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Cardiac arrhythmias are commonly noted in patients during infections with and recovery from COVID-19. Arrhythmic manifestations span the spectrum of innocuous and benign to life-threatening and deadly. Various pathophysiological mechanisms have been proposed. Debate continues on the impact of incident and exacerbated arrhythmias on the acute and chronic (recovery) phase of the illness. COVID-19 and COVID-19 vaccine-associated myocardial inflammation and autonomic disruption remain concerns. As the pandemic has transformed to an endemic, with discovery of new SARS-CoV-2 variants, updated vaccines, and potent antiviral drugs, vigilance for COVID-19-associated arrhythmic and dysautonomic manifestations remains. The objective of this American Heart Association scientific statement is to review the available evidence on the epidemiology, pathophysiology, clinical presentation, and management of cardiac arrhythmias and autonomic dysfunction in patients infected with and recovering from COVID-19 and to provide evidence-based guidance. The writing committee's consensus on implications for clinical practice, gaps in knowledge, and directions for future research are highlighted.

Background: Assessment of residual thromboembolic risk in patients with atrial fibrillation (AF) prescribed oral anticoagulants (OACs) remains unexplored. We performed hierarchical cluster analysis to identify phenotypic profiles of these patients and their risks of residual thromboembolic events., Methods: We utilised data from non-valvular AF patients on OACs, as documented in phases II and III of the GLORIA-AF (Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients With Atrial Fibrillation) registry. We performed a hierarchical cluster analysis to identify distinct phenotypic profiles. We compared the incidence and risks of thromboembolic events (composite of ischaemic stroke, transient ischaemic attack, or systemic embolism) and related outcomes (major bleeding and all-cause death) across the profiles. We determined the optimal number of profiles through visual inspection of the generated dendrograms., Results: We included 22,410 patients (mean age 70 ± 8 years; 56% male), from which five phenotypes were identified: profile 1 ("uncontrolled hypertension"), profile 2 ("young with a history of coronary artery disease"), profile 3 ("young and obese"), profile 4 ("frailty"), and profile 5 ("non-paroxysmal AF with tachycardia"). Profile 4 was associated with the highest rates of thromboembolic events (1.66/100 person-years [95% confidence interval, 1.46-1.89]), major bleeding (1.92/100 person-years [1.70-2.16]), and death (6.02/100 person-years [5.62-6.43]). Profile 3 was associated with the lowest risk across all measured outcomes (thromboembolic events, 0.64 events/100 person-years [0.48-0.82]; major bleeding, 0.83 events/100 person-years [0.65-1.04]; and death, 1.44 events/100 person-years [1.21-1.71]). Profile 1 had a moderate thromboembolic event rate (1.04/100 person-years [0.91-1.08]), while profiles 2 and 5 showed lower rates., Conclusions: The phenotypic profiles of patients with AF prescribed OACs identified using hierarchical cluster analysis are associated with distinct residual thromboembolic risks and related outcomes. This approach has the potential to enhance patient risk-stratification and holistic approaches to management., (© 2024. The Author(s).)

Background: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown., Methods: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis., Results: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup., Conclusions: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664., Competing Interests: Dr Lampert reports honoraria and research support from Medtronic, Abbott-St. Jude, and Boston Scientific, as well as serving on the Advisory Board for Medtronic. Dr Day received consulting and grant funding from Lexicon Pharmaceuticals, grant funding from Bristol Myers Squibb, and DMC from Cytokinetics. L. Salberg consulted for Biomarin. Dr Tome Esteban consulted for BMS and Cytokinetics. Dr Abrams served on the Scientific Advisory Board for Thryv Therapeutics and consulted for Rocket Pharmaceuticals. Dr Aziz served on the Medtronic Advisory Committee. Dr Behr consulted for Boston Scientific. Dr Berul received research funding from Medtronic. Dr Cerrone provided teaching and CME activities for Abbott and Medtronic. Dr Erickson received funding from Integer. Dr Estes reports consulting for Boston Scientific and Medtronic. Dr Ethridge reports funding from Spauling Research (ECG reading) and UpToDate. Dr James was a consultant for Pfizer and Lexeo Therapeutics and received research funding from Lexeo Therapeutics and StrideBio. Dr Law was a consultant for Medtronic and St. Jude and a speaker for Boston Scientific. Dr Olshansky, AstraZeneca DSMB (Data Safety Monitoring Board). Dr Noseworthy and Mayo Clinic have filed patents related to the application of artificial intelligence to the ECG for diagnosis and risk stratification and have licensed several A-ECG algorithms to Anumana. Dr Noseworthy and Mayo Clinic have a relationship with AliveCor related to the measurement of the QT interval on the Kardia device. Dr Shah was a consultant for Medtronic and Tenaya. Dr Ware received research support and/or consultancy fees from MyoKardia, Bristol Myers Squibb, Foresite Labs, Pfizer, and Health Lumen. Dr Ware is supported by Medical Research Council (UK), British Heart Foundation (RE/18/4/34215), and the NIHR Imperial College Biomedical Research Centre. Dr Ackerman has served as a consultant for Abbott, BioMarin Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Illumina, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. The other authors report no conflicts.

The effect of digoxin and beta-blockers on cardiovascular outcomes and mortality remains unclear. The study aimed to determine differences in cardiovascular (CV) outcomes and death rates among patients with atrial fibrillation (AF) who were prescribed with beta-blockers, digoxin or combination therapy. Data from phase II/III of the prospective Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) were analysed. The risk of major cardiovascular events (MACE) and death among patients with different prescriptions using COX proportional hazard regression was considered. Propensity score (PS) matching and weighting were further used to adjust for potential confounders of prescription use. A total of 14,201 patients [median age: 71.0 (IQR 64.0-77.0) years; 46.2% female] were recruited. After a median follow-up of 3.0 (IQR 2.4-3.1) years, 864 MACE, and 988 all-cause deaths were recorded. The incidence rate (IR) of MACE was 22.4 (95%CI 21.0-24.0) per 1000 person-years, while the IR of all-cause death was 25.4 (95%CI 23.8-27.0) per 1000 person-years. After multivariate adjustment with Cox regression, the risk of MACE (HR 1.35, 95% CI 1.09-1.68) and the risk of all-cause death (HR 1.28, 95%CI 1.04-1.57) were significantly higher in the combination therapy group, compared to the beta-blockers alone group. The risks of MACE and all-cause death remained significant in both PS matched and PS weighted cohort Among AF patients, combination therapy of beta-blockers and digoxin was associated with higher risks of MACE and all-cause death compared to beta-blockers alone., (© 2024. The Author(s).)

Clinical decision-making regarding syncope poses challenges, with risk of physician error due to the elusive nature of syncope pathophysiology, diverse presentations, heterogeneity of risk factors, and limited therapeutic options. Artificial intelligence (AI)-based techniques, including machine learning (ML), deep learning (DL), and natural language processing (NLP), can uncover hidden and nonlinear connections among syncope risk factors, disease features, and clinical outcomes. ML, DL, and NLP models can analyze vast amounts of data effectively and assist physicians to help distinguish true syncope from other types of transient loss of consciousness. Additionally, short-term adverse events and length of hospital stay can be predicted by these models. In syncope research, AI-based models shift the focus from causality to correlation analysis between entities. This prompts the search for patterns rather than defining a hypothesis to be tested a priori. Furthermore, education of students, doctors, and health care providers engaged in continuing medical education may benefit from clinical cases of syncope interacting with NLP-based virtual patient simulators. Education may be of benefit to patients. This article explores potential strengths, weaknesses, and proposed solutions associated with utilization of ML and DL in syncope diagnosis and management. Three main topics regarding syncope are addressed: 1) clinical decision-making; 2) clinical research; and 3) education. Within each domain, we question whether "AI will be better than humans," seeking evidence to support our objective inquiry., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Heart rate score (HRSc), the percentage of atrial depolarizations in the largest paced and sensed 10-beats/min histogram bin recorded in cardiac devices, is associated with several adverse outcomes, but it remains uncertain whether HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation., Objective: This study aimed to determine whether initial HRSc after PM implantation predicts new-onset AHREs in patients with SND., Methods: Patients had Boston Scientific PMs implanted for SND from 2012 to 2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implantation or AHREs within 3 months after implantation. Subsequent AHREs after implantation were evaluated and correlated with HRSc., Results: During 48.9 (interquartile range, 25.7-50.4) months, 130 consecutive PM patients (76 ± 10 years; 40% male) had a median initial HRSc of 74% (57%-86%). AHREs defined by >1%, >6 h/d burden, and atrial tachycardia response events >24 hours developed in 27 of 130 (21%), 15 of 130 (12%), and 9 of 130 (7%), respectively. For each definition, patients with HRSc ≥80% had higher occurrence of AHREs than those with HRSc <80% (both P = .008, log-rank test). After adjustment for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, and cumulative percentage of right atrial and right ventricular pacing, initial HRSc ≥80% (hazard ratio, 3.33; 95% CI, 1.35-8.18; P = .009) and male sex (hazard ratio, 2.59; 95% CI, 1.06-6.33; P = .04) independently predicted AHREs., Conclusion: HRSc ≥80% is associated with new-onset, device-determined AHREs for patients undergoing PM implantation for SND. HRSc may have prognostic and therapeutic implications., Competing Interests: Disclosures H.A.: research grant: Boston Scientific, Medtronic, Abbott. A.D.S.: consultant: VivaQuant, CardioSignal. G.Y.H.L.: consultant and speaker: BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. N.V.: research/consultant: Abbott, Biotronik, Boston Scientific, EP solutions, Implicity, Impulse Dynamics, Medtronic, Pacemate. B.L.W.: consultant and speaker: Boston Scientific, Medtronic, Abbott, Biotronik., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the association between metabolic status, body mass index (BMI), and natural history of patients with atrial fibrillation (AF)., Methods: The global, prospective GLORIA-AF Registry Phase II and III included patients with recent diagnosis of AF between November 2011 and December 2014 for Phase II and between January 2014 and December 2016 for Phase III. With this analysis, we categorized patients with AF according to BMI (normal weight [18.5 to 24.9 kg/m 2 ], overweight [25.0 to 29.9 kg/m 2 ], obese [30.0 to 60.0 kg/m 2 ]) and metabolic status (presence of hypertension, diabetes, and hyperlipidemia). We analyzed risk of major outcomes using multivariable Cox regression analyses; the primary outcome was the composite of all-cause death and major adverse cardiovascular events., Results: There were 24,828 (mean age, 70.1±10.3 years; 44.6% female) patients with AF included. Higher BMI was associated with metabolically unhealthy status and higher odds of receiving oral anticoagulants and other treatments. Normal-weight unhealthy patients showed a higher risk of the primary composite outcome (adjusted hazard ratio [aHR], 1.20; 95% CI, 1.01 to 1.42) and thromboembolism, whereas a lower risk of cardiovascular death (aHR, 0.35; 95% CI, 0.14 to 0.88) and major adverse cardiovascular events (aHR, 0.56; 95% CI, 0.33 to 0.93) was observed in metabolically healthy obese individuals. Unhealthy metabolic groups were also associated with increased risk of major bleeding (aHR, 1.51 [95% CI, 1.04 to 2.20] and aHR, 1.96 [95% CI, 1.34 to 2.85] in overweight and obese groups, respectively)., Conclusion: Increasing BMI was associated with poor metabolic status and with more intensive treatment. Prognosis was heterogeneous between BMI groups, with metabolically unhealthy patients showing higher risk of adverse events., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The pathophysiology of orthostatic hypotension (OH), a common clinical condition, associated with adverse outcomes, is incompletely understood. We examined the relationship between OH and circulating endostatin, an endogenous angiogenesis inhibitor with antitumour effects proposed to be involved in blood pressure (BP) regulation., Methods and Results: We compared endostatin levels in 146 patients with OH and 150 controls. A commercial chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin. Linear and multivariate logistic regressions were conducted to test the association between endostatin and OH. Endostatin levels were significantly higher in OH patients (59 024 ± 2513 pg/mL) vs. controls (44 090 ± 1978pg/mL, P < 0.001). A positive linear correlation existed between endostatin and the magnitude of systolic BP decline upon standing ( P < 0.001). Using multivariate analysis, endostatin was associated with OH (adjusted odds ratio per 10% increase of endostatin in the whole study population = 1.264, 95% confidence interval 1.141-1.402), regardless of age, sex, prevalent cancer, and cardiovascular disease, as well as traditional cardiovascular risk factors., Conclusion: Circulating endostatin is elevated in patients with OH and may serve as a potential clinical marker of increased cardiovascular risk in patients with OH. Our findings call for external validation. Further research is warranted to clarify the underlying pathophysiological mechanisms., Competing Interests: Conflict of interest: A.F. received speaker and consultation fees from Medtronic Inc., Finapres Medical Systems, and Bristol Myers Squibb. The remaining authors report no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Clinical complexity, as the interaction between ageing, frailty, multimorbidity and polypharmacy, is an increasing concern in patients with AF. There remains uncertainty regarding how combinations of comorbidities influence management and prognosis of patients with atrial fibrillation (AF). We aimed to identify phenotypes of AF patients according to comorbidities and to assess associations between comorbidity patterns, drug use and risk of major outcomes., Methods: From the prospective GLORIA-AF Registry, we performed a latent class analysis based on 18 diseases, encompassing cardiovascular, metabolic, respiratory and other conditions; we then analysed the association between phenotypes of patients and (i) treatments received and (ii) the risk of major outcomes. Primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). Secondary exploratory outcomes were also analysed., Results: 32,560 AF patients (mean age 70.0 ± 10.5 years, 45.4% females) were included. We identified 6 phenotypes: (i) low complexity (39.2% of patients); (ii) cardiovascular (CV) risk factors (28.2%); (iii) atherosclerotic (10.2%); (iv) thromboembolic (8.1%); (v) cardiometabolic (7.6%) and (vi) high complexity (6.6%). Higher use of oral anticoagulants was found in more complex groups, with highest magnitude observed for the cardiometabolic and high complexity phenotypes (odds ratio and 95% confidence interval CI): 1.76 [1.49-2.09] and 1.57 [1.35-1.81], respectively); similar results were observed for beta-blockers and verapamil or diltiazem. We found higher risk of the primary outcome in all phenotypes, except the CV risk factor one, with highest risk observed for the cardiometabolic and high complexity groups (hazard ratio and 95%CI: 1.37 [1.13-1.67] and 1.47 [1.24-1.75], respectively)., Conclusions: Comorbidities influence management and long-term prognosis of patients with AF. Patients with complex phenotypes may require comprehensive and holistic approaches to improve their prognosis., (© 2024. The Author(s).)

Cardioneuroablation (CNA) is being increasingly used to treat patients with vasovagal syncope (VVS). Bradycardia, in the cardioinhibitory subtype of VVS, results from transient parasympathetic overactivity leading to sinus bradycardia and/or atrioventricular block. By mitigating parasympathetic overactivity, CNA has been shown to improve VVS symptoms in clinical studies with relatively small sample sizes and short follow-up periods (<5 years) at selected centers. However, CNA may potentially tip the autonomic balance to a state of sympathovagal imbalance with attenuation of cardiac parasympathetic activity. A higher heart rate is associated with adverse cardiovascular events and increased mortality in healthy populations without cardiovascular diseases. Chronic sympathovagal imbalance may also affect the pathophysiology of spectra of cardiovascular disorders including atrial and ventricular arrhythmias. This review addresses potential long-term pathophysiological consequences of CNA for VVS., Competing Interests: Disclosures Dr Chakraborty is supported by the George Mines Travelling Fellowship by the Canadian Heart Rhythm Society. Dr Chen acknowledges grant support R01HL139829 and 1OT2OD028190-01 from the National Institutes of Health and 23IPA1052289 from the American Heart Association. Dr Chen is the Burns and Allen Chair in Cardiology Research at Cedars-Sinai Medical Center, Los Angeles, CA. The rest of the authors report no conflicts of interest., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) has led to a worldwide pandemic that continues to transform but will not go away. Cardiovascular dysautonomia in postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection has led to persistent symptoms in a large number of patients. Here, we define the condition and its associated symptoms as well as potential mechanisms responsible. We provide a careful and complete overview of the topic addressing novel studies and a generalized approach to the management of individuals with this complex and potentially debilitating problem. We also discuss future research directions and the important knowledge gaps to be addressed in ongoing and planned studies., (© 2023 Wiley Periodicals LLC.)