the transseptal needle could be visualized nonfluoroscopically and directed to the precise localization of the FO on the electroanatomic map. Results A total of 276 patients who underwent atrial fibrillation ablation were included. The central FO was identified in all cases with atrial electrogram voltage at 0.33 ± 0.21 mV. The amplitude of atrial potential at the FO annulus was 1.70 ± 0.72 mV (p Conclusions Electrographic characteristics of the FO center are distinct from those of the surrounding regions. This information can be leveraged to define the FO on 3D electroanatomic mappings, thereby facilitating safe TSP without the need of ancillary imaging with fluoroscopy or echocardiography.

Background: Personal digital devices may offer insights into patient recovery and an approach for remote monitoring after procedures. Objective: To examine associations between activity measured using personal digital devices, patient-reported outcome measures (PROMs), and clinical events among patients after catheter ablation for atrial fibrillation (AF) or bariatric surgery. Methods: We aggregated personal digital device, PROM, and electronic health record data in a study conducted at 2 health systems. We used Fitbit devices for step count assessments, KardiaMobile for cardiac rhythm assessments, and PROMs for pain and palpitations over 5 weeks. Results: Among 59 patients, 30 underwent AF ablation and 29 bariatric surgery. Thirty-six patients (63%) reported pain. There was no difference in median [interquartile range] daily steps between patients with and those without pain (4419 [3286–7041] vs 3498 [2609–5888]; P = .23). Among AF ablation patients, 21 (70%) reported palpitations. Median daily steps were lower among those with palpitations than among those without (4668 [3021–6116] vs 8040 [6853–10,394]; P = .03). When accounting for within-subject correlation, recordings of AF were associated with a significant mean decrease in median daily steps (–351; 95% confidence interval –524 to –177; P

ObjectivesTo determine the feasibility of using real-world data to assess the safety and effectiveness of two cardiac ablation catheters for the treatment of persistent atrial fibrillation and ischaemic ventricular tachycardia.DesignRetrospective cohort.SettingThree health systems in the USA.ParticipantsPatients receiving ablation with the two ablation catheters of interest at any of the three health systems.Main outcome measuresFeasibility of identifying the medical devices and participant populations of interest as well as the duration of follow-up and positive predictive values (PPVs) for serious safety (ischaemic stroke, acute heart failure and cardiac tamponade) and effectiveness (arrhythmia-related hospitalisation) clinical outcomes of interest compared with manual chart validation by clinicians.ResultsOverall, the catheter of interest for treatment of persistent atrial fibrillation was used for 4280 ablations and the catheter of interest for ischaemic ventricular tachycardia was used 1516 times across the data available within the three health systems. The duration of patient follow-up in the three health systems ranged from 91% to 97% at ≥7 days, 89% to 96% at ≥30 days, 77% to 90% at ≥6 months and 66% to 84% at ≥1 year. PPVs were 63.4% for ischaemic stroke, 96.4% for acute heart failure, 100% at one health system for cardiac tamponade and 55.7% for arrhythmia-related hospitalisation.ConclusionsIt is feasible to use real-world health system data to evaluate the safety and effectiveness of cardiac ablation catheters, though evaluations must consider the implications of variation in follow-up and endpoint ascertainment among health systems.

Background Remote monitoring of implantable cardioverter‐defibrillators has been associated with reduced rates of all‐cause rehospitalizations and mortality among device recipients, but long‐term economic benefits have not been studied. Methods and Results An economic model was developed using the PREDICT RM database comparing outcomes with and without remote monitoring. The database included patients ages 65 to 89 who received a Boston Scientific device from 2006 to 2010. Parametric survival equations were derived for rehospitalization and mortality to predict outcomes over a maximum time horizon of 25 years. The analysis assessed rehospitalization, mortality, and the cost‐effectiveness (expressed as the incremental cost per quality‐adjusted life year) of remote monitoring versus no remote monitoring. Remote monitoring was associated with reduced mortality; average life expectancy and average quality‐adjusted life years increased by 0.77 years and 0.64, respectively (6.85 life years and 5.65 quality‐adjusted life years). When expressed per patient‐year, remote monitoring patients had fewer subsequent rehospitalizations (by 0.08 per patient‐year) and lower hospitalization costs (by $554 per patient year). With longer life expectancies, remote monitoring patients experienced an average of 0.64 additional subsequent rehospitalizations with increased average lifetime hospitalization costs of $2784. Total costs of outpatient and physician claims were higher with remote monitoring ($47 515 vs $42 792), but average per patient‐year costs were lower ($6232 vs $6244). The base‐case incremental cost‐effectiveness ratio was $10 752 per quality‐adjusted life year, making remote monitoring high‐value care. Conclusion Remote monitoring is a cost‐effective approach for the lifetime management of patients with implantable cardioverter‐defibrillators.

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

IntroductionPersonal digital devices that provide health information, such as the Apple Watch, have developed an increasing array of cardiopulmonary tracking features which have received regulatory clearance and are directly marketed to consumers. Despite their widespread and increasing use, data about the impact of personal digital device use on patient-reported outcomes and healthcare utilization are sparse. Among a population of patients with atrial fibrillation undergoing cardioversion, our primary aim is to determine the impact of the heart rate measurement, irregular rhythm notification, and electrocardiogram features of the Apple Watch on quality of life and healthcare utilization.Methods and analysisWe are conducting a prospective, open-label multicenter pragmatic randomized clinical trial, leveraging a unique patient-centered health data sharing platform for enrollment and follow-up. A total of 150 patients undergoing cardioversion for atrial fibrillation (or atrial flutter, if they have a history of atrial fibrillation) will be randomized 1:1 to receive the Apple Watch Series 6 or Withings Move at the time of cardioversion. The primary outcome is the difference in the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) global score at six months post-cardioversion. Secondary outcomes include inpatient and outpatient healthcare utilization. Additional secondary outcomes include a comparison of the Apple Watch ECG and pulse oximeter features with gold standard data obtained in routine clinical care settings.Ethics and disseminationThe Institutional Review Boards at Yale University, Mayo Clinic, and Duke University Health System have approved the trial protocol. This trial will provide important data to policymakers, clinicians, and patients about the impact of the heart rate, irregular rhythm notification, and electrocardiogram features of widely used personal digital devices on patient quality of life and healthcare utilization. Findings will be disseminated to study participants, at professional society meetings, and in peer-reviewed journals.Trial registration numberNCT04468321Strengths and limitations of this studyThis randomized clinical trial will use a patient-centered health data sharing platform for study enrollment and follow-up, leveraging patient ownership over health data and patient engagement with researchers.This is the first study to examine the impact of electrocardiogram and irregular rhythm notification features of personal digital technologies on patient-reported quality-of-life among patients with atrial fibrillation.Due to costs of personal digital devices, our study is powered to identify a difference of 8.8 on the primary outcome of Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) global score, which is greater than the minimal clinically important difference of 5.Our study focuses on a subset of patients with atrial fibrillation, and the findings may not be generalizable to those who do not have atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Supplemental Digital Content is available in the text., Background: Coronavirus disease 2019 (COVID-19) has led to over 1 million deaths worldwide and has been associated with cardiac complications including cardiac arrhythmias. The incidence and pathophysiology of these manifestations remain elusive. In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we describe clinical characteristics associated with various arrhythmias, as well as global differences in modulations of routine electrophysiology practice during the pandemic. Methods: We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias. Patients with documented atrial fibrillation, atrial flutter, supraventricular tachycardia, nonsustained or sustained ventricular tachycardia, ventricular fibrillation, atrioventricular block, or marked sinus bradycardia (heart rate

Background: The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Methods: Eight kindreds with familial AF and slow conduction, including a family affected by early onset AF, heart block and incompletely penetrant non-ischemic cardiomyopathy (NICM) underwent whole exome sequencing. Results: A known pathogenic mutation in the desmin (DES) gene resulting in S13F substitution at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed NICM. Higher penetrance of the mutation for AF and heart block prompted the screening for DES modifier(s). A second deleterious mutation in the phosphodiesterase 4D interacting-protein (PDE4DIP) gene resulting in A123T substitution segregated with early onset AF, heart block and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIP in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of Desmin in response to isoproterenol stimulation compared to wildtype PDE4DIP. Conclusion: Our findings identify an epistatic interaction between DES and PDE4DIP variants, increasing the penetrance for conduction disease and arrhythmia.

Introduction: The American College of Cardiology developed the National Cardiovascular Data Registry (NCDR) AFib Ablation Registry to assess prevalence, demographics, procedural management and outcomes of patients undergoing atrial fibrillation (AFib) ablation procedures. The objective of this registry’s first presentation is to summarize initial AFib Ablation Registry data regarding patient characteristics, procedural characteristics, and in-hospital adverse events and outcomes in those undergoing AFib ablation enrolled in the registry. Methods: Data were tabulated and summarized with simple proportions for categorical data, and mean ± standard deviation for continuous data. Results: A total of 31,345 patients who underwent AFib ablation were included in the registry (mean age 65.0 ± 10.4, 65.2% male, 57.6% paroxysmal AFib), with ablations performed at 120 hospitals, by 501 physicians. The mean CHA2DS2-VASc score of was 2.6 ± 1.6, and mean HAS-BLED score was 1.1 ± 0.9. Successful pulmonary vein isolation was able to be achieved in all veins in 94.5% of patients. The prevalence of any complication during procedural admission was 3.1%; the most common were hematoma (0.5%) and pericardial effusion requiring intervention (0.42%). The mean length of stay during the index admission (days) was 1.4 ± 7.6, and in-hospital death prevalence was 0.04% [FIGURE] . Conclusions: In conclusion, the NCDR AFib Ablation Registry is a large, national, multi-center, prospective cohort study to describe events outside the clinical trial or research setting, demonstrating successful pulmonary vein isolation in the majority of patients and a low prevalence of adverse events. Future studies from the registry will be able to help support and develop evidence-based guidelines for AFib ablation treatment and optimize patient outcomes.

Introduction: The subcutaneous (S-) implantable cardioverter defibrillator (ICD) is an alternative to the transvenous (TV-) ICD that is increasingly implanted in younger patients. However, data on the safety and effectiveness of the S-ICD in older patients are lacking. Methods: We compared S-ICD and single chamber TV-ICD implants in Medicare beneficiaries (≥65yrs) using National Cardiovascular Data Registry ICD Registry data from 9/28/2012 through 12/31/2017. We excluded patients with prior pacemaker or ICD, an indication for pacing or resynchronization, and those undergoing implant in an acute setting. Mortality status was determined using the Medicare master summary beneficiary file. Cox regression analyses with overlap weights were used to compare all-cause mortality. Mean cumulative counts of all-cause readmissions were compared among for Fee for Service beneficiaries. Results: A total of 23,717 patients met inclusion criteria [mean age 72.7±5.8 years, 29% female, 69% ischemic heart disease, 33% atrial arrhythmias, 49% NYHA II, 31.7% NYHA III, ejection fraction (EF) 28±9%, 3% dialysis dependent, 20% with prior ventricular tachycardia]. Compared to TV-ICD patients (n=22,264), S-ICD patients (n=1,453, 6% overall) were more often male, black, diabetic, dialysis dependent and were less likely to have atrial or ventricular arrhythmias or ischemic heart disease. There was no difference in age or EF between the 2 groups. In adjusted analyses, during a median follow-up of 2.3 years (IQR: 1.2 - 3.5), there was no difference between the 2 groups in all-cause mortality (HR 1.04, CI 0.91-1.17, Figure A ) or readmissions (based on overlap of confidence intervals, Figure B ). Conclusions: In a large representative cohort of older patients undergoing ICD implant, all-cause mortality and readmission were similar among S-ICD and TV-ICD recipients. These findings support use of the S-ICD for the prevention of sudden cardiac death in appropriately selected older patients.

Background Electrophysiological (EP) properties have been studied mainly in the monocrotaline model of pulmonary arterial hypertension (PAH). Findings are confounded by major extrapulmonary toxicities, which preclude the ability to draw definitive conclusions regarding the role of PAH per se in EP remodeling. Objective The purpose of this study was to investigate the EP substrate and arrhythmic vulnerability of a new model of PAH that avoids extracardiopulmonary toxicities. Methods Sprague-Dawley rats underwent left pneumonectomy (Pn) followed by injection of the vascular endothelial growth factor inhibitor Sugen-5416 (Su/Pn). Five weeks later, cardiac magnetic resonance imaging was performed in vivo, optical action potential (AP) mapping ex vivo, and molecular analyses in vitro. Results Su/Pn rats exhibited right ventricular (RV) hypertrophy and were highly prone to pacing-induced ventricular tachycardia/fibrillation (VT/VF). Underlying this susceptibility was disproportionate RV-sided prolongation of AP duration, which promoted formation of right-sided AP alternans at physiological rates. While propagation was impaired at all rates in Su/Pn rats, the extent of conduction slowing was most severe immediately before the emergence of interventricular lines of block and onset of VT/VF. Measurement of the cardiac wavelength revealed a decrease in Su/Pn relative to control. Nav1.5 and total connexin 43 expression was not altered, while connexin 43 phosphorylation was decreased in PAH. Col1a1 and Col3a1 transcripts were upregulated coinciding with myocardial fibrosis. Once generated, VT/VF was sustained by multiple reentrant circuits with a lower frequency of RV activation due to wavebreak formation. Conclusion In this pure model of PAH, we document RV-predominant remodeling that promotes multiwavelet reentry underlying VT. The Su/Pn model represents a severe form of PAH that allows the study of EP properties without the confounding influence of extrapulmonary toxicity.

Combined use of hydroxychloroquine and azithromycin was globally adopted, in part due to paucity and high cost of alternative therapies. However the utility of these medications has been questioned; and thus safety becomes a major concern given clinical equipoise regarding efficacy. Both hydroxychloroquine and azithromycin continue to be administered in US clinical trials examining their potential role in prevention of infection, treatment of mild infection in ambulatory patients, and in combination with other medical regimens in treatment of patients with severe disease. These drugs also continue to be clinically utilized in hospitalized patients around the globe, often without continuous telemetry due to lack of resources. Concern regarding use of hydroxychloroquine without adequate rhythm monitoring in clinical trials has been recently expressed.1 A review of clinicaltrials.gov at the time of submission of this correspondence reveals actively recruiting trials of combined hydroxychloroquine/azithromycin with or without additional COVID-19 therapies, for both ambulatory and hospitalized patients within and outside the US. The potential for hydroxychloroquine and azithromycin to cause QT prolongation is counterbalanced by very low risk of pro-arrhythmia in the general population, and emerging evidence of relatively low risk of Torsades de Pointes (TdP) in COVID-19 patients.2,3,4,5 Thus delineation of the determinants of significant QTc prolongation and pro-arrhythmic risk for hydroxychloroquine/azithromycin is very important, especially given mounting evidence of inefficacy in COVID-19 treatment.

Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.

The use of mechanical circulatory support has become an increasingly common practice in patients with heart failure, whether used as bridge to transplantation or as destination therapy. The last couple of decades has seen a drastic change in the functioning of the left ventricular assist devices (LVAD), changing from the first generation devices running on pulsatile flow to the current continuous flow devices. Atrial and ventricular arrhythmias are common among heart failure patients, and though the systematic circulation is well supported in patients on mechanical circulatory support, these arrhythmias can still be the cause of detrimental symptoms and lead to potentially fatal outcomes. Several studies have shown that mortality rates in LVAD recipients secondary to lethal arrhythmias are uncommon, and newer generation continuous flow devices particularly seem to support hemodynamic support well. While it is common practice to implant ICDs in patients with LVADs and a history of ventricular arrhythmias, the efficacy behind this practice at preventing sudden death in this population is unknown. In this review, we highlight what is already known about the complications, management and treatment of atrial and ventricular arrhythmias in patients with LVAD devices.

Background Long QT syndrome (LQT) is a pro-arrhythmogenic condition with life-threatening complications. Fifteen genes have been associated with congenital LQT, however, the genetic causes remain unknown in more than 20% of cases. Materials and methods Eighteen patients with history of palpitations, pre-syncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole-exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from 16 subjects with no identifiable cause of LQT. Results Deleterious and novel SCN10A mutations were identified in 3 of the 16 patients (19%) with idiopathic LQT. These included 2 frameshifts and 1 missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified 2 damaging SCN10A mutations with allele frequencies of approximately 0.2% (p.R14L and p.R1268Q) in 2 independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H and p.R485C) were also identified in the 2 subjects on QT prolonging medications. Conclusion Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss-of-function as the underlying disease mechanism. The common association with atrial fibrillation suggests a unique mechanism of disease for this LQT gene.

This study sought to define electrographic characteristics of the fossa ovalis (FO) and use these findings in developing a 3-dimensional (3D) transseptal puncture (TSP) technique that does not rely on fluoroscopy or echocardiography.Traditional TSP method based on fluoroscopy or echocardiography is basically a 2-dimensional (2D) technique. A valid 3D method of TSP has not been sufficiently clarified.The shape of the FO and its center were "electrographically" defined by comparing their potential characteristics to those of the surrounding limbus. After validation by intracardiac echocardiography, this FO mapping was incorporated into 3D electroanatomical reconstruction of the right atrium. Using a new catheter connection, the transseptal needle could be visualized nonfluoroscopically and directed to the precise localization of the FO on the electroanatomic map.A total of 276 patients who underwent atrial fibrillation ablation were included. The central FO was identified in all cases with atrial electrogram voltage at 0.33 ± 0.21 mV. The amplitude of atrial potential at the FO annulus was 1.70 ± 0.72 mV (p 0.001). By incorporating the electrographically defined FO into the 3D electroanatomic mapping and using the transseptal needle visualization approach, TSP was successful in all patients, with 91% of the cases at the first attempt. Atrial fibrillation ablation was completed in all patients with no major complication.Electrographic characteristics of the FO center are distinct from those of the surrounding regions. This information can be leveraged to define the FO on 3D electroanatomic mappings, thereby facilitating safe TSP without the need of ancillary imaging with fluoroscopy or echocardiography.

Aims Atrial fibrillation (AF) has been associated with tricuspid annulus (TA) dilation in patients with severe functional tricuspid regurgitation (TR); however, the impact of AF is less clear in patients without severe TR. Our aim was to characterize TA remodelling in patients with AF in the absence of severe TR using 3D transoesophageal echocardiography (TOE). Methods and results Ninety patients underwent clinically indicated transthoracic and TOE: non-structural (NS)-AF (n = 30); AF with left heart disease (LHD) (n = 30), and controls in sinus rhythm (n = 30). Three-dimensional TOE datasets were analysed to measure TA dimensions using novel dedicated tricuspid valve software. The NS-AF group showed biatrial dilatation and normal right ventricular (RV) size with decreased longitudinal function compared to controls, whereas the LHD-AF group showed biatrial dilatation, RV enlargement, decreased biventricular function, and higher systolic pulmonary artery pressure compared with the other groups. Indexed TA area, minimum diameter, maximum diameter, and total perimeter were significantly larger in the NS-AF group than in controls (measurements in end-diastole: 6.4 ± 1.1 vs. 5.0 ± 0.6 cm2/m2, 1.8 ± 0.3 vs. 1.6 ± 0.2 cm/m2, 2.1 ± 0.3 vs. 1.9 ± 0.2 cm/m2, and 6.6 ± 0.9 vs. 5.9 ± 0.7 cm/m2, respectively, all P Conclusion AF is associated with right atrial and tricuspid annular remodelling independent of the presence of LHD in patients with intrinsically normal tricuspid leaflets without severe TR.

Real-world data sources, including electronic health records (EHR) and personal digital device data, are increasingly available, but are often siloed and cannot be easily integrated for clinical, research, or regulatory purposes. We conducted a prospective cohort study of 60 patients undergoing bariatric surgery or catheter-based atrial fibrillation ablation at two U.S. tertiary care hospitals, testing the feasibility of using a patient-centered health data sharing platform to obtain and aggregate health data from multiple sources. We successfully obtained EHR data for all patients at both hospitals, as well as from 10 additional health systems, which were successfully aggregated with pharmacy data obtained for patients using CVS or Walgreens pharmacies, personal digital device data from activity monitors, digital weight scales, and single-lead ECGs, and patient-reported outcome measure data obtained through surveys to assess post-procedure recovery and disease-specific symptoms. A patient-centered health data sharing platform successfully aggregated data from multiple sources.

Background Left atrial appendage occlusion (LAAO) to prevent stroke in patients with atrial fibrillation has been evaluated in 2 randomized trials; post-approval clinical data are limited. Objectives The purpose of this study was to describe the National Cardiovascular Data Registry (NCDR) LAAO Registry and present patient, hospital, and physician characteristics and in-hospital adverse event rates for Watchman procedures in the United States during its first 3 years. Methods The authors describe the LAAO Registry structure and governance, the outcome adjudication processes, and the data quality and collection processes. They characterize the patient population, performing hospitals, and in-hospital adverse event rates. Results A total of 38,158 procedures from 495 hospitals performed by 1,318 physicians in the United States were included between January 2016 and December 2018. The mean patient age was 76.1 ± 8.1 years, the mean CHA2DS2-VASc (congestive heart failure, hypertension, 65 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) score was 4.6 ± 1.5, and the mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score was 3.0 ± 1.1. The median annual number of LAAO procedures performed for hospitals was 30 (interquartile range: 4 to 56) and for physicians was 12 (interquartile range: 0 to 14). Procedures were canceled or aborted in 7% of cases; among cases in which a device was deployed, 98.1% were implanted with Conclusions The LAAO Registry has enrolled >38,000 patients implanted with the device. Patients were generally older with more comorbidities than those enrolled in the pivotal trials; however, major in-hospital adverse event rates were lower than reported in those trials.