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Introduction: There is a longstanding clinical uncertainty regarding the optimal timing of initiating oral anticoagulants (OAC) for non-valvular atrial fibrillation following acute ischemic stroke. Current international recommendations are based on expert opinions, while significant diversity among clinicians is noted in everyday practice., Methods: We conducted an updated systematic review and meta-analysis including all available randomized-controlled clinical trials (RCTs) and observational cohort studies that investigated early versus later OAC-initiation for atrial fibrillation after acute ischemic stroke. The primary outcome was defined as the composite of ischemic and hemorrhagic events and mortality at follow-up. Secondary outcomes included the components of the composite outcome (ischemic stroke recurrence, intracranial hemorrhage, major bleeding, and all-cause mortality). Pooled estimates were calculated with random-effects model., Results: Nine studies (two RCTs and seven observational) were included comprising a total of 4946 patients with early OAC-initiation versus 4573 patients with later OAC-initiation following acute ischemic stroke. Early OAC-initiation was associated with reduced risk of the composite outcome (RR = 0.74; 95% CI:0.56-0.98; I 2  = 46%) and ischemic stroke recurrence (RR = 0.64; 95% CI:0.43-0.95; I 2  = 60%) compared to late OAC-initiation. Regarding safety outcomes, similar rates of intracranial hemorrhage (RR = 0.98; 95% CI:0.57-1.69; I 2  = 21%), major bleeding (RR = 0.78; 95% CI:0.40-1.51; I 2  = 0%), and mortality (RR = 0.94; 95% CI:0.61-1.45; I 2  = 0%) were observed. There were no subgroup differences, when RCTs and observational studies were separately evaluated., Conclusions: Early OAC-initiation in acute ischemic stroke patients with non-valvular atrial fibrillation appears to have better efficacy and a similar safety profile compared to later OAC-initiation., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The OCEANIC-AF trial was terminated early due to inferiority of asundexian compared with apixaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation. 1 However, the promisingly low bleeding rates support continued exploration of factor XIa inhibitors. Future efforts should focus on achieving greater factor XIa inhibition and identifying patient populations that may benefit most from these therapies., Competing Interests: Declaration of interests L.P. served as an investigator in the OCEANIC-AF trial and serves as an investigator in the OCEANIC-STROKE trial. G.T. served as a local principal investigator in the OCEANIC-AF trial and serves as a national principal investigator in the OCEANIC-STROKE trial. He also serves on the Steering Committee of the OCEANIC-STROKE trial., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Intravenous thrombolysis (IVT) and/or endovascular therapy (EVT) are currently considered best practices in acute stroke patients. Data regarding the efficacy and safety of reperfusion therapies in patients with atrial fibrillation (AF) are conflicting as regards haemorrhagic transformation, mortality, and functional outcome. This study sought to investigate for any differences, in terms of safety and effectiveness, between AF patients with acute ischaemic stroke (AIS) treated and untreated with reperfusion therapies., Methods: Data from two multicenter cohort studies (RAF and RAF-NOACs) on consecutive patients with AF and AIS were analyzed to compare patients treated and not treated with reperfusion therapies (IVT and/or EVT). Multivariable logistic regression analysis was performed to identify independent predictors for outcome events: 90-day good functional outcome and mortality. A propensity score matching (PSM) analysis compared treated and untreated patients., Results: Overall, 441 (25.4%) were included in the reperfusion-treated group and 1,295 (74.6%) in the untreated group. The multivariable model suggested that reperfusion therapies were significantly associated with good functional outcome. Rates of mortality and disability were higher in patients not treated, especially in the case of higher NIHSS scores. In the PSM comparison, 173/250 patients (69.2%) who had received reperfusion therapies had good functional outcome at 90 days, compared to 146/250 (58.4%) untreated patients (p = 0.009, OR: 1.60, 95% CI:1.11-2.31)., Conclusions: Patients with AF and AIS treated with reperfusion therapies had a significantly higher rate of good functional outcome and lower rates of mortality compared to those patients with AF and AIS who had undergone conservative treatment., (© 2024. The Author(s).)

Atrial fibrillation (AF) is the most common heart rhythm disorder, especially in people over the age of 50, which affects more than 40 million people worldwide. Many studies have highlighted the association between hypertension with the development of AF. Blood pressure variability (BPV) is a dynamic size obtained by recording blood pressure oscillations using specific readings and at specific time intervals. A multitude of internal and external factors shape BPV while at the same time constituting a common pathogenetic pathway with the development of AF. Until recently, BPV has been applied exclusively in preclinical and clinical studies, without significant implications in clinical practice. Indeed, even from the research side, the determination of BPV is limited to patients without AF due to doubts about the accuracy of its measurement methods in patients with AF. In this review, we present the current evidence on common pathogenic pathways between BPV and AF, the reliability of quantification of BPV in patients with AF, the prognostic role of BPV in these patients, and discuss the future clinical implications of BPV in patients with AF., (© 2024. Crown.)

Background: Adults with congenital heart disease (ACHD) and atrial arrhythmias (AA) face an increased risk of thromboembolic events. Limited data exist on the use of non-vitamin K oral anticoagulants for thromboprophylaxis in ACHD. We aimed to assess the effectiveness and safety of apixaban in ACHD patients with AA., Methods: PROTECT-AR (NCT03854149) was a prospective, multicenter, observational study conducted from 2019 to 2023. ACHD patients with atrial fibrillation, atrial flutter, or intra-atrial re-entrant tachycardia on routine apixaban treatment were included. The historical control group consisted of patients previously on vitamin K antagonist (VKA), who were analyzed prior to their transition to apixaban. The primary effectiveness endpoint was the composite of stroke or thromboembolism. The primary safety endpoint was major bleeding., Results: The study enrolled 218 ACHD patients with AA on apixaban, of which 73 were previous VKA users. The analysis covered 527 patient-years of prospective exposure to apixaban and 169 patient-years of retrospective exposure to VKA. The annualized rate of stroke or thromboembolism was 0.6% in the apixaban group and 1.8% in the VKA group (absolute difference - 1.2%; upper limit of one-sided 95% confidence interval [CI] 0.9%, lower than the predefined non-inferiority margin of +1.8%, P non-inferiority  < 0.001). The annualized rate of major bleeding was 1.5% in the apixaban group and 2.4% in the VKA group (hazard ratio 0.64; 95% CI 0.19-2.10, P = 0.48)., Conclusion: In ACHD patients with AA, routine apixaban use exhibited a non-inferior rate of stroke or thromboembolism compared to historical VKA use, alongside a similar rate of major bleeding., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

This comprehensive review explores the incidence, pathophysiology, and management of atrial fibrillation (AF) following percutaneous closure of patent foramen ovale (PFO). Although AF is considered a common adverse event post PFO closure, its incidence, estimated at <5%, varies based on monitoring methods. The review delves into the challenging task of precisely estimating AF incidence, given subclinical AF and diverse diagnostic approaches. Notably, a temporal pattern emerges, with peak incidence around the 14th day after closure and a subsequent decline after the 45th day, mimicking general population AF trends. The pathophysiological mechanisms behind post PFO closure AF remain elusive, with proposed factors including local irritation, device-related interference, tissue stretch, and nickel hypersensitivity. Management considerations encompass rhythm control, with flecainide showing promise, and anticoagulation tailored to individual risk profiles. The authors advocate for a personalized approach, weighing factors like age, comorbidities, and device characteristics. Notably, postclosure AF is generally considered benign, often resolving spontaneously within 45 days, minimizing thromboembolic risks. Further studies are required to refine understanding and provide evidence-based guidelines.

Background: Atrial fibrillation (AF) is a frequent underlying cause of cryptogenic stroke (CS) and its detection can be increased using implantable cardiac monitoring (ICM). We sought to evaluate different risk scores and assess their diagnostic ability in identifying patients with CS with underlying AF on ICM., Methods: Patients with CS, being admitted to a single tertiary stroke center between 2017 and 2022 and receiving ICM, were prospectively evaluated. The CHA 2 DS 2 -VASc, HAVOC, Brown ESUS-AF, and C 2 HEST scores were calculated at baseline. The primary outcome of interest was the detection of AF, which was defined as at least 1 AF episode on ICM lasting for 2 consecutive minutes or more. The diagnostic accuracy measures and the net reclassification improvement were calculated for the 4 risk scores. Stroke recurrence was evaluated as a secondary outcome., Results: A total of 250 patients with CS were included, and AF was detected by ICM in 20.4% (n=51) during a median monitoring period of 16 months. Patients with CS with AF detection were older compared with the rest ( P =0.045). The median HAVOC, Brown ESUS-AF, and C 2 HEST scores were higher among the patients with AF compared with the patients without AF (all P <0.05), while the median CHA 2 DS 2 -VASc score was similar between the 2 groups. The corresponding C statistics for CHA 2 DS 2 -VASc, HAVOC, Brown ESUS-AF, and C 2 HEST for AF prediction were 0.576 (95% CI, 0.482-0.670), 0.612 (95% CI, 0.523-0.700), 0.666 (95% CI, 0.587-0.746), and 0.770 (95% CI, 0.699-0.839). The C 2 HEST score presented the highest diagnostic performance based on C statistics ( P <0.05 after correction for multiple comparisons) and provided significant improvement in net reclassification for AF detection (>70%) compared with the other risk scores. Finally, stroke recurrence was documented in 5.6% of the study population, with no difference regarding the 4 risk scores between patients with and without recurrent stroke., Conclusions: The C 2 HEST score was superior to the CHA 2 DS 2 -VASc, HAVOC, and Brown ESUS-AF scores for discriminating patients with CS with underlying AF using ICM., Competing Interests: Disclosures Dr Tsioufis reports the following interests that are unrelated to the present work: research grants from Medtronic, Recor, and Recordati and honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bayer, Chiesi, Medtronic, Menarini, Novartis, Pfizer, Pharmanel, Sanofi, Servier, and Viatris. Dr Filippatos reports the following interests that are unrelated to the present work: Amgen (other), Bayer (other), Boehringer Ingelheim (other), European Commission (grant/contract), Impulse Dynamics, Inc (other), Medtronic (other), Novartis (other), Servier (other), and Vifor Pharma (End Point Review Committee). The other authors report no conflicts.

Atrial fibrillation (AF) and acute heart failure (AHF) are two closely interrelated conditions that frequently coexist in a manifold manner, with AF serving either as the causative factor or as the consequence or even as an innocent bystander. The interplay between these two clinical conditions is complex, given that they share common pathophysiological pathways and they can reciprocally exacerbate each other, thus triggering a vicious cycle that worsens the prognosis and increases the thromboembolic risk. The optimal management of AF in the context of AHF in the emergency department remains a challenge depending on the time onset, as well as the nature and the severity of the associated symptoms. Acute rate control, along with early rhythm control, when indicated, and anticoagulation represent the main pillars of the therapeutic intervention. The purpose of this review is to elucidate the pathophysiological link between AF and AHF and accordingly present a stepwise algorithmic approach for the management of AF in AHF patients in the emergency setting.

Purpose: Cardiovascular disease is commonly accompanied by renal dysfunction. Multimorbidity in hospitalized patients impacts unfavorably on prognosis and hospital stay. We aimed to illustrate the contemporary burden of cardiorenal morbidity across inpatient cardiology care in Greece., Methods: The Hellenic Cardiorenal Morbidity Snapshot (HECMOS) used an electronic platform to collect demographic and clinically relevant information about all patients hospitalized on March 3, 2022, in Greece. The participating institutions covered all levels of inpatient cardiology care and most of the country's territories to collect a real-world, nation representative sample., Results: A total of 923 patients (men 68.4%, median age 73 ± 14.8 years) were admitted to 55 different cardiology departments. 57.7% of the participants were aged >70 years. Hypertension was highly prevalent and present in 66% of the cases. History of chronic HF, diabetes mellitus, atrial fibrillation, and chronic kidney disease was present in 38%, 31.8%, 30%, and 26%, respectively. Furthermore, 64.1% of the sample exhibited at least one of these 4 entities. Accordingly, a combination of ≥2 of these morbid conditions was recorded in 38.7%, of ≥3 in 18.2%, whereas 4.3% of the sample combined all 4 in their medical history. The most common combination was the coexistence of heart failure-atrial fibrillation accounting for 20.6% of the sample. Nine of 10 nonelectively admitted patients were hospitalized due to acute HF (39.9%), acute coronary syndrome (33.5%), or tachyarrhythmias (13.2%)., Conclusion: HECMOS participants carried a remarkable burden of cardio-reno-metabolic disease. HF in conjunction with atrial fibrillation was found to be the most prevalent combination among the studied cardiorenal nexus of morbidities in the whole study population., (Copyright © 2023 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Despite left ventricular global longitudinal strain is an eminent and validated marker of cardiovascular disease, assessment of left atrial size and function may have incremental role in diagnosis and management of cardiovascular disease. Left atrial strain, measured by 2-dimensional speckle tracking echocardiography, is a non-invasive biomarker for the assessment of left atrial function. This novel marker, has additional value to traditional echocardiography markers of left atrial function such as left atrial diameter and volume for the diagnosis and management of left ventricular diastolic dysfunction, heart failure with preserved ejection fraction, atrial fibrillation and valvular disease. However, there are potent limitations for its use in the daily clinical practice, regarding loading conditions, image acquisition and heart rate. The aim of this review is to summarize the published evidence about left atrial strain, as assessed by speckle tracking imaging, and to discuss its clinical implications and its potent limitations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: B-blockers are regarded as beneficial pharmacologic agents in cardiac care, but their role in the acute setting remains ambiguous. Increasing evidence supports the important role of landiolol in critical care, a highly cardioselective intravenous b-blocker with rapid onset of action and short elimination time. Among its most valuable properties, which may aid to overcome special reservations related to b-blocker therapy in the acute setting, landiolol has a potent negative chronotropic effect while at the same time it exhibits a mild negative inotropic effect., Areas Covered: This expert opinion review aims to present basic pharmacologic aspects of landiolol and provide current clinical research focused on its efficacy and safety., Expert Opinion: Landiolol is a valuable and safe pharmacologic agent in acute cardiac care. Japanese and European guidelines have incorporated its use for the management of atrial tachyarrhythmia in patients with cardiac dysfunction. Although emerging clinical trials have experimented its use in patients with sustained ventricular tachycardia/fibrillation, acute myocardial infarction undergoing primary percutaneous intervention and in patients with septic cardiomyopathy, more studies are needed in order to establish its value in such cardiac conditions.

Introduction: Prolonged cardiac monitoring (PCM) substantially improves the detection of subclinical atrial fibrillation (AF) among patients with history of ischemic stroke (IS), leading to prompt initiation of anticoagulants. However, whether PCM may lead to IS prevention remains equivocal., Patients and Methods: In this systematic review and meta-analysis, randomized-controlled clinical trials (RCTs) reporting IS rates among patients with known cardiovascular risk factors, including but not limited to history of IS, who received PCM for more than 7 days versus more conservative cardiac rhythm monitoring methods were pooled., Results: Seven RCTs were included comprising a total of 9048 patients with at least one known cardiovascular risk factor that underwent cardiac rhythm monitoring. PCM was associated with reduction of IS occurrence compared to conventional monitoring (Risk Ratio: 0.76; 95% CI: 0.59-0.96; I 2  = 0%). This association was also significant in the subgroup of RCTs investigating implantable cardiac monitoring (Risk Ratio: 0.75; 95% CI: 0.58-0.97; I 2  = 0%). However, when RCTs assessing PCM in both primary and secondary prevention settings were excluded or when RCTs investigating PCM with a duration of 7 days or less were included, the association between PCM and reduction of IS did not retain its statistical significance. Regarding the secondary outcomes, PCM was related to higher likelihood for AF detection and anticoagulant initiation. No association was documented between PCM and IS/transient ischemic attack occurrence, all-cause mortality, intracranial hemorrhage, or major bleeding., Conclusion: PCM may represent an effective stroke prevention strategy in selected patients. Additional RCTs are warranted to validate the robustness of the reported associations., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© European Stroke Organisation 2022.)

Abstract: GReek-AntiPlatElet Atrial Fibrillation registry is a multicenter, observational, noninterventional study of atrial fibrillation patients undergoing percutaneous coronary intervention. Primary endpoint included clinically significant bleeding rate at 12 months between different antithrombotic regimens prescribed at discharge; secondary endpoints included major adverse cardiovascular events and net adverse clinical events. A total of 647 patients were analyzed. Most (92.9%) were discharged on novel oral anticoagulants with only 7.1% receiving the vitamin K antagonist. A little over half of patients (50.4%) received triple antithrombotic therapy (TAT)-mostly (62.9%) for ≤1 month-whereas the rest (49.6%) received dual antithrombotic therapy (DAT). Clinically significant bleeding risk was similar between TAT and DAT [Hazard ratio (HR) = 1.08; 95% confidence interval (CI), 0.66-1.78], although among TAT-receiving patients, the risk was lower in those receiving TAT for ≤1 month (HR = 0.50; 95% CI, 0.25-0.99). Anticoagulant choice (novel oral anticoagulant vs. vitamin K antagonist) did not significantly affect bleeding rates ( P = 0.258). Age, heart failure, leukemia/myelodysplasia, and acute coronary syndrome were associated with increased bleeding rates. Risk of major adverse cardiovascular events and net adverse clinical events was similar between ΤAT and DAT (HR = 1.73; 95% CI, 0.95-3.18, P = 0.075 and HR = 1.39; 95% CI, 0.93-2.08, P = 0.106, respectively). In conclusion, clinically significant bleeding and ischemic rates were similar between DAT and TAT, although TAT >1 month was associated with higher bleeding risk., Competing Interests: D. Alexopoulos has received lecturing honoraria/advisory board fees from Astrazeneca, Bayer, Boehringer Ingelheim, Pfizer, Medtronic, Biotronik, and Chiesi Hellas. I. Zarifis has received lecturing honoraria from Boehringer Ingelheim. L. Poulimenos has received research grants and honoraria from Astra Zeneca, Bayer, Boehringer-Ingelheim, ELPEN, Menarini, MSD, Novartis, Pfizer, Servier outside the submitted work. E. Skalidis has received lecturing honoraria/advisory board fees from Astrazeneca, Bayer, Boehringer Ingelheim, Medtronic. V. Voudris has received lecturing honoraria/advisory board fees from Bayer and Medtronic. Other authors report no relationships that could be construed as a conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Platelet function testing (PFT) could be a useful clinical tool to guide individualized antithrombotic treatment in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). We aimed to investigate platelet reactivity (PR) in the context of a contemporary registry. "Real-world" data were retrieved from a nationwide, multicenter, observational study of AF patients on oral anticoagulants (OAC) undergoing PCI. Patients treated with a P2Y 12 inhibitor, namely clopidogrel or ticagrelor, as part of double or triple antithrombotic therapy, were submitted to PFT before discharge and were followed up for 12 months. Out of 101 patients included in the study, 66 were submitted to PFT while on clopidogrel and 35 while on ticagrelor; PR was 162.9 ± 68 PRU and 46.02 ± 46 PRU, respectively (P < 0.001). High on-treatment PR (HTPR) was observed in 15 patients under clopidogrel (22.7%); 7 of them escalated to ticagrelor. Low on-treatment PR (LTPR) was found in 9 clopidogrel and 28 ticagrelor-treated patients (13.6% vs. 80%, P < 0.001), of whom only 1 de-escalated to clopidogrel. PR did not differ by OAC regimen. PFT results had no impact on aspirin prescription at discharge, while failed to predict significant bleeding events at follow up. Ticagrelor administration led to lower PR and lower incidence of HTPR in comparison with clopidogrel. Physicians' behavior in response to knowledge of a patient's PR was variable. Further studies are required to elucidate the role of PFT as a tool to guide individualized antithrombotic treatment in this clinical scenario., (© 2022. The Author(s).)

Background: Digoxin is widely used in atrial fibrillation (AF) and heart failure (HF). However, current evidence regarding its association with clinical outcomes is conflicting., Aim: To investigate the relationship between digoxin therapy and adverse outcomes in patients with AF, with or without HF, in a contemporary AF cohort., Methods: We performed a retrospective analysis of data from 698 patients, who were followed over a median of 2.5 years. The primary outcome was all-cause mortality and the secondary outcome was all-cause hospitalization, in a time-to-event analysis. Propensity scores were used to derive matched populations, balanced on key baseline covariates. To limit potential confounding, inverse probability of treatment weighting (IPTW) analysis was performed., Results: Among patients with HF, 39 (10.5%) were administered digoxin at baseline, whereas 331 (89.5%) were not. Digoxin administration was not associated with an increased risk of death (hazard ratio (HR) in the digoxin group, 1.21; 95% Confidence Interval (CI), 0.69 to 2.13, p = 0.50) or hospitalization of any cause (HR 1.15; 95% CI, 0.67 to 1.96; p = 0.60). Among patients without HF, 11 (3.5%) were administered digoxin, with neutral effects on all-cause mortality (HR: 3.25; 95% CI, 0.98 to 10.70), p = 0.06) and all-cause hospitalization (HR, 1.15; 95% CI, 0.67 to 1.96, p = 0.60). Qualitatively, consistent results were observed using IPTW., Conclusions: Among patients with AF, digoxin administration was not associated with an increased risk of death and hospitalization for any cause, irrespective of HF status., (Copyright © 2022 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Aims: Limited data exist regarding the prognostic relevance of changes in left atrial (LA) dimensions in patients with heart failure (HF). We assessed changes in LA dimension and their relation with outcomes after optimization of guideline-directed medical therapy (GDMT) in patients with new-onset or worsening HF., Methods and Results: Left atrial diameter was assessed at baseline and 9 months after GDMT optimization in 632 patients (mean age 65.8 ± 12.1 years, 22.3% female) enrolled in BIOSTAT-CHF. LA adverse remodelling (LAAR) was defined as an increase in LA diameter on transthoracic echocardiography between baseline and 9 months. After the 9-month visit, patients were followed for a median of 13 further months. LAAR was observed in 247 patients (39%). Larger baseline LA diameter (odds ratio [OR] 0.90; 95% confidence interval [CI] 0.87-0.93; p < 0.001) and up-titration to higher doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs) (OR 0.56; 95% CI 0.34-0.92; p = 0.022) were independently associated with lower likelihood of LAAR. LAAR was associated with an increased risk of the composite of all-cause mortality or HF hospitalization (log-rank p = 0.007 and adjusted hazard ratio 1.73, 95% CI 1.22-2.45, p = 0.002). The association was more pronounced in patients without a history of atrial fibrillation (p for interaction = 0.009)., Conclusion: Among patients enrolled in BIOSTAT-CHF, LAAR was associated with an unfavourable outcome and was prevented by ACEi/ARB up-titration. Changes in LA dimension may be a useful marker of response to treatment and improve risk stratification in patients with HF., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses., Methods and Results: From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were up-regulated in patients with AF and HF. In the validation cohort, eight biomarkers were up-regulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, P = 1.33 × 10-12), insulin-like growth factor-binding protein-1 (fold change 1.32, P = 1.08 × 10-8), and insulin-like growth factor-binding protein-7 (fold change 1.33, P = 1.35 × 10-18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort., Conclusion: In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies., Competing Interests: Conflict of interest: A.A.V. and/or his institution received grants and/or consultancy reimbursements from Amgen, AstraZeneca, Bayer AG, Boehringer, Cytokinetics, Merck, Myokardia, Novartis, Roche, and Novo Nordisk. B.T.S. received funding from the Dutch Heart Foundation (2019T094). I.C.V.G. reports support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch heart Foundation (CVON 2014-9 and CVON 2018-28) and support from Medtronic to the institution. F.Z. reports personal fees from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer, Boston Scientific, Cardior, Cardiorenal, Cereno pharmaceutical, Cirius, CVCT, CVRx, Janssen, Novartis, Merck, and Vifor Fresenius. P.v.d.M. received consultancy fees and/or grants from Novartis, Servier, Vifor, Pharma, Astra Zeneca, Pfizer, and Ionis. C.S.P.L. is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd and Corpus; and serves as co-founder and non-executive director of eKo.ai. G.F. is committee member in trials and/or registries sponsored by Medtronic, Novartis, BI, Vifor, Servier, outside the submitted work. S.D.A. reports receiving fees from Abbott Vascular, Bayer, Boehringer Ingelheim, Cardiac Dimension, Impulse Dynamics, Novartis, Servier, and Vifor Pharma, and grant support from Abbott Vascular and Vifor Pharma. V.A.A. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant (754425). None of the funders had any role in the trial design, the collection or analysis of the data, or the writing of the manuscript. All other authors declare no conflict of interest., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain., Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment., Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7])., Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

The most frequent arrhythmia treated is atrial fibrillation (AF), which necessitates the use of oral anticoagulants (OACs) to reduce the risk of thromboembolism and stroke. Patients with chronic kidney disease are more likely to develop AF, with a 10% frequency among those on chronic dialysis. Warfarin is the most widely prescribed OAC for individuals with end-stage kidney disease (ESKD). On the other hand, direct OACs (DOACs) are generally safer than warfarin, with fewer fatal bleeding events and a fixed dose that does not require close international normalized ratio (INR) monitoring. For those patients, warfarin and apixaban appear to be FDA-approved, whereas dabigatran, rivaroxaban, and edoxaban are not recommended yet. Due to a lack of large randomized studies, data from major trials cannot be extended to dialysis patients. In this review, we summarize the available data and literature referring to patients on chronic hemodialysis with concomitant AF. Due to the scarcity of data, we try to assist clinicians in selecting the appropriate therapy according to the specific characteristics of each patient. Finally, future directions are provided in two key areas of focus: left atrial appendage closure therapies and genetic research., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Atrial fibrillation (AF) and Heart failure (HF) constitute two frequently coexisting cardiovascular diseases, with a great volume of the scientific research referring to strategies and guidelines associated with the best management of patients suffering from either of the two or both of these entities. The common pathophysiological paths, the adverse outcomes, the hospitalization rates, and the mortality rates that occur from various reports and trials indicate that a targeted therapy to the common background of these cardiovascular conditions may reverse the progression of their interrelating development. Among other optimal treatments concerning the prevalence of both AF and HF, the introduction of rhythm and rate control strategies in the guidelines has underlined the importance of sinus rhythm and heart rate control in the prevention of deleterious complications. The use of these strategies in the clinical practice has led to a debate about the superiority of rhythm versus rate control. The current guidelines as well as the published randomized trials and studies have not proved that rhythm control is more beneficial than the rate control treatments in the terms of survival, all-cause mortality, hospitalization rates, and quality of life. Therefore, the current therapeutic strategy is based on the therapy guidelines and the clinical judgment and experience. The aim of this review was to elucidate the endpoints of pharmacologic randomized clinical trials and the clinical data of each antiarrhythmic or rate-limiting medication, so as to promote their effective, individualized, evidence-based clinical use.

Objective: Ischemic stroke etiology remains undetermined in 30% of cases. We explored the genetic architecture of stroke classified as undetermined to test if mechanisms and risk factors underlying large-artery atherosclerotic (LAAS), cardioembolic (CES), and small-vessel stroke (SVS) contribute to its pathogenesis., Methods: We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls. Using polygenic risk scores for LAAS, CES, and SVS, we assessed the genetic overlap with stroke of undetermined source and used pairwise genomewide association study (GWAS-PW) to search for shared loci. We then applied Mendelian randomization (MR) to identify potentially causal risk factors of stroke of undetermined source., Results: Genetic risk for LAS, CES, and SVS was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise analyses revealed 19 shared loci with LAAS, 2 with CES, and 5 with SVS that have been implicated in atherosclerosis-related phenotypes. Genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. MR analyses showed effects of genetically determinants of blood pressure, diabetes, waist-to-hip ratio, inflammatory pathways (IL-6 signaling, MCP-1/CCL2 levels), and factor XI levels on stroke of undetermined source., Interpretation: Stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The potentially causal associations with carotid atherosclerosis and atherosclerotic risk factors might have implications for prevention strategies targeting these mechanisms. ANN NEUROL 2022;91:640-651., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: In standard dosing, direct Oral Anticoagulants (DOACs) are used as an alternative to warfarin to prevent ischemic stroke and systemic embolism in non-valvular Atrial Fibrillation (AF). However, randomized comprehensive evidence considering the efficacy and safety of the low-dose DOACs in the same setting is still lacking. Toward this end, we conducted a meta-analysis of randomized trials to estimate the risk/benefit ratio, in terms of net clinical benefit, by comparing a reduced dose of DOACs and warfarin., Methods: We searched three electronic databases, covering the period until end-February 2021. All-cause death, non-fatal stroke/systemic embolism, and major bleeding events, with or without the inclusion of myocardial infarction, were used to define two different net clinical benefit outcomes. In addition, we evaluated different component outcomes of net clinical benefit as secondary outcomes. Finally, risk ratios and 95% Confidence Intervals (CI) of each outcome were calculated (random-effects model)., Results: In the four randomized trials included (n = 29,779 patients), the net clinical benefit - with or without the inclusion of myocardial infarction - of low-dose DOACs, compared to warfarin, was a 12% (95% CI, 7%-16%) or a 10% (95% CI, 5%-13%) reduction of events, respectively. Compared to warfarin, the reduced dose of DOACs decreased death outcomes, major bleeding events, and hemorrhagic stroke, whereas all thrombotic outcomes were not different among the groups., Conclusions: DOACs at low dosing present a more favorable net clinical benefit profile compared to warfarin., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To investigate the safety and effectiveness of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) after recent stroke in patients with atrial fibrillation (AF) aged ≥85 years., Methods: Individual patient data analysis from seven prospective stroke cohorts. We compared DOAC versus VKA treatment among patients with AF and recent stroke (<3 months) aged ≥85 versus <85 years. Primary outcome was the composite of recurrent stroke, intracranial hemorrhage (ICH) and all-cause death. We used simple, adjusted, and weighted Cox regression to account for confounders. We calculated the net benefit of DOAC versus VKA by balancing stroke reduction against the weighted ICH risk., Results: In total, 5,984 of 6,267 (95.5%) patients were eligible for analysis. Of those, 1,380 (23%) were aged ≥85 years and 3,688 (62%) received a DOAC. During 6,874 patient-years follow-up, the impact of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome did not differ between patients aged ≥85 (HR ≥85y  = 0.65, 95%-CI [0.52, 0.81]) and < 85 years (HR <85y  = 0.79, 95%-CI [0.66, 0.95]) in simple (p interaction  = 0.129), adjusted (p interaction  = 0.094) or weighted (p interaction  = 0.512) models. Analyses on recurrent stroke, ICH and death separately were consistent with the primary analysis, as were sensitivity analyses using age dichotomized at 90 years and as a continuous variable. DOAC had a similar net clinical benefit in patients aged ≥85 (+1.73 to +2.66) and < 85 years (+1.90 to +3.36 events/100 patient-years for ICH-weights 1.5 to 3.1)., Interpretation: The favorable profile of DOAC over VKA in patients with AF and recent stroke was maintained in the oldest old. ANN NEUROL 2022;91:78-88., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Herpes simplex virus-1 (HSV-1) encephalitis, the most common and potentially life-threatening type of encephalitis, may rarely present as a stroke mimic. Prompt diagnosis is of paramount importance for the timely initiation of antiviral treatment and to avert intravenous thrombolysis., Case Report: A 60-year-old man with a history of lone paroxysmal atrial fibrillation without prior antithrombotic treatment was admitted due to mild gait unsteadiness and intermittent dysarthria of acute onset. On admission, the patient was afebrile, whereas neurological examination revealed only a mild pronator drift on the left. Brain magnetic resonance imaging (MRI) showed an extensive right temporo-occipital and thalamic lesion with restricted diffusion and 3 small-sized hemorrhagic foci. Brain MR-angiography did not show large vessel stenosis or occlusion. On the basis of careful observation and the depiction of several imaging discrepancies, such as early vasogenic edema and hemorrhagic transformation, as well as uncus involvement, but also the lack of significant neurological deficits despite the size of the brain lesion we suspected viral encephalitis which was confirmed by the detection of HSV-1 DNA in the cerebrospinal fluid., Conclusion: HSV-encephalitis might occasionally result in the development of unilateral brain MRI lesions with extensive cytotoxic edema, resembling an acute ischemic stroke. Therefore, HSV-encephalitis must be considered in the differential diagnosis of acute ischemic stroke with atypical presentation. The presence of a significant dissociation between the brain MRI lesion volume and the neurological deficits, as well as certain brain MRI imaging discrepancies might serve as "red flags" to extend the diagnostic workup., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Heart failure (HF) and atrial fibrillation (AF) often coexist, being closely interrelated as the one increases the prevalence and incidence and worsens the prognosis of the other. Their frequent coexistence raises several challenges, including under-diagnosis of HF with preserved ejection fraction in AF and of AF in HF, characterization and diagnosis of atrial cardiomyopathy, target and impact of rate control therapy on outcomes, optimal rhythm control strategy in the era of catheter ablation, HF-related thromboembolic risk and management of anticoagulation in patients with comorbidities, such as chronic kidney disease or transient renal function worsening, coronary artery disease or acute coronary syndromes, valvular or structural heart disease interventions and cancer. In the present document, derived by an expert panel meeting, we sought to focus on the above challenging issues, outlining the existing evidence and identifying gaps in knowledge that need to be addressed., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models., Objectives: This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study., Methods: Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to <75 ml/min/1.73 m 2 and received optimized doses of renin-angiotensin system blockade. Effect on new-onset AFF was evaluated as a pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF., Results: Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53-0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively)., Conclusions: In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline. (EudraCT 2015-000990-11 [A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease]; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD]; NCT02540993)., Competing Interests: Funding Support and Author Disclosures The FIDELIO-DKD trial was conducted and funded by Bayer AG, Berlin, Germany. Analyses were conducted by the sponsor, and all authors had access to and participated in the interpretation of the data. Dr. Filippatos has received lectures fees and/or that he is a committee member of trials and registries sponsored by Bayer, Novartis, Vifor Pharma, Medtronic, Servier, Amgen, and Boehringer Ingelheim; is a senior consulting editor for JACC: Heart Failure; and has received research support from the European Union. Dr. Bakris has received research funding, paid to the University of Chicago Medicine, from Bayer, during the conduct of the study; has received research funding, paid to the University of Chicago Medicine, from Novo Nordisk and Vascular Dynamics; has acted as a consultant and received personal fees from for Merck, Relypsa, and Alnylam Pharmaceuticals; is an editor of American Journal of Nephrology, Nephrology, and Hypertension, and section editor of UpToDate; and is an associate editor of Diabetes Care and Hypertension Research. Dr. Pitt has received consultant fees for Bayer, AstraZeneca, Sanofi/Lexicon, scPharmaceuticals, SQ Innovation, G3 Pharmaceuticals, Sarfez Pharmaceutical, Inc., PhaseBio, Vifor Pharma/Relypsa, Cereno Scientific, Ardelyx, KBP Biosciences, Boehringer Ingelheim, Brainstorm Medical, and Tricida; has stock options for Ardelyx, KBP Biosciences, SQ Innovation, Sarfez Pharmaceutical, scPharmaceuticals, Cereno Scientific, G3 Pharmaceuticals, Vifor Pharma/Relypsa, Brainstorm Medical, and Tricida; and also holds a patent for site-specific delivery of eplerenone to the myocardium (US patent #9931412) and a provisional patent for histone-acetylation-modulating agents for the treatment and prevention of organ injury (provisional patent US 63/045,784). Dr. Agarwal has received personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals during the conduct of the study; has received personal fees and nonfinancial support from Akebia Therapeutics, Janssen, Relypsa, Vifor Pharma, Boehringer Ingelheim, Sanofi, Eli Lilly and Company, AstraZeneca, and Fresenius; has received personal fees from Ironwood Pharmaceuticals, Merck & Co., Lexicon, and Reata Pharmaceuticals; has received nonfinancial support from Otsuka America Pharmaceutical, OPKO Health, and E. R. Squibb & Sons; is a member of data safety monitoring committees for Amgen, AstraZeneca, and Celgene; is a member of steering committees of randomized trials for Akebia Therapeutics, Bayer, Janssen, and Relypsa Inc.; is a member of adjudication committees for AbbVie, Bayer, Boehringer Ingelheim, and Janssen; has served as associate editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation and has been an author for UpToDate; and has received research grants from the U.S. Veterans Administration and the National Institutes of Health. Dr. Rossing has received personal fees from Bayer, during the conduct of the study; has received research support and personal fees from AstraZeneca and Novo Nordisk; and has received personal fees from Eli Lilly and Company, Boehringer Ingelheim, Astellas Pharma, Gilead, Mundipharma, Sanofi, and Vifor Pharma. All fees are given to Steno Diabetes Center Copenhagen. Dr. Butler serves as a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, V-Wave, and Vifor Pharma. Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/ Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, Us2.ai, Janssen Research & Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, and WebMD Global; and serves as co-founder and non-executive director of Us2.ai. Dr. Kolkhof is a full-time employee of Bayer AG, Division Pharmaceuticals, Germany; and is the co-inventor of finerenone and holds U.S. and European patents relating to finerenone (US8436180B2 and EP2132206B1). Dr. Roberts is a full-time employee of Bayer PLC, GD Medical, Great Britain. Drs. Tasto and Joseph are full-time employees of Bayer AG, Division Pharmaceuticals, Germany. Dr. Anker has received research support from Abbott Vascular and Vifor Pharma; and has received personal fees from Abbott Vascular, Boehringer Ingelheim, Bayer, BRAHMS, Novartis, Servier, Vifor Pharma, Impulse Dynamics, and Cardiac Dimensions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

[Figure: see text].

Abstract: Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating serum HSP70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (the duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, serum interleukin-2 (sIL-2), and serum interleukin-4 (sIL-4) with the presence of cardioversion and AF recurrence within a year was investigated. Toll-like receptor 4 (TLR4) signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared with controls. Serum HSP70 was independently associated with ROAF (P = 0.005) and correlated with sIL-2 (r = 0.494, P < 0.001) and sIL-4 (r = -0.550, P < 0.001). By 48 hours, 71 of the 90 patients were cardioverted, with noncardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38 of the 71 cardioverted patients in 1 year. A cutoff value of sHSP70 ≥0.65 ng/mL and sIL-2 ≥0.21 pg/mL was the only independent factor associated with AF recurrence (hazard ratio: 3.311, 95% confidence interval: 1.503-7.293, P = 0.003 and hazard ratio: 3.144, 95% confidence interval: 1.341-7.374, P = 0.008, respectively). The exposure of smooth muscle cell to HSP70 in vitro increased the expression of IL-2 (5×) and IL-4 (1.5×) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) are a high-risk subset of patients, whose optimal antithrombotic treatment strategy, involving a combination of anticoagulant and antiplatelet agents, has not been well defined. Our study aims to investigate contemporary "real-world" trends of antithrombotic treatment strategies in AF patients undergoing PCI, as well as identify factors affecting decision-making at hospital discharge., Methods: "Real-world" data were retrieved from the GReek-AntiPlatElet Atrial Fibrillation (GRAPE-AF) registry, a contemporary, nationwide, multicenter, observational study of AF patients undergoing PCI. Characteristics of patients discharged on triple antithrombotic therapy (TAT) or dual antithrombotic therapy (DAT) were compared in order to identify factors that could influence treatment decisions., Results: A total of 654 patients were enrolled (42% with stable coronary artery disease, 58% with acute coronary syndrome). TAT was adopted in 49.9% and DAT in 49.2% of patients at discharge. Regarding anticoagulants, the vast majority of patients (92.9%) received non-vitamin K antagonist oral anticoagulants (NOACs) and only 7.1% received vitamin K antagonists (VKAs). Dyslipidemia, insulin-dependent diabetes mellitus, prior myocardial infarction, acute coronary syndrome at presentation, and regional variations were predictive of TAT adoption, whereas the use of NOACs or ticagrelor was predictive of DAT adoption., Conclusion: Contemporary "real-world" data concerning antithrombotic treatment in AF patients undergoing PCI indicate a strong shift towards the use of NOACs instead of VKAs, along with a large subset of patients adopting an aspirin-free strategy early after index PCI, with clinical as well as treatment characteristics affecting decision-making., Trial Registration: ClinicalTrials.gov Identifier: NCT03362788 (First Posted: December 5, 2017).

Patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have traditionally received triple antithrombotic therapy (TAT) consisting of aspirin and a P2Y 12 inhibitor plus an oral anticoagulant (OAC) to reduce atherothrombotic events, even though this strategy is associated with a high risk of severe bleeding. Recent trials have indicated that dual antithrombotic therapy (DAT), consisting of a P2Y 12 inhibitor plus an OAC, may be superior to TAT in terms of bleeding risk; however, the trade-off regarding ischemic complications may be questionable. Patients who have had a myocardial infarction (MI) before undergoing PCI warrant special consideration because of the accompanying high ischemic risk, including stent thrombosis, which might be exacerbated by an aspirin-free strategy such as DAT. In particular, in the acute phase of ST-segment elevation MI (STEMI), the highly prothrombotic milieu may necessitate initial TAT, though durations may vary, making a tailored antithrombotic regimen for this high-risk subset of patients a fairly challenging and difficult scenario for clinicians. Since patients with MI, especially STEMI, are underrepresented in randomized trials, data regarding the optimal antithrombotic treatment in such patients are sparse. This review aims to analyze the outcomes of different antithrombotic regimens in patients with MI and AF undergoing PCI, define the role of DAT versus TAT regarding safety and efficacy outcomes, and address controversial issues and future perspectives.

Objective: In 2008, the radiofrequency ablation (RFA) procedures registry of the Hellenic Society of Cardiology was created. This online database allowed electrophysiologists around the country to input data for all performed ablation procedures. The aim of this study is to provide a thorough report and interpretation of the data submitted to the registry between 2008 and 2018., Methods: In 2008, a total of 27 centers/medical teams in 24 hospitals were licensed to perform RFA in Greece. By 2018, the number had risen to 31. Each center was tasked with inserting their own data into the registry, which included patient demographics (anonymized), type of procedure and technique, complications, and outcomes., Results: A total of 18587 procedures in 17900 patients were recorded in the period of 2008-2018. By 2018, slightly more than 70% of procedures were performed in 7 high-volume centers (>100 cases/year). The most common procedure since 2014 was atrial fibrillation ablation, followed by atrioventricular nodal reentry tachycardia ablation. Complication rates were low, and success rates remained high, whereas the 6-month relapse rates declined steadily., Conclusion: This online RFA registry has proved that ablation procedures in Greece have reached a very high standard, with results and complication rates comparable to European and American standards. Ablation procedures for atrial fibrillation are increasing constantly, with it being the most common intervention over the last 6-year period, although the absolute number of procedures still remains low, compared to other European countries., (Copyright © 2020 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: In this pooled analysis of seven multicentre cohorts potential differences were investigated in the incidence, characteristics and outcomes between intracranial haemorrhages (ICHs) associated with the use of non-vitamin K antagonist oral anticoagulants (NOAC-ICH) or with vitamin K antagonists (VKA-ICH) in ischaemic stroke patients after oral anticoagulant treatment initiation for atrial fibrillation (AF)., Methods: Data from 4912 eligible AF patients who were admitted in a stroke unit with ischaemic stroke or transient ischaemic attack and who were treated with either VKAs or NOACs within 3 months post-stroke were included. Fatal ICH was defined as death occurring during the first 30 days after ICH onset. A meta-analysis of available observational studies reporting 30-day mortality rates from NOAC-ICH or VKA-ICH onset was additionally performed., Results: During 5970 patient-years of follow-up 71 participants had an ICH, of whom 20 were NOAC-ICH and 51 VKA-ICH. Patients in the two groups had comparable baseline characteristics, except for the higher prevalence of kidney disease in VKA-ICH patients. There was a non-significant higher number of fatal ICH in patients with VKAs (11 events per 3385 patient-years) than in those with NOACs (three events per 2623 patient-years; hazard ratio 0.32, 95% confidence interval 0.09-1.14). Three-month functional outcomes were similar (P > 0.2) in the two groups. The meta-analysis showed a lower 30-day mortality risk for patients with NOAC-ICH compared to VKA-ICH (relative risk 0.70, 95% confidence interval 0.51-0.95)., Conclusions: Non-vitamin K oral anticoagulants for intracranial haemorrhages and VKA-ICH occurring during secondary stroke prevention of AF patients have comparable baseline characteristics and outcomes except for the risk of fatal ICH within 30 days, which might be greater in VKA-ICH., (© 2020 European Academy of Neurology.)

Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention., Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features., Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02])., Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant.

Background and Purpose: Evidence suggests that cardioembolism represents the underlying mechanism in the minority of embolic strokes of undetermined source (ESUS). In this population-based study, we sought to compare the clinical and imaging characteristics as well as outcomes in patients with ESUS and cardioembolic stroke (CE)., Methods: We included consecutive patients with first-ever ischemic stroke (IS) from the previously published population-based Evros-Stroke-Registry identified as ESUS or CE according to standardized criteria. Baseline characteristics, admission NIHSS scores, cerebral edema, hemorrhagic transformation, stroke recurrence, functional outcomes (determined by modified Rankin Scale [mRS] scores), and mortality rates were recorded during the 1-year follow-up period., Results: We identified 21 ESUS (3.7% of IS) and 211 CE (37.1% of IS) cases. Patients with ESUS were younger (median age: 68 years [interquartile range [IQR]: 61-75] vs 80 years [IQR: 75-84]; P < .001), had lower median admission NIHSS scores (4 points [IQR: 2-8] vs 10 points [IQR: 5-17]; P < .001), and lower prevalence of cerebral edema on neuroimaging studies (0 vs. 33.3%, P = .002). Functional outcomes were more favorable in ESUS at 28 (median mRS score: 2 [IQR: 1-3] vs 4 [IQR: 4-5]; P < .001), 90 (median mRS score: 1 [IQR: 0-2] vs 4 [IQR: 3-5]; P < .001), and 365 days (median mRS score: 1 [IQR: 0-2] vs 4 [IQR: 2-4]; P < 0.001). At 1-year, the mortality rate was lower in ESUS (0% [95% confidence interval [CI]: 0-13.5%] vs 34.6% [95% CI: 28.2-41.0%]; P < .001); the 1-year recurrent rate was also lower numerically (0% [95% CI: 0-13.5%] vs 9.5% [95% CI: 5.5-13.4%]; P = .140) but this difference failed to reach statistical significance due to the small study population., Conclusions: The clinical and neuroimaging profiles as well as clinical outcomes vary substantially between ESUS and CE indicating different underlying mechanisms., (© 2019 by the American Society of Neuroimaging.)

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P<0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Objective: We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia., Methods: We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs)., Results: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09)., Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823-834., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Approximately 7% of patients undergoing percutaneous coronary intervention (PCI) with stent implantation have atrial fibrillation. The optimal antithrombotic treatment in such of patients remains one of the most challenging and difficult scenarios in Cardiology. Triple antithrombotic therapy (TAT), consisting of dual antiplatelet therapy plus an oral anticoagulant, has been used for decades in order to reduce ischemic and thromboembolic events, while significantly increasing the risk for severe bleeding. Recently, results of several clinical trials suggest that the use of dual antithrombotic therapy (DAT), consisting of single antiplatelet therapy plus an oral anticoagulant, reduces the risk of bleeding, while maintaining the same level of efficacy as compared to TAT. These data have been interpreted in a variety of ways, often giving conflicting recommendations and leaving many unanswered questions on the optimal antithrombotic treatments of patients with atrial fibrillation who undergo PCI. DAT consisting of a non-vitamin K antagonist oral anticoagulant and clopidogrel, while omitting aspirin from the immediate post discharge period, appears as an attractive, simplified strategy for most patients and supported by many experts in the field. In this review we aim to better define the role of DAT versus TAT in atrial fibrillation patients undergoing PCI and analyze remaining controversial issues and future expectations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Catheter ablation for rhythm control is recommended in specific patient populations with paroxysmal, persistent, or long-standing persistent atrial fibrillation. Pulmonary vein isolation is the cornerstone of the ablative therapy for atrial fibrillation. However, relapse is still common since the single procedure efficacy of atrial fibrillation ablation was estimated to be 60-80% in paroxysmal and 50-70% in persistent atrial fibrillation. It is important to identify predictors of successful atrial fibrillation patients ablation. In the present review, we will assess the role of available biomarkers to predict responders of an initial atrial fibrillation catheter ablation. Emphasis has been given on the role of myocardial injury biomarkers, natriuretic peptides and traditional inflammatory markers. Novel inflammatory markers, oxidative stress biomarkers and microRNAs have also been examined as predictors of a successful atrial fibrillation procedure. Notably, the impact of procedural and short-term administration of steroids, as well as the role of colchicine on preventing atrial fibrillation recurrence after ablation is thoroughly presented., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT ; 53.1% of patients with  HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability.

Atrial fibrillation (AF) following on-pump coronary artery bypass grafting (CABG) is a common condition associated with increased morbidity and mortality. We investigated the possibility that miRs may play a contributory role in postoperative AF and associated apoptosis. A total of 42 patients (31 males and 11 females, mean age 65.0 ± 1.3 years) with sinus rhythm and without a history of AF were prospectively enrolled. We examined the levels of the muscle-specific miRs 1 and 133A and markers of apoptosis including TUNEL staining, caspase-3 activation, Bcl2 and Bax mRNAs in right atrial appendage (RAA) biopsies and blood plasma taken before aortic cross-clamping and after reperfusion. After reperfusion, indices of apoptosis increased the RAA. There was no change in tissue or plasma miR -1 and -133A levels compared to pre CABG. However, in patients who postoperatively developed AF (n = 14, 7 males and 7 females), compared to patients that remained in SR (n = 28, 24 males and 4 females) post CABG, tissue miR-1 increased whereas miR-133A decreased and negatively correlated with RAA apoptosis. Mechanistically, overexpression of miR-133A inhibited hypoxia-induced rat neonatal cardiomyocyte apoptosis and phosphorylated pro-survival Akt, responses abolished by a miR-133A antisense inhibitor oligonucleotide or by pre-treatment with an Akt inhibitor. In postoperative AF, differential regulation of pro- and anti-apoptotic miRs-1 and -133A respectively in the RAA, may contribute to postoperative apoptosis. These results provide new insights into molecular mechanisms of postoperative AF with potential therapeutic implications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Approximately 5 to 7% of patients undergoing percutaneous coronary intervention (PCI) for the treatment of coronary artery disease require chronic oral anticoagulation (OAC) on top of aspirin and a P2Y 12 receptor antagonist, mainly due to non-valvular atrial fibrillation (AF). The advent of non-vitamin K antagonist oral anticoagulants (NOACs) increased treatment options, while there is cumulative evidence that dual combination of a NOAC and a P2Y 12 receptor antagonist attenuates risk of bleeding, compared to traditional triple therapy, consisting of a vitamin K antagonist (VKA), aspirin, and a P2Y 12 receptor antagonist, without significantly compromising efficacy., Study Design: Greek AntiPlatElet Atrial Fibrillation (GRAPE-AF, NCT 03362788) is an observational, nationwide study of non-valvular AF patients undergoing PCI, planning to enroll over 1-year period > 500 participants in 25 tertiary and non-tertiary PCI centers in Greece. Key data to be collected pre-discharge include demographics, detailed past medical history, and antithrombotic and concomitant treatment. Patients will be followed up at 1, 6, and 12 months post hospital discharge. Αt each follow-up visit, data on antithrombotic treatment, ischemic, bleeding, and adverse events will be collected. Study's primary endpoint is clinically significant bleeding (Bleeding Academic Research Consortium, BARC ≥ 2) at 12 months, between VKAs and NOACs-treated patients, analyzed using Cox proportional hazards models, by an intention-to-treat principle. An independent endpoint committee will adjudicate all clinical events., Conclusions: This study aims at providing "real-world" information on current antithrombotic treatment patterns and clinical outcome of patients with non-valvular AF undergoing PCI.

Direct or new oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have recently revolutionized the field of antithrombotic therapy for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (NVAF). Randomized controlled trials have shown that these agents have at least comparable efficacy with vitamin K antagonists along with superior safety, at least in what concerns intracranial hemorrhage. As a result, NOACs are indicated as first-line anticoagulation therapy for NVAF patients with at least one risk factor for stroke or systemic embolism. The rapid introduction, however, of NOACs in a field dominated for decades by vitamin antagonists and the variety of agents and dosing schemes may create difficulties in decision making. In the present article, we attempt to determine a practical approach to the choice of agent and dose in different clinical scenarios by considering not only the results of seminal randomized trials and post hoc analyses but also data from real-world patient populations as well as the recently available possibility of rapid NOAC reversal., (© 2018 S. Karger AG, Basel.)

Aims: Vagal responses (VR) during left atrial ablation for atrial fibrillation (AF) treatment have been reported to be associated with less recurrences, presumably because they are a sign of ganglionated plexi modification. Our objective was to evaluate whether coincidentally elicited VR during left atrial ablation are associated with lower AF recurrence rates., Methods and Results: This is a post hoc analysis of a prospective study of 291 patients with paroxysmal AF undergoing radiofrequency pulmonary vein isolation (PVI). Vagal responses were defined as episodes of heart rate <40 bpm or asystole lasting >5 s elicited during energy application. Sixty-eight patients (23.4%) had a VR during ablation. In Kaplan-Meier analysis, mean recurrence-free survival was 449 days (95% confidence interval 411-488) in patients with VR when compared with 435 days (95% confidence interval 415-455) in those without (P = 0.310). The 12-month recurrence rate estimates were 25 and 27%, respectively. In an unadjusted Cox model, VR was associated with an odds ratio for recurrence of 0.77 (95% confidence interval 0.46-1.28)., Conclusion: Coincidentally elicited VR during radiofrequency PVI in patients with paroxysmal AF do not appear to be related to lower risk of arrhythmia recurrence. This may mean that, even if a VR is truly a sign of coincidental ablation of a ganglionated plexus, this does not necessarily mean that a therapeutic modification has been effected, at least to a degree associated with clinical benefit., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention., Methods and Results: Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA 2 DS 2 -VASc score >4 and less reduced renal function. Thirty-two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOACs within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke., Conclusions: In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)