Topic: Electrophysiology

Abstract

Comparison of Atrial Remodeling Caused by Sustained Atrial Flutter Versus Atrial Fibrillation.

Guichard JB, Naud P, Xiong F, Qi X, ... Da Costa A, Nattel S
Background
Atrial flutter (AFL) and atrial fibrillation (AF) are associated with AF-promoting atrial remodeling, but no experimental studies have addressed remodeling with sustained AFL.
Objectives
This study aimed to define the atrial remodeling caused by sustained atrial flutter (AFL) and/or atrial fibrillation (AF).
Methods
Intercaval radiofrequency lesions created a substrate for sustained isthmus-dependent AFL, confirmed by endocavity mapping. Four groups (6 dogs per group) were followed for 3 weeks: sustained AFL; sustained AF (600 beats/min atrial tachypacing); AF superimposed on an AFL substrate (AF+AFLs); sinus rhythm (SR) with an AFL substrate (SR+AFLs; control group). All dogs had atrioventricular-node ablation and ventricular pacemakers at 80 beats/min to control ventricular rate.
Results
Monitoring confirmed spontaneous AFL maintenance >99% of the time in dogs with AFL. At terminal open-chest study, left-atrial (LA) effective refractory period was reduced similarly with AFL, AF+AFLs and AF, while AF vulnerability to extrastimuli increased in parallel. Induced AF duration increased significantly in AF+AFLs and AF, but not AFL. Dogs with AF+AFLs had shorter cycle lengths and substantial irregularity versus dogs with AFL. LA volume increased in AF+AFLs and AF, but not dogs with AFL, versus SR+AFLs. Optical mapping showed significant conduction slowing in AF+AFLs and AF but not AFL, paralleling atrial fibrosis and collagen-gene upregulation. Left-ventricular function did not change in any group. Transcriptomic analysis revealed substantial dysregulation of inflammatory and extracellular matrix-signaling pathways with AF and AF+ALs but not AFL.
Conclusions
Sustained AFL causes atrial repolarization changes like those in AF but, unlike AF or AF+AFLs, does not induce structural remodeling. These results provide novel insights into AFL-induced remodeling and suggest that early intervention may be important to prevent irreversible fibrosis when AF intervenes in a patient with AFL.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jul 2020; 76:374-388
Guichard JB, Naud P, Xiong F, Qi X, ... Da Costa A, Nattel S
J Am Coll Cardiol: 27 Jul 2020; 76:374-388 | PMID: 32703507
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Abstract

Pulsed Field Ablation in Patients With Persistent Atrial Fibrillation.

Reddy VY, Anic A, Koruth J, Petru J, ... Kawamura I, Neuzil P
Background
Unlike for paroxysmal atrial fibrillation (AF), pulmonary vein isolation (PVI) alone is considered insufficient for many patients with persistent AF. Adjunctive ablation of the left atrial posterior wall (LAPW) may improve outcomes, but is limited by both the difficulty of achieving lesion durability and concerns of damage to the esophagus-situated behind the LAPW.
Objectives
This study sought to assess the safety and lesion durability of pulsed field ablation (PFA) for both PVI and LAPW ablation in persistent AF.
Methods
PersAFOne is a single-arm study evaluating biphasic, bipolar PFA using a multispline catheter for PVI and LAPW ablation under intracardiac echocardiographic guidance. A focal PFA catheter was used for cavotricuspid isthmus ablation. No esophageal protection strategy was used. Invasive remapping was mandated at 2 to 3 months to assess lesion durability.
Results
In 25 patients, acute PVI (96 of 96 pulmonary veins [PVs]; mean ablation time: 22 min; interquartile range [IQR]: 15 to 29 min) and LAPW ablation (24 of 24 patients; median ablation time: 10 min; IQR: 6 to 13 min) were 100% acutely successful with the multispline PFA catheter alone. Using the focal PFA catheter, acute cavotricuspid isthmus block was achieved in 13 of 13 patients (median: 9 min; IQR: 6 to 12 min). The median total procedure time was 125 min (IQR: 108 to 166 min) (including a median of 28 min [IQR: 25 to 33 min] for voltage mapping), with a median of 16 min (IQR: 12 to 23 min) fluoroscopy. Post-procedure esophagogastroduodenoscopy and repeat cardiac computed tomography revealed no mucosal lesions or PV narrowing, respectively. Invasive remapping demonstrated durable isolation (defined by entrance block) in 82 of 85 PVs (96%) and 21 of 21 LAPWs (100%) treated with the pentaspline catheter. In 3 patients, there was localized scar regression of the LAPW ablation, albeit without conduction breakthrough.
Conclusions
The unique safety profile of PFA potentiated efficient, safe, and durable PVI and LAPW ablation. This extends the potential role of PFA beyond paroxysmal to persistent forms of AF. (Pulsed Fields for Persistent Atrial Fibrillation [PersAFOne]; NCT04170621).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 31 Aug 2020; 76:1068-1080
Reddy VY, Anic A, Koruth J, Petru J, ... Kawamura I, Neuzil P
J Am Coll Cardiol: 31 Aug 2020; 76:1068-1080 | PMID: 32854842
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Abstract

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.

Kirchhof P, Camm AJ, Goette A, Brandes A, ... Breithardt G,
Background
Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk.
Methods
In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated.
Results
In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups.
Conclusions
Early rhythm-control therapy was associated with a lower risk of cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Aug 2020; epub ahead of print
Kirchhof P, Camm AJ, Goette A, Brandes A, ... Breithardt G,
N Engl J Med: 28 Aug 2020; epub ahead of print | PMID: 32865375
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Abstract

Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

Okumura K, Akao M, Yoshida T, Kawata M, ... Yamashita T,
Background
Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding.
Methods
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.
Results
A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36).
Conclusions
In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Aug 2020; epub ahead of print
Okumura K, Akao M, Yoshida T, Kawata M, ... Yamashita T,
N Engl J Med: 29 Aug 2020; epub ahead of print | PMID: 32865374
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Abstract

Atrial Fibrillation and Dementia.

Bunch TJ

Atrial fibrillation is associated with multiple adverse comorbidities, including the development of dementia in patients with and without a history of stroke. Mechanistic models have been proposed to explain the association of AF and dementia. Alterations of brain perfusion from embolic events, bleeding, and rhythm-related hypoperfusion underlie many of these models. Multiple mediators such as oxidative injury, inflammatory and autoimmune mechanisms, and genetic predisposition also interplay in the disease association. There are potential therapeutic opportunities to reduce dementia risk, including early and effective use of anticoagulation and strategies to improve brain perfusion through rhythm and rate control approaches. Prospective trials are needed to evaluate these therapeutic opportunities that carefully measure cognitive function and dementia incidence.



Circulation: 17 Aug 2020; 142:618-620
Bunch TJ
Circulation: 17 Aug 2020; 142:618-620 | PMID: 32804567
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Abstract

Mortality in Patients With Atrial Fibrillation Receiving Nonrecommended Doses of Direct Oral Anticoagulants.

Camm AJ, Cools F, Virdone S, Bassand JP, ... Kakkar AK,
Background
The recommended doses for direct oral anticoagulants (DOACs) to prevent stroke and systemic embolism (SE) in patients with atrial fibrillation (AF) are described in specific regulatory authority approvals.
Objectives
The impact of DOAC dosing, according to the recommended guidance on all-cause mortality, stroke/SE, and major bleeding, was assessed at 2-year follow-up in patients with newly diagnosed AF.
Methods
Of a total of 34,926 patients enrolled (2013 to 2016) in the prospective GARFIELD-AF (Global Anticoagulant Registry in the FIELD-AF), 10,426 patients received a DOAC.
Results
The majority of patients (72.9%) received recommended dosing, 23.2% were underdosed, and 3.8% were overdosed. Nonrecommended dosing (underdosage and overdosage combined) compared with recommended dosing was associated with a higher risk of all-cause mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.48); HR: 1.25 (95% CI: 1.04 to 1.50) for underdosing, and HR: 1.19 (95% CI: 0.83 to 1.71) for overdosing. The excess deaths were cardiovascular including heart failure and myocardial infarction. The risks of stroke/SE and major bleeding were not significantly different irrespective of the level of dosing, although underdosed patients had a significantly lower risk of bleeding. A nonsignificant trend to higher risks of stroke/SE (HR: 1.51; 95% CI: 0.79 to 2.91) and major bleeding (HR: 1.29; 95% CI: 0.59 to 2.78) was observed in patients with overdosing.
Conclusions
In GARFIELD-AF, most patients received the recommended DOAC doses according to country-specific guidelines. Prescription of nonrecommended doses was associated with an increased risk of death, mostly cardiovascular death, compared with patients on recommended doses, after adjusting for baseline factors. (Global Anticoagulant Registry in the Field-AF [GARFIELD-AF]; NCT01090362).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Sep 2020; 76:1425-1436
Camm AJ, Cools F, Virdone S, Bassand JP, ... Kakkar AK,
J Am Coll Cardiol: 21 Sep 2020; 76:1425-1436 | PMID: 32943160
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Abstract

Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation.

Wallentin L, Lindbäck J, Eriksson N, Hijazi Z, ... Oldgren J, Siegbahn A
Aims
The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability.
Methods and results
Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level.
Conclusions
Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 26 Sep 2020; epub ahead of print
Wallentin L, Lindbäck J, Eriksson N, Hijazi Z, ... Oldgren J, Siegbahn A
Eur Heart J: 26 Sep 2020; epub ahead of print | PMID: 32984892
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Abstract

Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study.

Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Aims
Accumulating evidence shows that atrial fibrillation (AF) is associated with an increased risk of dementia. Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving the quality of life. We investigated the association of catheter ablation for AF with the occurrence of dementia.
Methods and results
Using the Korean National Health Insurance Service database, among 194 928 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, we studied 9119 patients undergoing ablation and 17 978 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score-matching was used to correct for differences between the groups. During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed lower incidence and risk of overall dementia (8.1 and 5.6 per 1000 person-years, respectively; hazard ratio 0.73, 95% confidence interval 0.58-0.93). The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (hazard ratio 0.76, 95% confidence interval 0.61-0.95) and more pronounced in cases of ablation success whereas no significant differences observed in cases of ablation failure. Ablation was associated with lower risks of dementia subtypes including Alzheimer\'s disease and vascular dementia.
Conclusion
In this nationwide cohort of AF patients treated with catheter ablation or medical therapy, ablation was associated with decreased dementia risk. This relationship was evident after censoring for stroke and adjusting for clinical confounders.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 05 Oct 2020; epub ahead of print
Kim D, Yang PS, Sung JH, Jang E, ... Lip GYH, Joung B
Eur Heart J: 05 Oct 2020; epub ahead of print | PMID: 33022705
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Abstract

Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

Haldar S, Khan HR, Boyalla V, Kralj-Hans I, ... Wong T,
Aims
Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF.
Methods and results
We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients\' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02).
Conclusion
Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA.
Clinical trial registration
ISRCTN18250790 and ClinicalTrials.gov: NCT02755688.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 28 Aug 2020; epub ahead of print
Haldar S, Khan HR, Boyalla V, Kralj-Hans I, ... Wong T,
Eur Heart J: 28 Aug 2020; epub ahead of print | PMID: 32860414
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Abstract

Heart Failure and Atrial Fibrillation Modify the Associations of Nocturnal Blood Pressure Dipping Pattern With Mortality in Hemodialysis Patients.

Mayer CC, Schmaderer C, Loutradis C, Matschkal J, ... Wassertheurer S, Sarafidis PA

Heart failure (HF), hypertension, and abnormal nocturnal blood pressure dipping are highly prevalent in hemodialysis patients. Atrial fibrillation (AF) and HF might be important mediators for the association of abnormal dipping patterns with worse prognosis. Thus, the aim of this study is to investigate the association of dipping with mortality in hemodialysis patients and to assess the influence of AF and HF. In total, 525 hemodialysis patients underwent 24-hour ambulatory blood pressure monitoring. All-cause and cardiovascular mortality served as end points. Patients were categorized according to their systolic dipping pattern (dipper, nondipper, and reverse dipper). Cox regression analysis was performed to determine the association between dipping pattern and study end points with dipping as reference. Subgroup analysis was performed for patients with and without AF or HF. In total, 185 patients with AF or HF and 340 patients without AF or HF were included. During a median follow-up of 37.8 months, 177 patients died; 81 from cardiovascular causes. Nondipping and reverse dipping were significantly associated with all-cause mortality in the whole cohort (nondipper: hazard ratio, 1.95 [1.22-3.14]; =0.006; reverse dipper: hazard ratio, 2.31 [1.42-3.76]; <0.001) and in patients without AF or HF (nondipper: hazard ratio, 2.78 [1.16-6.66]; =0.02; reverse dipper: hazard ratio, 4.48 [1.87-10.71]; <0.001) but not in patients with AF or HF. For cardiovascular mortality, associations were again significant in patients without AF or HF and in the whole cohort. The observed associations remained significant after adjustment for possible confounders. This study provides well-powered evidence for the association between abnormal dipping patterns and mortality in hemodialysis patients and suggests that HF or AF modifies this association.



Hypertension: 29 Sep 2020; 76:1231-1239
Mayer CC, Schmaderer C, Loutradis C, Matschkal J, ... Wassertheurer S, Sarafidis PA
Hypertension: 29 Sep 2020; 76:1231-1239 | PMID: 32862707
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Abstract

Genetics of height and risk of atrial fibrillation: A Mendelian randomization study.

Levin MG, Judy R, Gill D, Vujkovic M, ... Voight BF, Damrauer SM
Background
Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.
Methods and findings
In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.
Conclusions
In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.



PLoS Med: 29 Sep 2020; 17:e1003288
Levin MG, Judy R, Gill D, Vujkovic M, ... Voight BF, Damrauer SM
PLoS Med: 29 Sep 2020; 17:e1003288 | PMID: 33031386
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Abstract

Association Between the European Society of Cardiology/European Society of Hypertension Heart Rate Thresholds for Cardiovascular Risk and Neuroadrenergic Markers.

Grassi G, Quarti-Trevano F, Seravalle G, Dell\'Oro R, Facchetti R, Mancia G

The recent European Society of Cardiology/European Society of Hypertension hypertension guidelines identify resting heart rate (HR) values >80 bpm as predictors of cardiovascular risk, with the unproven assumption that this might reflect the presence of a sympathetic overdrive. In the present study, we tested this hypothesis throughout the use of direct and indirect sympathetic markers. In 193 untreated moderate essential hypertensives aged 50.4±0.6 years (mean±SEM), we measured clinic and ambulatory blood pressure and corresponding HR, venous plasma norepinephrine (high performance liquid chromatography), and muscle sympathetic nerve traffic (microneurography). We then subdivided the study population into 2 groups according to HR < or >80 bpm. Eighty-four patients displayed resting HR >80 bpm, which was this cutoff value in the remaining 109 patients, the 2 groups showing superimposable age, and sex distribution. Clinic and ambulatory blood pressure were similar in the 2 groups, whereas left ventricular mass index was significantly greater in the group with HR >80 bpm. Muscle sympathetic nerve traffic values were also significantly greater in this latter group (72.77±0.9 versus vs 36.83±1.3 bursts/min, <0.0001); this being the case also for norepinephrine (293.0±8.7 versus 254.1±8.9 pg/mL, <0.002). In the whole population, there was a significant direct relationship between muscle sympathetic nerve traffic, norepinephrine, left ventricular mass index, and HR values. Similar results were obtained when 24-hour HR values were analyzed. Thus patients with hypertension displaying HR >80 bpm are characterized by a marked sympathetic overdrive, particularly when direct adrenergic markers are used. This finding suggests that cardiac and peripheral sympathetic activation are involved in the increased cardiovascular risk detected in this group of patients.



Hypertension: 30 Jul 2020; 76:577-582
Grassi G, Quarti-Trevano F, Seravalle G, Dell'Oro R, Facchetti R, Mancia G
Hypertension: 30 Jul 2020; 76:577-582 | PMID: 32594806
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Abstract

Chemokine Receptor CXCR-2 Initiates Atrial Fibrillation by Triggering Monocyte Mobilization in Mice.

Zhang YL, Cao HJ, Han X, Teng F, ... Guo SB, Li HH

Atrial fibrillation (AF) is frequently associated with increased inflammatory response characterized by infiltration of monocytes/macrophages. The chemokine receptor CXCR-2 is a critical regulator of monocyte mobilization in hypertension and cardiac remodeling, but it is not known whether CXCR-2 is involved in the development of hypertensive AF. AF was induced by infusion of Ang II (angiotensin II; 2000 ng/kg per minute) for 3 weeks in male C57BL/6 wild-type mice, CXCR-2 knockout mice, bone marrow-reconstituted chimeric mice, and mice treated with the CXCR-2 inhibitor SB225002. Microarray analysis revealed that 4 chemokine ligands of CXCR-2 were significantly upregulated in the atria during 3 weeks of Ang II infusion. CXCR-2 expression and the number of CXCR2 immune cells markedly increased in Ang II-infused atria in a time-dependent manner. Moreover, Ang II-infused wild-type mice had increased blood pressure, AF inducibility, atrial diameter, fibrosis, infiltration of macrophages, and superoxide production compared with saline-treated wild-type mice, whereas these effects were significantly attenuated in CXCR-2 knockout mice and wild-type mice transplanted with CXCR-2-deficient bone marrow cells or treated with SB225002. Moreover, circulating blood CXCL-1 levels and CXCR2 monocyte counts were higher and associated with AF in human patients (n=31) compared with sinus rhythm controls (n=31). In summary, this study identified a novel role for CXCR-2 in driving monocyte infiltration of the atria, which accelerates atrial remodeling and AF after hypertension. Blocking CXCR-2 activation may serve as a new therapeutic strategy for AF.



Hypertension: 30 Jul 2020; 76:381-392
Zhang YL, Cao HJ, Han X, Teng F, ... Guo SB, Li HH
Hypertension: 30 Jul 2020; 76:381-392 | PMID: 32639881
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Abstract

Pathophysiology of Atrial Fibrillation and Chronic Kidney Disease.

Ding WY, Gupta D, Wong CF, Lip GYH

Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related conditions with shared risk factors. The growing prevalence of both AF and CKD indicates that more patients will suffer from concurrent conditions. There are various complex interlinking mechanisms with important implications for the management of these patients. Furthermore, there is uncertainty regarding the use of oral anticoagulation in AF and CKD that is reflected by a lack of consensus between international guidelines. Therefore, the importance of understanding the implications of co-existing AF and CKD should not be underestimated. In this review, we discuss the pathophysiology and association between AF and CKD, including the underlying mechanisms, risk of thromboembolic and bleeding complications, influence on stroke management, and evidence surrounding the use of oral anticoagulation for stroke prevention.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 31 Aug 2020; epub ahead of print
Ding WY, Gupta D, Wong CF, Lip GYH
Cardiovasc Res: 31 Aug 2020; epub ahead of print | PMID: 32871005
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Abstract

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation.

Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Aims
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.
Methods/results
We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.
Conclusion
Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Sep 2020; epub ahead of print
Carnicelli AP, Al-Khatib SM, Xavier D, Dalgaard F, ... Wallentin L, Granger CB
Heart: 15 Sep 2020; epub ahead of print | PMID: 32938772
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Abstract

Atrial fibrillation and the prothrombotic state: revisiting Virchow\'s triad in 2020.

Ding WY, Gupta D, Lip GYH

Atrial fibrillation (AF) is characterised by an increased risk of pathological thrombus formation due to a disruption of physiological haemostatic mechanisms that are better understood by reference to Virchow\'s triad of \'abnormal blood constituents\', \'vessel wall abnormalities\' and \'abnormal blood flow\'. First, there is increased activation of the coagulation cascade, platelet reactivity and impaired fibrinolysis as a result of AF per se, and these processes are amplified with pre-existing comorbidities. Several prothrombotic biomarkers including platelet factor 4, von Willebrand factor, fibrinogen, β-thromboglobulin and D-dimer have been implicated in this process. Second, structural changes such as atrial fibrosis and endothelial dysfunction are linked to the development of AF which promote further atrial remodelling, thereby providing a suitable platform for clot formation and subsequent embolisation. Third, these factors are compounded by the presence of reduced blood flow secondary to dilatation of cardiac chambers and loss of atrial systole which have been confirmed using various imaging techniques. Overall, an improved understanding of the various factors involved in thrombus formation will allow better clinical risk stratification and targeted therapies in AF.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Sep 2020; 106:1463-1468
Ding WY, Gupta D, Lip GYH
Heart: 29 Sep 2020; 106:1463-1468 | PMID: 32675218
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Abstract

Risk of Ischemic Stroke in Patients With Atrial Fibrillation After Extracranial Hemorrhage.

Zhou E, Lord A, Boehme A, Henninger N, ... Elkind MSV, Yaghi S
Background and purpose
Anticoagulation therapy not only reduces the risk of ischemic stroke in atrial fibrillation (AF) but also predisposes patients to hemorrhagic complications. There is limited knowledge on the risk of first-ever ischemic stroke in patients with AF after extracranial hemorrhage (ECH).
Methods
We conducted a retrospective study using the California State Inpatient Database including all nonfederal hospital admissions in California from 2005 to 2011. The exposure variable was hospitalization with a diagnosis of ECH with a previous diagnosis of AF. The outcome variable was a subsequent hospitalization with acute ischemic stroke. We excluded patients with stroke before or at the time of ECH diagnosis. We calculated adjusted hazard ratios for ischemic stroke during follow-up and at 6-month intervals using Cox regression models adjusted for pertinent demographics and comorbidities. In subgroup analyses, subjects were stratified by primary ECH diagnosis, severity/type of ECH, age, CHADS-VASc score, or the presence/absence of a gastrointestinal or genitourinary cancer.
Results
We identified 764 257 patients with AF (mean age 75 years, 49% women) without a documented history of stroke. Of these, 98 647 (13%) had an ECH-associated hospitalization, and 22 748 patients (3%) developed an ischemic stroke during the study period. Compared to patients without ECH, subjects with ECH had ≈15% higher rate of ischemic stroke (overall adjusted hazard ratio, 1.15 [95% CI, 1.11-1.19]). The risk appeared to remain elevated for at least 18 months after the index ECH. In subgroup analyses, the risk was highest in subjects with a primary admission diagnosis of ECH, severe ECH, gastrointestinal-type ECH, with gastrointestinal or genitourinary cancer, and age ≥60 years.
Conclusions
Patients with AF hospitalized with ECH may have a slightly elevated risk for future ischemic stroke. Particular consideration should be given to the optimal balance between the benefits and risks of anticoagulation therapy and the use of nonanticoagulant alternatives, such as left atrial appendage closure in this vulnerable population.



Stroke: 07 Oct 2020:STROKEAHA120029959; epub ahead of print
Zhou E, Lord A, Boehme A, Henninger N, ... Elkind MSV, Yaghi S
Stroke: 07 Oct 2020:STROKEAHA120029959; epub ahead of print | PMID: 33028172
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Abstract

Association of household income and adverse outcomes in patients with atrial fibrillation.

LaRosa AR, Claxton J, O\'Neal WT, Lutsey PL, ... Alonso A, Magnani JW
Background
Social determinants of health are relevant to cardiovascular outcomes but have had limited examination in atrial fibrillation (AF).
Objectives
The purpose of this study was to examine the association of annual household income and cardiovascular outcomes in individuals with AF.
Methods
We analysed administrative claims for individuals with AF from 2009 to 2015 captured by a health claims database. We categorised estimates of annual household income as <$40 000; $40-$59 999; $60-$74 999; $75-$99 999; and ≥$100 000. Covariates included demographics, education, cardiovascular disease risk factors, comorbid conditions and anticoagulation. We examined event rates by income category and in multivariable-adjusted models in reference to the highest income category (≥$100 000).
Results
Our analysis included 336 736 individuals (age 72.7±11.9 years; 44.5% women; 82.6% white, 8.4% black, 7.0% Hispanic and 2.1% Asian) with AF followed for median (25th and 75th percentile) of 1.5 (95% CI 0.6 to 3.0) years. We observed an inverse association between income and heart failure and myocardial infarction (MI) with evidence of progressive risk across decreased income categories. Individuals with household income <$40 000 had the greatest risk for heart failure (HR 1.17; 95% CI 1.05 to 1.30) and MI (HR 1.18; 95% CI 0.98 to 1.41) compared with those with income ≥$100 000.
Conclusions
We identified an association between lower household income and adverse outcomes in a large cohort of individuals with AF. Our findings support consideration of income in the evaluation of cardiovascular risk in individuals with AF.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2020; 106:1679-1685
LaRosa AR, Claxton J, O'Neal WT, Lutsey PL, ... Alonso A, Magnani JW
Heart: 30 Oct 2020; 106:1679-1685 | PMID: 32144188
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Abstract

Changes in quality of life, cognition and functional status following catheter ablation of atrial fibrillation.

Piccini JP, Todd DM, Massaro T, Lougee A, ... Di Biase L, Kirchhof P
Objective
To investigate changes in quality of life (QoL), cognition and functional status according to arrhythmia recurrence after atrial fibrillation (AF) ablation.
Methods
We compared QoL, cognition and functional status in patients with recurrent atrial tachycardia (AT)/AF versus those without recurrent AT/AF in the AXAFA-AFNET 5 clinical trial. We also sought to identify factors associated with improvement in QoL and functional status following AF ablation by overall change scores with and without analysis of covariance (ANCOVA).
Results
Among 518 patients who underwent AF ablation, 154 (29.7%) experienced recurrent AT/AF at 3 months. Patients with recurrent AT/AF had higher mean CHADS-VASc scores (2.8 vs 2.3, p<0.001) and more persistent forms of AF (51 vs 39%, p=0.012). Median changes in the SF-12 physical (3 (25th, 75th: -1, 8) vs 1 (-5, 8), p=0.026) and mental scores (2 (-3, 9) vs 0 (-4, 5), p=0.004), EQ-5D (0 (0,2) vs 0 (-0.1, 0.1), p=0.027) and Karnofsky functional status scores (10 (0, 10) vs 0 (0, 10), p=0.001) were more favourable in patients without recurrent AT/AF. In the overall cohort, the proportion with at least mild cognitive impairment (Montreal Cognitive Assessment <26) declined from 30.3% (n=157) at baseline to 21.8% (n=113) at follow-up. ANCOVA identified greater improvement in Karnofsky functional status (p<0.001) but not SF-12 physical (p=0.238) or mental scores (p=0.065) in those without recurrent AT/AF compared with patients with recurrent AT/AF.
Conclusions
Patients without recurrent AT/AF appear to experience greater improvement in functional status but similar QoL as those with recurrent AT/AF after AF ablation.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Heart: 11 Oct 2020; epub ahead of print
Piccini JP, Todd DM, Massaro T, Lougee A, ... Di Biase L, Kirchhof P
Heart: 11 Oct 2020; epub ahead of print | PMID: 33046527
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Abstract

Cessation of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

Middeldorp ME, Gupta A, Elliott A, Kadhim K, ... Lau D, Sanders P
Objective
To characterise the rate, causes and predictors of cessation of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF).
Patients and methods
Consecutive patients with AF with a long-term anticoagulation indication treated with NOACs (dabigatran, apixaban and rivaroxaban) in our centre from September 2010 through December 2016 were included. Prospectively collected data with baseline characteristics, causes of cessation, mean duration-to-cessation and predictors of cessation were analysed.
Results
The study comprised 1415 consecutive patients with AF, of whom 439 had a CHADS-VASc≥1 and were on a NOAC. Mean age was 71.9±8.7 years and 37% were females. Over a median follow-up of 3.6 years (IQR=2.7-5.3), 147 (33.5%) patients ceased their index-NOAC (113 switched to a different form of OAC), at a rate of 8.8 per 100 patient-years. Serious adverse events warranting NOAC cessation occurred in 28 patients (6.4%) at a rate of 1.6 events per 100 patient-years. The mean duration-to-cessation was 4.9 years (95% CI 4.6 to 5.1) and apixaban had the longest duration-to-cessation with (5.1, 95% CI 4.8 to 5.4) years, compared with dabigatran (4.6, 95% CI 4.2 to 4.9) and rivaroxaban (4.5, 95% CI 3.9 to 5.1), pairwise log-rank p=0.002 and 0.025, respectively. In multivariable analyses, age was an independent predictor of index-NOAC cessation (HR 1.03, 95% CI 1.01 to 1.05; p=0.006). Female gender (HR 2.2, 95% CI 1.04 to 4.64; p=0.04) independently predicted serious adverse events.
Conclusion
In this \'real world\' cohort, NOAC use is safe and well-tolerated when prescribed in an integrated care clinic. Whether apixaban is better tolerated compared with other NOACs warrants further study.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Oct 2020; epub ahead of print
Middeldorp ME, Gupta A, Elliott A, Kadhim K, ... Lau D, Sanders P
Heart: 15 Oct 2020; epub ahead of print | PMID: 33067328
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Abstract

Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation.

Heijman J, Muna AP, Veleva T, Molina CE, ... Wehrens XHT, Dobrev D
Rationale
Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown.
Objective
To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery.
Methods and results
Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca]-recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca-transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca-release events and L-type Ca-current alternans occurred more frequently. CaMKII (Ca/calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca-content was unchanged in POAF despite greater SR Ca-leak, with a trend towards increased SR Ca-ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca-release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca-uptake are sufficient to reproduce the Ca-handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β.
Conclusions
Preexisting Ca-handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca-releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.



Circ Res: 24 Sep 2020; 127:1036-1055
Heijman J, Muna AP, Veleva T, Molina CE, ... Wehrens XHT, Dobrev D
Circ Res: 24 Sep 2020; 127:1036-1055 | PMID: 32762493
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Abstract

Global variations in the prevalence, treatment, and impact of atrial fibrillation in a multi-national cohort of 153,152 middle-aged individuals.

Joseph PG, Healey JS, Raina P, Connolly SJ, ... Rangarajan S, Yusuf S
Aims
To compare the prevalence of electrocardiogram (ECG)-documented atrial fibrillation (or flutter) (AF) across eight regions of the world, and to examine anti-thrombotic use and clinical outcomes.
Methods and results
Baseline ECGs were collected in 153,152 middle-aged participants (ages 35 to 70 years) to document AF in two community-based studies, spanning 20 countries. Medication use and clinical outcome data (mean follow up of 7.4 years) were available in one cohort. Cross sectional analyses were performed to document the prevalence of AF and medication use, and associations between AF and clinical events were examined prospectively. Mean age of participants was 52.1 years, and 57.7% were female. Age and sex-standardized prevalence of AF varied 12-fold between regions; with the highest in North America, Europe, China and Southeast Asia (270-360 cases per 100,000 persons); and lowest in the Middle East, Africa, and South Asia (30-60 cases per 100,000 persons)(p < 0.001). Compared with low-income countries (LICs), AF prevalence was 7-fold higher in middle-income countries (MICs) and 11-fold higher in high-income countries (HICs)(p < 0.001). Differences in AF prevalence remained significant after adjusting for traditional AF risk factors. In LICs/MICs, 24% of participants with AF and a CHADS2 score ≥1 received anti-thrombotic therapy, compared with 85% in HICs. AF was associated with an increased risk of stroke (hazard ratio [HR: 2.29; 95% confidence interval [CI] 1.49-3.52) and death (HR: 2.97; 95% CI 2.25-3.93); with similar rates in different country income levels.
Conclusions
Large variations in AF prevalence occur in different regions and country income settings, but this is only partially explained by traditional AF risk factors. Anti-thrombotic therapy is infrequently used in poorer countries despite the high risk of stroke associated with AF.
Translational perspective
We examined atrial fibrillation (AF) prevalence in 153,152 middle-aged participants spanning 20 countries. Age and sex-standardized prevalence of AF varied by as much as 12-fold between regions; highest in North America, Europe, China and Southeast Asia (270-360 cases per 100,000 persons); and lowest in the Middle East, Africa, and South Asia (30-60 cases per 100,000 persons)(p < 0.001); and by as much as 11-fold between groups of countries at different income levels (p < 0.001). Global variations were poorly explained by traditional AF risk factors. Future studies are needed to understand the predominant determinants driving the variation in AF burden across different regions of the world.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 09 Aug 2020; epub ahead of print
Joseph PG, Healey JS, Raina P, Connolly SJ, ... Rangarajan S, Yusuf S
Cardiovasc Res: 09 Aug 2020; epub ahead of print | PMID: 32777820
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Abstract

Prevalence and Outcome of Potential Candidates for Left Atrial Appendage Closure After Stroke With Atrial Fibrillation: WATCH-AF Registry.

Ong E, Meseguer E, Guidoux C, Lavallée PC, ... Nighoghossian N, Amarenco P
Background and purpose
As a result of contraindications (eg, frailty, cognitive impairment, comorbidities) or patient refusal, many patients with stroke and atrial fibrillation cannot be discharged on oral anticoagulant. Among them, the proportion of potential candidates for left atrial appendage closure (LAAC) and their 12-month outcome is not well known.
Methods
The prospective WATCH-AF registry (Warfarin Aspirin Ten-A Inhibitors and Cerebral Infarction and Hemorrhage and Atrial Fibrillation) enrolled consecutive patients admitted within 72 hours of an acute stroke associated with atrial fibrillation in 2 stroke centers. Scales to evaluate stroke severity, disability, functional independence, risk of fall, cognition, ischemic and hemorrhagic risk-stratification, and comorbidities were systematically collected at admission, discharge, 3, 12 months poststroke. The 2 main end points were death or dependency (modified Rankin Scale score >3) and recurrent stroke (brain infarction and brain hemorrhage).
Results
Among 400 enrolled patients (370 with brain infarction, 30 with brain hemorrhage), 31 died before discharge and 57 (14.3%) were possible European Heart Rhythm Association/European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Rhythm Society candidates for LAAC. At 12 months, the rate of death or dependency was 17.9%, and the rate of stroke recurrence was 9.8% in the 274/400 (68.5%) patients discharged on a long-term oral anticoagulant strategy, as compared with 17.5% and 24.7%, respectively, in 57 patients candidate for LAAC. As compared with patients on a long-term oral anticoagulant strategy, there was a 2-fold increase in the risk of stroke recurrence in the group with an indication for LAAC (adjusted hazard ratio, 2.58 [95% CI, 1.40-4.76]; P=0.002).
Conclusions
Fourteen percent of patients with stroke associated with atrial fibrillation were potential candidates for LAAC. The 12-month stroke risk of these candidates was 3-fold the risk of anticoagulated patients.



Stroke: 30 Jul 2020; 51:2355-2363
Ong E, Meseguer E, Guidoux C, Lavallée PC, ... Nighoghossian N, Amarenco P
Stroke: 30 Jul 2020; 51:2355-2363 | PMID: 32640939
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Abstract

Tailoring anticoagulant treatment of patients with atrial fibrillation using a novel bleeding risk score.

Chu G, Valerio L, van der Wall SJ, Barco S, ... Huisman MV, Klok FA
Objectives
Current international guidelines advocate the application of bleeding risk scores only to identify modifiable risk factors, but not to withhold treatment in patients at high risk of bleeding. VTE-BLEED (ActiVe cancer, male with uncontrolled hyperTension, anaEmia, history of BLeeding, agE and rEnal Dysfunction) is a simple bleeding risk score that predicts major bleeding (MB) in patients with venous thromboembolism, but has never been evaluated in patients with atrial fibrillation (AF). We sought to evaluate VTE-BLEED in patients with AF included in the Randomised Evaluation of Long-term anticoagulant therapY (RE-LY) trial, to assess whether score classes (high vs low bleeding risk) interact with the tested dabigatran doses (150 vs 110 mg twice daily), and to investigate whether dose reductions based on this interaction might help to lower the incidence of the composite outcome MB, stroke/systemic embolism or death.
Methods
The score was calculated in the safety population of RE-LY (n=18 040) and recalibrated for AF (AF-adapted VTE-BLEED or AF-BLEED). HRs were calculated to evaluate the score\'s predictive accuracy for MB. The risk ratios (RRs) for the composite outcome comparing dabigatran 150 and 110 mg twice daily were calculated for the high-risk group.
Results
AF-BLEED classified 3534 patients (19.6%) at high bleeding risk, characterised by a 2.9-fold to 3.4-fold higher risk of bleeding than low bleeding risk patients, across the treatment arms. High bleeding risk patients randomised to 110 mg twice daily had a lower incidence of the composite outcome than those randomised to 150 mg twice daily, for an RR of 0.52 (95% CI 0.35 to 0.78). Compared with the label criteria for dose reduction, AF-BLEED identified an additional 11% of patients who might have benefited from dose reduction.
Conclusions
AF-BLEED identified patients with AF at high risk of bleeding. Our findings raise the hypothesis that dabigatran 110 mg twice daily might be considered in patients classified as high risk according to the AF-BLEED score. This study provides a basis for future studies to explore safe dose reductions of direct oral anticoagulants in selected patient groups based on bleeding scores.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 08 Sep 2020; epub ahead of print
Chu G, Valerio L, van der Wall SJ, Barco S, ... Huisman MV, Klok FA
Heart: 08 Sep 2020; epub ahead of print | PMID: 32907824
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Impact:
Abstract

Impact of different anticoagulation management strategies on outcomes in atrial fibrillation: Dutch and Belgian results from the GARFIELD-AF registry.

Seelig J, Hemels MEW, Xhaët O, Bongaerts MCM, ... Ten Cate H,
Background
The uptake rate of non-vitamin K oral anticoagulants (NOAC) for the treatment of non-valvular atrial fibrillation (AF) was far lower in the Netherlands (NL) compared to Belgium (BE). Also, patients on VKA in NL were treated with a higher target international normalized ratio (INR) range of 2.5 to 3.5.
Objectives
To explore the effect of these differences on thromboembolism (TE) and bleeding.
Methods
Data from the GARFIELD-AF registry was used. Patients with new-onset AF and ≥1 investigator-determined risk factor for stroke were included between 2010 and 2016. Event rates from 2 years of follow-up were used.
Results
In NL and BE, 1186 and 1705 patients were included, respectively. Female sex (42.3% vs 42.2%), mean age (70.7 vs 71.3 years), CHA DS -VASc (3.1 vs 3.1), and HAS-BLED score (1.4 vs 1.5) were comparable between NL and BE. At diagnosis in NL vs BE, 72.1% vs 14.6% received vitamin K antagonists (VKA) and 17.8% vs 65.5% NOACs, varying greatly across cohorts. Mean INR was 2.9 (±1.0) and 2.4 (±1.0) in NL and BE, respectively. Event rates per 100 patient-years in NL and BE, respectively, of all-cause mortality (3.38 vs 3.90; hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65-1.15), ischemic stroke/TE (0.82 vs 0.72; HR 1.14, 95% CI 0.62-2.11), and major bleeding (2.06 vs 1.54; HR 1.33, 95% CI 0.89-1.99) did not differ significantly.
Conclusions
In GARFIELD-AF, despite similar characteristics, patients on anticoagulants were treated differently in NL and BE. Although the rate of major bleeding was 33% higher in NL, variations in bleeding, mortality, and TE rates were not statistically significant.

© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 03 Sep 2020; epub ahead of print
Seelig J, Hemels MEW, Xhaët O, Bongaerts MCM, ... Ten Cate H,
J Thromb Haemost: 03 Sep 2020; epub ahead of print | PMID: 32886853
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Impact:
Abstract

Residual risks of ischaemic stroke and systemic embolism among atrial fibrillation patients with anticoagulation: large-scale real-world data (F-CREATE project).

Maeda T, Nishi T, Funakoshi S, Tada K, ... Yoshimura C, Arima H
Objective
Among patients with atrial fibrillation, the risks of ischaemic stroke and systemic embolism (IS/SE) are high even with effective anticoagulation. Using large-scale, real-world data from Japan, this study aims to clarify residual risks of IS/SE attributable to modifiable risk factors among patients with atrial fibrillation who are taking oral anticoagulants.
Methods
The study design we employed was a retrospective cohort. Health check-ups and insurance claims data of Japanese health insurance companies were accumulated from January 2005 to June 2017. We identified 11 848 participants with atrial fibrillation who were on oral anticoagulants during the study period. We set the modifiable risk factors as hypertension, diabetes and dyslipidaemia. A Cox proportional hazards model was used to obtain the effects of the risk factors for IS/SE.
Results
During an average of 3 years\' follow-up, 200 cases of IS/SE occurred (incidence rate 0.57 per 100 person-years). In multivariable analyses, older age (65-74 vs <65 years; adjusted HR 2.02 (95% CI 1.49 to 2.73)), hypertension (adjusted HR 1.41 (1.04 to 1.92)) and dyslipidaemia (adjusted HR 1.46 (1.07 to 1.98)) were significantly associated with increased risk of IS/SE. Percentage of IS/SE risk attributable to modifiable risk factors (hypertension, diabetes and dyslipidaemia) was 30.0% (16.1% to 41.6%).
Conclusion
Among patients with atrial fibrillation on anticoagulant therapy, approximately one-third of the residual risks were estimated to be attributable to modifiable risk factors such as hypertension, diabetes and dyslipidaemia.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 13 Aug 2020; epub ahead of print
Maeda T, Nishi T, Funakoshi S, Tada K, ... Yoshimura C, Arima H
Heart: 13 Aug 2020; epub ahead of print | PMID: 32817313
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Impact:
Abstract

Prevalence and incidence rates of atrial fibrillation in Norway 2004-2014.

Kjerpeseth LJ, Igland J, Selmer R, Ellekjær H, ... Tell GS, Ariansen I
Objective
To study time trends in incidence of atrial fibrillation (AF) in the entire Norwegian population from 2004 to 2014, by age and sex, and to estimate the prevalence of AF at the end of the study period.
Methods
A national cohort of patients with AF (≥18 years) was identified from inpatient admissions with AF and deaths with AF as underlying cause (1994-2014), and AF outpatient visits (2008-2014) in the Cardiovascular Disease in Norway (CVDNOR) project. AF admissions or out-of-hospital death from AF, with no AF admission the previous 10 years defined incident AF. Age-standardised incidence rates (IR) and incidence rate ratios (IRR) were calculated. All AF cases identified through inpatient admissions and outpatient visits and alive as of 31 December 2014 defined AF prevalence.
Results
We identified 175 979 incident AF cases (30% primary diagnosis, 69% secondary diagnosis, 0.6% out-of-hospital deaths). AF IRs (95% confidence intervals) per 100 000 person years were stable from 2004 (433 (426-440)) to 2014 (440 (433-447)). IRs were stable or declining across strata of sex and age with the exception of an average yearly increase of 2.4% in 18-44 year-olds: IRR 1.024 (1.014-1.034). In 2014, the prevalence of AF in the adult population was 3.4%.
Conclusions
We found overall stable IRs of AF for the adult Norwegian population from 2004 to 2014. The prevalence of AF was 3.4% at the end of 2014, which is higher than reported in previous studies. Signs of an increasing incidence of early-onset AF (<45 years) are worrying and need further investigation.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 19 Aug 2020; epub ahead of print
Kjerpeseth LJ, Igland J, Selmer R, Ellekjær H, ... Tell GS, Ariansen I
Heart: 19 Aug 2020; epub ahead of print | PMID: 32820014
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Impact:
Abstract

Initial Stroke Severity in Patients With Atrial Fibrillation According to Antithrombotic Therapy Before Ischemic Stroke.

Jung YH, Kim YD, Kim J, Han SW, ... Lee JS, Lee KY
Background and purpose
Atrial fibrillation (AF) is the leading cause of ischemic stroke. Preventive antithrombotic use, especially for anticoagulation, reduces the incidence of ischemic stroke in patients with AF. Using data from the nationwide multicenter stroke registry, we investigated the trends of preceding antithrombotic medication use in patients with acute ischemic stroke (AIS) with AF and its association with initial stroke severity and in-hospital outcomes.
Methods
This study included 6786 patients with AIS with known AF before stroke admission across 39 hospitals between June 2008 and December 2018. We collected the data on antithrombotic medication use (no antithrombotic/antiplatelet/anticoagulant) preceding AIS. Initial stroke severity was measured using the National Institutes of Health Stroke Scale, and in-hospital outcome was determined by modified Rankin Scale score at discharge.
Results
During the study period, anticoagulant use continued to increase. However, nearly one-third of patients with AIS with known AF did not receive antithrombotics before stroke. Initial National Institutes of Health Stroke Scale scores varied according to preceding antithrombotic therapy (<0.001). It was higher in patients who did not receive antithrombotics than in those who received antiplatelets or anticoagulants (median National Institutes of Health Stroke Scale score: 8 versus 7 and 8 versus 6, respectively). Favorable outcome at discharge (modified Rankin Scale score, 0-2) was more prevalent in patients who received antiplatelets or anticoagulants (<0.001). Use of antiplatelets (odds ratio, 1.23 [95% CI, 1.09-1.38]) and anticoagulants (odds ratio, 1.31 [95% CI, 1.15-1.50]) was associated with a mild initial neurological deficit (National Institutes of Health Stroke Scale score ≤5) in patients with AIS with AF.
Conclusions
Throughout the study period, the proportion of patients taking anticoagulants increased among patients with AIS with known AF. However, a large portion of AF patients still did not receive antithrombotics before AIS. Furthermore, prehospitalization use of anticoagulants was associated with a significantly higher likelihood of a mild initial neurological deficit and favorable outcome at discharge.



Stroke: 30 Aug 2020; 51:2733-2741
Jung YH, Kim YD, Kim J, Han SW, ... Lee JS, Lee KY
Stroke: 30 Aug 2020; 51:2733-2741 | PMID: 32811392
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Impact:
Abstract

Direct-Acting Oral Anticoagulants Versus Warfarin in Medicare Patients With Chronic Kidney Disease and Atrial Fibrillation.

Wetmore JB, Roetker NS, Yan H, Reyes JL, Herzog CA
Background and purpose
The comparative effectiveness of direct-acting oral anticoagulants, compared with warfarin, for risks of stroke/systemic embolism, major bleeding, or death have not been studied in Medicare beneficiaries with atrial fibrillation and nondialysis-dependent chronic kidney disease.
Methods
Medicare data from 2011 to 2017 were used to identify patients with stages 3, 4, or 5 chronic kidney disease and new atrial fibrillation who received a new prescription for warfarin, apixaban, rivaroxaban, or dabigatran. We estimated marginal hazard ratios with 95% CIs for the association of each direct-acting oral anticoagulant, compared with warfarin, for the outcomes of interest using inverse-probability-of-treatment weighted Cox proportional hazards models in as-treated and intention-to-treat analyses.
Results
A total of 22 739 individuals met criteria (46.3% warfarin, 29.6% apixaban, 17.2% rivaroxaban, 6.9% dabigatran). Across the groups of anticoagulant users, mean age was 78.4 to 79.0 years; 50.3% to 51.4% were women, and 80.3% to 82.8% had stage 3 chronic kidney disease. In the as-treated analysis, for stroke/systemic embolism, hazard ratios, all compared with warfarin, were 0.70 (0.51-0.96) for apixaban, 0.80 (0.54-1.17) for rivaroxaban, and 1.15 (0.69-1.94) for dabigatran. For major bleeding, analogous hazard ratios were 0.47 (0.37-0.59) for apixaban, 1.05 (0.85-1.30) for rivaroxaban, and 0.95 (0.70-1.31) for dabigatran. There was no difference in the risk of all-cause mortality between the direct-acting oral anticoagulants and warfarin. Results of the intention-to-treat analysis were similar.
Conclusions
Apixaban, compared with warfarin, was associated with decreased risk of stroke/systemic embolism and major bleeding; risks for both outcomes with rivaroxaban and dabigatran did not differ from risks with warfarin.



Stroke: 30 Jul 2020; 51:2364-2373
Wetmore JB, Roetker NS, Yan H, Reyes JL, Herzog CA
Stroke: 30 Jul 2020; 51:2364-2373 | PMID: 32640949
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Impact:
Abstract

Safety of Anticoagulation in Patients Treated With Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation.

Giustozzi M, Acciarresi M, Agnelli G, Caso V, ... Paciaroni M, Masotti L
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.



Stroke: 30 Jul 2020; 51:2347-2354
Giustozzi M, Acciarresi M, Agnelli G, Caso V, ... Paciaroni M, Masotti L
Stroke: 30 Jul 2020; 51:2347-2354 | PMID: 32646335
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Impact:
Abstract

Diagnostic accuracy of handheld electrocardiogram devices in detecting atrial fibrillation in adults in community versus hospital settings: a systematic review and meta-analysis.

Wong KC, Klimis H, Lowres N, von Huben A, Marschner S, Chow CK

With increasing use of handheld ECG devices for atrial fibrillation (AF) screening, it is important to understand their accuracy in community and hospital settings and how it differs among settings and other factors. A systematic review of eligible studies from community or hospital settings reporting the diagnostic accuracy of handheld ECG devices (ie, devices producing a rhythm strip) in detecting AF in adults, compared with a gold standard 12-lead ECG or Holter monitor, was performed. Bivariate hierarchical random-effects meta-analysis and meta-regression were performed using R V.3.6.0. The search identified 858 articles, of which 14 were included. Six studies recruited from community (n=6064 ECGs) and eight studies from hospital (n=2116 ECGs) settings. The pooled sensitivity was 89% (95% CI 81% to 94%) in the community and 92% (95% CI 83% to 97%) in the hospital. The pooled specificity was 99% (95% CI 98% to 99%) in the community and 95% (95% CI 90% to 98%) in the hospital. Accuracy of ECG devices varied: sensitivity ranged from 54.5% to 100% and specificity ranged from 61.9% to 100%. Meta-regression showed that setting (p=0.032) and ECG device type (p=0.022) significantly contributed to variations in sensitivity and specificity. The pooled sensitivity and specificity of single-lead handheld ECG devices were high. Setting and handheld ECG device type were significant factors of variation in sensitivity and specificity. These findings suggest that the setting including user training and handheld ECG device type should be carefully reviewed.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Jul 2020; 106:1211-1217
Wong KC, Klimis H, Lowres N, von Huben A, Marschner S, Chow CK
Heart: 30 Jul 2020; 106:1211-1217 | PMID: 32393588
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Impact:
Abstract

Impact of atrial fibrillation in patients with heart failure and reduced, mid-range or preserved ejection fraction.

Son MK, Park JJ, Lim NK, Kim WH, Choi DJ
Objective
To determine the prognostic value of atrial fibrillation (AF) in patients with heart failure (HF) and preserved, mid-range or reduced ejection fraction (EF).
Methods
Patients hospitalised for acute HF were enrolled in the Korean Acute Heart Failure registry, a prospective, observational, multicentre cohort study, between March 2011 and February 2014. HF types were defined as reduced EF (HFrEF, LVEF <40%), mid-range EF (HFmrEF, LVEF 40%-49%) or preserved EF (HFpEF, LVEF ≥50%).
Results
Of 5414 patients enrolled, HFrEF, HFmrEF and HFpEF were seen in 3182 (58.8%), 875 (16.2%) and 1357 (25.1%) patients, respectively. The prevalence of AF significantly increased with increasing EF (HFrEF 28.9%, HFmrEF 39.8%, HFpEF 45.2%; p for trend <0.001). During follow-up (median, 4.03 years; IQR, 1.39-5.58 years), 2806 (51.8%) patients died. The adjusted HR of AF for all-cause death was 1.06 (0.93-1.21) in the HFrEF, 1.10 (0.87-1.39) in the HFmrEF and 1.22 (1.02-1.46) in the HFpEF groups. The HR for the composite of all-cause death or readmission was 0.97 (0.87-1.07), 1.14 (0.93-1.38) and 1.03 (0.88-1.19) in the HFrEF, HFmrEF and HFpEF groups, respectively, and the HR for stroke was 1.53 (1.03-2.29), 1.04 (0.57-1.91) and 1.90 (1.13-3.20), respectively. Similar results were observed after propensity score matching analysis.
Conclusions
AF was more common with increasing EF. AF was seen to be associated with increased mortality only in patients with HFpEF and was associated with an increased risk of stroke in patients with HFrEF or HFpEF.
Trial registration number
NCT01389843.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Jul 2020; 106:1160-1168
Son MK, Park JJ, Lim NK, Kim WH, Choi DJ
Heart: 30 Jul 2020; 106:1160-1168 | PMID: 32341140
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Impact:
Abstract

Atrial fibrillation detection with a portable device during cardiovascular screening in primary care.

Diamantino AC, Nascimento BR, Beaton AZ, Nunes MCP, ... Sable C, Brant LCC
Introduction
A novel handheld dual-electrode stick is a portable atrial fibrillation (AF) screening device (AFSD). We evaluated AFSD performance in primary care patients referred for echocardiogram (echo).
Methods
The AFSD has a light indication of irregular rhythm and single-lead ECG recording. Patients were instructed to hold the device for 1 min, and AF indication was recorded. A 12-lead ECG was performed for all AFSD-positive patients and 250 patients with negative AFSD screen. Echos were performed based on a clinical risk score: all high-risk patients and a sampling of low-risk patients underwent complete echo. Intermediate risk patients first had a screening echocardiogram, with a follow-up complete study if abnormality was suspected.
Results
In 5 days, 1518 patients underwent clinical evaluation and cardiovascular risk stratification: mean age 58±16 years, 66% women. The AFSD was positive in 6.4%: 12.6% high risk, 6.1% intermediate risk and 2.2% low risk. Older age was a risk factor (9.3% vs 4.8% in those more than and less than 65 years, p=0.001). AFSD positive was independently associated with heart disease in echo (OR=3.9, 95% CI 2.1 to 7.2, p<0.001). Compared with 12-lead ECG, the AFSD had sensitivity of 90.2% (95% CI 77.0% to 97.3%) and specificity of 84.0% (95% CI 79.3% to 88.0%) for AF detection.
Conclusion
AFSD demonstrated high sensitivity for AF detection in primary care patients referred for echo. AF prevalence was substantial and independently associated with structural or functional heart disease, suggesting that AFSD screening could be a useful primary care tool to stratify risk and prioritise echo.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Jul 2020; 106:1261-1266
Diamantino AC, Nascimento BR, Beaton AZ, Nunes MCP, ... Sable C, Brant LCC
Heart: 30 Jul 2020; 106:1261-1266 | PMID: 32019822
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Impact:
Abstract

Usefulness of Neuromuscular Co-morbidity, Left Bundle Branch Block, and Atrial Fibrillation to Predict the Long-Term Prognosis of Left Ventricular Hypertrabeculation/Noncompaction.

Stöllberger C, Hasun M, Winkler-Dworak M, Finsterer J

The prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) is assessed controversially. LVHT is associated with other cardiac abnormalities and with neuromuscular disorders (NMD). Aim of the study was to assess cardiac and neurological findings as predictors of mortality rate in adult LVHT-patients. Included were patients with LVHT diagnosed between 1995 and 2019 in 1 echocardiographic laboratory. Patients underwent a baseline cardiologic examination and were invited for a neurological investigation. In January 2020, their survival status was assessed. End points were death or heart transplantation. LVHT was diagnosed by echocardiography in 310 patients (93 female, aged 53 ± 18 years) with a prevalence of 0.4%/year. A neurologic investigation was performed in 205 patients (67%). A specific NMD was found in 33 (16%), NMD of unknown etiology in 123 (60%) and the neurological investigation was normal in 49 (24%) patients. During follow-up of 84 ± 71 months, 59 patients received electronic devices, 105 patients died, and 6 underwent heart transplantation. The mortality was 4.7%/year, the rate of heart transplantation/death 5%/year. By multivariate analysis, the following parameters were identified to elevate the risk of mortality/heart transplantation: increased age (p = 0.005), inpatient (p = 0.001), presence of a specific NMD (p = 0.0312) or NMD of unknown etiology (p = 0.0365), atrial fibrillation (p = 0.0000), ventricular premature complexes (p = 0.0053), exertional dyspnea (p = 0.0023), left bundle branch block (p = 0.0201), and LVHT of the posterior wall (p = 0.0158). In conclusion, LVHT patients should be systematically investigated neurologically since neurological co-morbidity has a prognostic impact.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Jul 2020; 128:168-173
Stöllberger C, Hasun M, Winkler-Dworak M, Finsterer J
Am J Cardiol: 31 Jul 2020; 128:168-173 | PMID: 32650915
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Impact:
Abstract

Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation.

Friedman DM, Kim M, Costedoat-Chalumeau N, Clancy R, ... Izmirly P, Buyon JP

- Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine (HCQ) is being considered as prophylaxis and treatment of COVID-19. Although HCQ is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematous and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy.- To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal electrocardiograms (ECGs) and HCQ blood levels were available in a recently completed study evaluating the efficacy of HCQ 400mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro antibodies.- Forty-five ECGs were available for QTc measurement, and levels of HCQ were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of HCQ and the neonatal QTc (R = 0.02, P = 0.86) or the mean of HCQ values obtained throughout each individual pregnancy and the QTc (R = 0.04, P = 0.80). In total 5 (11%; 95% CI: 4% - 24%) neonates had prolongation of the QTc > 2SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal.- In aggregate, these data provide reassurances that the maternal use of HCQ is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered.



Circ Arrhythm Electrophysiol: 08 Sep 2020; epub ahead of print
Friedman DM, Kim M, Costedoat-Chalumeau N, Clancy R, ... Izmirly P, Buyon JP
Circ Arrhythm Electrophysiol: 08 Sep 2020; epub ahead of print | PMID: 32907357
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Impact:
Abstract

Impact of Left Ventricular Function and Heart Failure Symptoms on Outcomes Post Ablation of Atrial Fibrillation in Heart Failure: CASTLE-AF Trial.

Sohns C, Zintl K, Zhao Y, Dagher L, ... Brachmann J, Marrouche NF

- Recent data demonstrates promising effects on left ventricular (LV) dysfunction and LV ejection fraction (EF) improvement following ablation for atrial fibrillation (AF) in patients with heart failure (HF). We sought to study the relationship between LVEF, NYHA class on presentation and the endpoints of mortality and HF admissions in the CASTLE-AF study population. Furthermore, predictors for LVEF improvement were examined.- The CASTLE-AF patients with coexisting HF and AF (n=363) were randomized in a multicenter prospective controlled fashion to ablation (n=179) vs pharmacological therapy (n=184). LV function and NYHA class were assessed at baseline (after randomization) and at each follow-up visit.- In the ablation arm, a significantly higher number of patients experienced an improvement in their LVEF to >35% at the end of the study (OR=2.17; p<0.001). Compared to the pharmacological therapy arm, both ablation patient groups with severe (<20%) or moderate/severe (≥20% and <35%)) baseline LVEF had a significantly lower number of composite endpoints (hazard ratio (HR) =0.60; p=0.006), all-cause mortality (HR=0.54; p=0.019) and cardiovascular (CV) hospitalizations (HR=0.66; p=0.017). In the ablation group, NYHA I/II patients at the time of treatment had the strongest improvement in clinical outcomes (primary endpoint: HR=0.43; p<0.001; mortality: HR=0.30; p=0.001).- Compared to pharmacological treatment, AF ablation was associated with a significant improvement in LVEF, independent from the severity of LV dysfunction. AF ablation should be performed at early stages of the patient\'s HF symptoms.



Circ Arrhythm Electrophysiol: 08 Sep 2020; epub ahead of print
Sohns C, Zintl K, Zhao Y, Dagher L, ... Brachmann J, Marrouche NF
Circ Arrhythm Electrophysiol: 08 Sep 2020; epub ahead of print | PMID: 32903044
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Impact:
Abstract

Prospective STAR Guided Ablation in Persistent AF using Sequential Mapping with Multipolar Catheters.

Honarbakhsh S, Schilling RJ, Finlay M, Keating E, Hunter RJ

- A novel \'STAR\' mapping approach to guide AF ablation using basket catheters recently showed high rates of AF termination and subsequent freedom from AF.- This study aimed to determine whether STAR mapping using sequential recordings from conventional pulmonary vein mapping catheters could achieve similar results. Patients with persistent AF <2 years were included. Following pulmonary vein isolation (PVI) AF drivers (AFDs) were identified on sequential STAR maps created with PentaRay, IntellaMap Orion, or Advisor HD Grid catheters. Patients had a minimum of 10 multipolar recordings of 30-seconds each. These were processed in real-time and AFDs were targeted with ablation. An ablation response was defined as AF termination or CL slowing ≥30ms.- Thirty patients were included (62.4±7.8 years old, AF duration 14.1±4.3 months) of which 3 had AF terminated on PVI, leaving 27 patients that underwent STAR-guided AFD ablation. Eighty-three potential AFDs were identified (3.1±1.0 per patient) of which 70 were targeted with ablation (2.6±1.0 per patient). An ablation response was seen at 54 AFD (77.1% of AFD; 21 AF termination and 33 CL slowing) and occurred in all 27 patients. No complications occurred. At 17.3±10.1 months, 22/27 (81.5%) patients undergoing STAR guided ablation were free from AF/AT off anti-arrhythmic drugs.- STAR-guided AFD ablation through sequential mapping with a multipolar catheter effectively achieved an ablation response in all patients. AF terminated in a majority of patients, with a high freedom from AF/AT off anti-arrhythmic drugs at long-term follow-up.



Circ Arrhythm Electrophysiol: 08 Sep 2020; epub ahead of print
Honarbakhsh S, Schilling RJ, Finlay M, Keating E, Hunter RJ
Circ Arrhythm Electrophysiol: 08 Sep 2020; epub ahead of print | PMID: 32903033
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Impact:
Abstract

Long-Term Outcome in High-Risk Patients with Hypertrophic Cardiomyopathy after Primary Prevention Defibrillator Implants.

Rowin EJ, Burrows A, Madias C, Estes Iii NAM, ... Maron MS, Maron BJ

- The implantable cardioverter-defibrillator (ICD) is effective for preventing sudden death in patients with hypertrophic cardiomyopathy (HCM). However, data on performance and complications of implanted ICDs over particularly long time periods to inform clinical practice is presently incomplete.- The study cohort comprises 217 consecutive HCM patients with primary prevention ICDs implanted prior to 2008 and followed for ≥10 years (mean 12 ± 4; range to 31).- Patients were 38 ± 17 years at implant and 45 (21%) experienced appropriate interventions terminating VT/VF. The majority of ICD discharges occurred ≥ 5 years after implant (29 patients; 64%), including ≥10 years in 16 patients (36%). Initial device therapy increased in frequency from 2.3% of patients at <1 year to 8.5% of patients at ≥ 10 years post implant (p=0.005). Inappropriate ICD shocks in 39 patients occurred most commonly <5 years after implant (54%) and decreased in frequency with increasing time from implant (from 9.7% of patients at <5-years to 3.8% at ≥10years, p=0.02). Other major device complications including infection and/or lead fractures and dislodgement occurred in 27 patients (12%), but did not increase in frequency over follow-up (p=0.47). There were no arrhythmic sudden death events among the 217 ICD patients.- In HCM, primary prevention ICD therapies increase progressively over time after implant, including a substantial proportion with prolonged periods of device dormancy, including two-thirds of patients ≥ 5-years and for ≥ 10 years in one-third. Frequency of inappropriate shocks decreased over follow-up, likely reflecting changes in device programming, while occurrence of device complications such as lead fractures/infection did not increase during follow-up.



Circ Arrhythm Electrophysiol: 07 Sep 2020; epub ahead of print
Rowin EJ, Burrows A, Madias C, Estes Iii NAM, ... Maron MS, Maron BJ
Circ Arrhythm Electrophysiol: 07 Sep 2020; epub ahead of print | PMID: 32897759
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Impact:
Abstract

Power, Lesion Size Index and Oesophageal Temperature Alerts during Atrial Fibrillation Ablation: A Randomized Study.

Leo M, Pedersen M, Rajappan K, Ginks MR, ... Bashir Y, Betts TR

- Low radiofrequency (RF) powers are commonly used on the posterior wall of the left atrium (LA) for atrial fibrillation (AF) ablation to prevent esophageal damage. Compared with higher powers, they require longer ablation durations to achieve a target lesion size index (LSI). Esophageal heating during ablation is the result of a time-dependent process of conductive heating produced by nearby RF delivery. This randomized study was conducted to compare risk of esophageal heating and acute procedure success of different LSI-guided ablation protocols combining higher or lower RF power and different target LSI values.- Eighty consecutive patients were prospectively enrolled and randomized to one of 4 combinations of RF power and target LSI for ablation on the LA posterior wall (20W/LSI 4, 20W/LSI 5, 40W/LSI 4 and 40W/LSI 5). The primary endpoint of the study was the occurrence and number of esophageal temperature alerts (ETAs) per patient during ablation. Acute indicators of procedure success were considered as secondary end-points. Long term follow-up data were also collected for all patients.- Esophageal temperature alerts (ETAs) occurred in a similar proportion of patients in all groups. Significantly shorter RF durations were required to achieve the target LSI in the 40W groups. Less than 50% of the RF lesions reached the target LSI of 5 when using 20W despite a longer RF duration. A lower rate of first-pass Pulmonary Vein Isolation and a higher rate of acute Pulmonary Vein Reconnection were recorded in the group 20W/LSI 5. A lower AF recurrence rate was observed in the 40W groups compared to the 20W groups at 29 months follow-up.- When guided by LSI, posterior wall ablation with 40W is associated with a similar rate of ETAs and a lower AF recurrence rate at follow-up if compared to 20W. These data will provide a basis to plan future randomized trials.



Circ Arrhythm Electrophysiol: 07 Sep 2020; epub ahead of print
Leo M, Pedersen M, Rajappan K, Ginks MR, ... Bashir Y, Betts TR
Circ Arrhythm Electrophysiol: 07 Sep 2020; epub ahead of print | PMID: 32898435
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Impact:
Abstract

Pulmonary Vein Isolation with Single Pulse Irreversible Electroporation: A First in Human Study in 10 Patients with Atrial Fibrillation.

Loh P, van Es R, Groen MHA, Neven K, ... Wittkampf FHM, Doevendans PAFM

- Irreversible electroporation (IRE) is a promising new non-thermal ablation technology for pulmonary vein (PV) isolation in patients with atrial fibrillation (AF). Experimental data suggest that IRE ablation produces large enough lesions without the risk of PV stenosis, artery, nerve or esophageal damage. This study aimed to investigate the feasibility and safety of single pulse IRE PV isolation in patients with AF.- Ten patients with symptomatic paroxysmal or persistent AF underwent single pulse IRE PV isolation under general anesthesia. Three-dimensional reconstruction and electroanatomical voltage mapping (EnSite Precision, Abbott) of left atrium and PVs were performed using a conventional circular mapping catheter. PV isolation was performed by delivering non-arcing, non-barotraumatic 6 ms, 200 J direct current IRE applications via a custom non-deflectable 14-polar circular IRE ablation catheter with a variable hoop diameter (16-27 mm). A deflectable sheath (Agilis, Abbott) was used to maneuver the ablation catheter. A minimum of two IRE applications with slightly different catheter positions were delivered per vein to achieve circular tissue contact, even if PV potentials were abolished after the first application. Bidirectional PV isolation was confirmed with the circular mapping catheter and a post ablation voltage map. After a 30-minute waiting period, adenosine testing (30 mg) was used to reveal dormant PV conduction.- All 40 PVs could be successfully isolated with a mean of 2.4±0.4 IRE applications per PV. Mean delivered peak voltage and peak current were 2154 ± 59 V and 33.9 ± 1.6 A, respectively. No PV reconnections occurred during the waiting period and adenosine testing. No periprocedural complications were observed.- In the 10 patients of this first-in-human study, acute bidirectional electrical PV isolation could be achieved safely by single pulse IRE ablation.



Circ Arrhythm Electrophysiol: 07 Sep 2020; epub ahead of print
Loh P, van Es R, Groen MHA, Neven K, ... Wittkampf FHM, Doevendans PAFM
Circ Arrhythm Electrophysiol: 07 Sep 2020; epub ahead of print | PMID: 32898450
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Impact:
Abstract

Long-lasting Ventricular Fibrillation in Humans ECG Characteristics and Effect of Radio-frequency Ablation.

Maury P, Duchateau J, Rollin A, Hocini M, ... Haïssaguerre M, Dubois R

- Studies of ventricular fibrillation (VF) in humans are limited because of the short available duration. We sought to study surface ECG waveforms and effect of ablation in long-lasting VF in patients with left assist devices.- Continuous 12 lead-ECG of 5 episodes of long-lasting VF occurring in 3 patients with left ventricular assist device were analyzed. Spectral analysis (dominant frequency, DF) and quantification of waveform amplitude, regularity (URI) and complexity (NDI) were performed over a median of 24 minutes of VF. RF ablation was performed during VF in two patients.- There was a significant increase in DF between VF onset and termination but none of the other parameters significantly changed. Some VF parameters varied from patient to patient and from lead to lead. DF decreased after RF ablation in both cases and VF terminated spontaneously shortly after ablation in one case. The previously incessant VFs in these two patients did not recur afterward.- VF rate increases over time in patients with left ventricular assist devices and is lowered by ablation. Long-lasting VF may be modified or even terminated by ablation.



Circ Arrhythm Electrophysiol: 09 Sep 2020; epub ahead of print
Maury P, Duchateau J, Rollin A, Hocini M, ... Haïssaguerre M, Dubois R
Circ Arrhythm Electrophysiol: 09 Sep 2020; epub ahead of print | PMID: 32911973
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Impact:
Abstract

Cost-Effectiveness of an Antibacterial Envelope for CIED Infection Prevention in the US Healthcare System from the WRAP-IT Trial.

Wilkoff BL, Boriani G, Mittal S, Poole JE, ... Seshadri S, Tarakji KG

- In the WRAP-IT trial, adjunctive use of an absorbable antibacterial envelope resulted in a 40% reduction of major cardiac implantable electronic device (CIED) infection without increased risk of complication in 6,983 patients undergoing CIED revision, replacement, upgrade, or initial cardiac resynchronization therapy defibrillator (CRT-D) implant. There is limited information on the cost-effectiveness of this strategy. As a pre-specified objective, we evaluated antibacterial envelope cost-effectiveness compared to standard-of-care infection prevention strategies in the US healthcare system.- A decision tree model was used to compare costs and outcomes of antibacterial envelope (TYRX) use adjunctive to standard-of-care infection prevention vs. standard-of-care alone over a lifelong time horizon. The analysis was performed from an integrated payer-provider network perspective. Infection rates, antibacterial envelope effectiveness, infection treatment costs and patterns, infection-related mortality, and utility estimates were obtained from the WRAP-IT trial. Life expectancy and long-term costs associated with device replacement, follow-up, and healthcare utilization were sourced from the literature. Costs and quality-adjusted life years (QALYs) were discounted at 3%. An upper willingness-to-pay (WTP) threshold of $150,000 per QALY was used to determine cost-effectiveness, in alignment with American College of Cardiology and American Heart Association (ACC/AHA) practice guidelines and as supported by the World Health Organization (WHO) and contemporary literature.- The base-case incremental cost-effectiveness ratio (ICER) of the antibacterial envelope compared to standard-of-care was $112,603/QALY. The ICER remained lower than the WTP threshold in 74% of iterations in the probabilistic sensitivity analysis and was most sensitive to the following model inputs: infection-related mortality, life expectancy, and infection cost.- The absorbable antibacterial envelope was associated with a cost-effectiveness ratio below contemporary benchmarks in the WRAP-IT patient population, suggesting that the envelope provides value for the US healthcare system by reducing the incidence of CIED infection.



Circ Arrhythm Electrophysiol: 10 Sep 2020; epub ahead of print
Wilkoff BL, Boriani G, Mittal S, Poole JE, ... Seshadri S, Tarakji KG
Circ Arrhythm Electrophysiol: 10 Sep 2020; epub ahead of print | PMID: 32915063
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Abstract

Characteristics of Esophageal Injury in Ablation of Atrial Fibrillation using a High-Power Short-Duration Setting.

Kaneshiro T, Kamioka M, Hijioka N, Yamada S, ... Yoshihisa A, Takeishi Y

- The mechanism of esophageal thermal injury (ETI; esophageal mucosal injury and periesophageal nerve injury leading to gastric hypomotility) remains unknown when using a high-power short-duration (HP-SD) setting. This study sought to evaluate the characteristics of esophageal injuries in atrial fibrillation (AF) ablation using a high-power short-duration (HP-SD) setting.- After exclusion of 5 patients with their esophagus at the right portion of left atrium (LA) and 21 patients with additional ablations such as box isolation and/or low voltage ablation in LA posterior wall, 271 consecutive patients (62 ± 10 years, 56 women) who underwent pulmonary vein isolation (PVI) by radiofrequency catheter ablation were analyzed. In the 101 patients, a HP-SD setting at 45-50 W with an Ablation Index module® was used (HP-SD group). In the remaining 170 patients before introduction of the HP-SD setting, a conventional power setting of 20-30 W with contact force monitoring was used (Conventional group). We performed esophagogastroduodenoscopy after PVI in all patients and investigated the incidence and characteristics of ETI.- Although the incidence of ETI was significantly higher in the HP-SD group compared to the Conventional group (37% vs. 22%, P = 0.011), the prevalence of esophageal lesions did not differ between the groups (7% vs. 8%). Multivariate logistic regression analysis revealed that the use of the HP-SD setting (odds ratio: 6.09, P < 0.001), and the parameters that suggest anatomical proximity surrounding the esophagus, were independent predictors of ETI. However, the majority of ETI in the HP-SD group was gastric hypomotility, and the thermal injury was limited to the shallow layer of the periesophageal wall using the HP-SD setting.- Although the use of the HP-SD setting was a strong predictor of ETI, it could avoid deeper thermal injuries that reach the esophageal mucosal layer.



Circ Arrhythm Electrophysiol: 10 Sep 2020; epub ahead of print
Kaneshiro T, Kamioka M, Hijioka N, Yamada S, ... Yoshihisa A, Takeishi Y
Circ Arrhythm Electrophysiol: 10 Sep 2020; epub ahead of print | PMID: 32915644
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Abstract

Permanent His Bundle Pacing Implantation Facilitated by Visualization of the Tricuspid Valve Annulus.

Gu M, Niu H, Hu Y, Liu X, ... Hua W, Zhang S

- His bundle pacing (HBP) is the most physiologic pacing modality. However, HBP has longer procedure times with frequent high capture thresholds, which likely contributes to the low adoption of this approach. The aim of this study is to compare HBP implantation with a novel imaging technique versus the standard implantation technique.- This study included 50 patients with standard pacing indications randomized to HBP with visualization of the tricuspid valve annulus (TVA, N=25, the visualization group) or with the standard method (N=25, the control group). In the visualization group, the TVA was imaged by contrast injection in the right ventricle during fluoroscopy. The site for HBP was identified in relationship to the tricuspid septal leaflet and interventricular septum.- Permanent HBP was successful in 92% in the visualization group and 88% in the control group. The fluoroscopic time for HBP lead placement was significantly shorter in the visualization group (7.1±3.3min) compared with the control group (10.1±5.6min, P=0.03). Total procedural and fluoroscopic times were also significantly shorter in the visualization group (91.0±15.7min and 9.6±3.8min) than the control group (104.4±17.8min and 12.7±6.2min, P=0.01 and 0.04, respectively). There was no significant difference in capture threshold between groups. In the visualization group, there was a quantitative association between the HBP site and the TVA.- The visualization technique shortens the procedural and fluoroscopic times for HBP implantation. Moreover, anatomic localization of HBP sites is strongly associated with physiologic characteristics of pacing, which can help guide optimal lead placement.



Circ Arrhythm Electrophysiol: 09 Sep 2020; epub ahead of print
Gu M, Niu H, Hu Y, Liu X, ... Hua W, Zhang S
Circ Arrhythm Electrophysiol: 09 Sep 2020; epub ahead of print | PMID: 32911981
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Abstract

Catheter-free Arrhythmia Ablation using Scanned Proton Beams: Electrophysiologic Outcomes, Biophysics and Characterization of Lesion Formation in a Porcine Model.

Suzuki A, Deisher AJ, Rettmann ME, Lehmann HI, ... Herman MG, Packer DL

- Proton beam therapy offers radiophysical properties that are appealing for noninvasive arrhythmia elimination. This study was conducted to use scanned proton beams for ablation of cardiac tissue, investigate electrophysiologic outcomes, and characterize the process of lesion formation in a porcine model using particle therapy.- Twenty-five animals received scanned proton beam irradiation. ECG-gated CT scans were acquired at end-expiration breath hold. Structures (atrioventricular junction [AVJ] or left ventricular myocardium [LV]) and organs at risk were contoured. Doses of 30, 40, and 55Gy were delivered during expiration to the AVJ (AVJ; n=5) and LV myocardium (LV; n=20) of intact animals.- In this study, procedural success was tracked by pacemaker interrogation in the AVJ group, time-course magnetic resonance imaging (MR) in the LV group, and correlation of lesion outcomes displayed in gross and microscopic pathology. Protein extraction (active caspase-3) was performed to investigate tissue apoptosis. Doses of 40 and 55Gy caused slowing and interruption of cardiac impulse propagation at the AVJ. In 40 LV irradiated targets, all lesions were identified on MR after twelve weeks, being consistent with outcomes from gross pathology. In the majority of cases, lesion size plateaued between 12 and 16 weeks. Active caspase-3 was seen in lesions 12 and 16 weeks after irradiation, but not after 20 weeks.- Scanned proton beams can be used as a tool for catheter-free ablation, and time-course of tissue apoptosis was consistent with lesion maturation.



Circ Arrhythm Electrophysiol: 12 Sep 2020; epub ahead of print
Suzuki A, Deisher AJ, Rettmann ME, Lehmann HI, ... Herman MG, Packer DL
Circ Arrhythm Electrophysiol: 12 Sep 2020; epub ahead of print | PMID: 32921132
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Abstract

Optical Mapping-Validated Machine Learning Improves Atrial Fibrillation Driver Detection by Multi-Electrode Mapping.

Zolotarev AM, Hansen BJ, Ivanova EA, Helfrich KM, ... Dylov DV, Fedorov VV

- Atrial fibrillation (AF) can be maintained by localized intramural reentrant drivers. However, AF driver detection by clinical surface-only multi-electrode mapping (MEM) has relied on subjective interpretation of activation maps. We hypothesized that application of Machine Learning (ML) to electrogram frequency spectra may accurately automate driver detection by MEM and add some objectivity to the interpretation of MEM findings.- Temporally and spatially stable single AF drivers were mapped simultaneously in explanted human atria (n=11) by subsurface near-infrared optical mapping (NIOM) (0.3mm resolution) and 64-electrode MEM (Higher-Density (HD) or Lower-Density (LD) with 3mm and 9mm resolution, respectively). Unipolar MEM and NIOM recordings were processed by Fourier Transform analysis into 28407 total Fourier spectra. Thirty-five features for ML were extracted from each Fourier spectrum.- Targeted driver ablation and NIOM activation maps efficiently defined the center and periphery of AF driver preferential tracks and provided validated classifications for driver vs non-driver electrodes in MEM arrays. Compared to analysis of single electrogram frequency features, averaging the features for each surrounding 8 electrodes neighborhood, significantly improved classification of AF driver electrograms. The classification metrics increased when less strict annotation including driver periphery electrodes were added to driver center annotation. Notably, f1-score for the binary classification of HD catheter dataset were significantly higher than that of LD catheter (0.81 ± 0.02 vs 0.66 ± 0.04, p<0.05). The trained algorithm correctly highlighted 86% of driver regions with HD but only 80% with LD MEM arrays (81% for LD+HD arrays together).- The ML model pre-trained on Fourier spectrum features allows efficient classification of electrograms recordings as AF driver or non-driver compared to the NIOM gold-standard. Future application of NIOM-validated ML approach may improve the accuracy of AF driver detection for targeted ablation treatment in patients.



Circ Arrhythm Electrophysiol: 12 Sep 2020; epub ahead of print
Zolotarev AM, Hansen BJ, Ivanova EA, Helfrich KM, ... Dylov DV, Fedorov VV
Circ Arrhythm Electrophysiol: 12 Sep 2020; epub ahead of print | PMID: 32921129
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Abstract

Genetic Loss of Causes Adrenergic-Induced Phase 3 Early Afterdepolariz ations and Polymorphic and Bidirectional Ventricular Tachycardia.

Reilly L, Alvarado FJ, Lang D, Abozeid S, ... Glukhov AV, Eckhardt LL
Background
Arrhythmia syndromes associated withmutations have been described clinically; however, little is known of the underlying arrhythmia mechanism. We create the first patient inspiredtransgenic mouse and study effects of this mutation on cardiac function, , and Ca handling, to determine the underlying cellular arrhythmic pathogenesis.
Methods
A cardiac-specific -R67Q mouse was generated and bred for heterozygosity (R67Q). Echocardiography was performed at rest, under anesthesia. In vivo ECG recording and whole heart optical mapping of intact hearts was performed before and after adrenergic stimulation in wild-type (WT) littermate controls and R67Q mice.measurements, action potential characterization, and intracellular Ca imaging from isolated ventricular myocytes at baseline and after adrenergic stimulation were performed in WT and R67Q mice.
Results
R67Q mice (n=17) showed normal cardiac function, structure, and baseline electrical activity compared with WT (n=10). Following epinephrine and caffeine, only the R67Q mice had bidirectional ventricular tachycardia, ventricular tachycardia, frequent ventricular ectopy, and/or bigeminy and optical mapping demonstrated high prevalence of spontaneous and sustained ventricular arrhythmia. Both R67Q (n=8) and WT myocytes (n=9) demonstrated typical n-shapedrelationship; however, following isoproterenol, max outwardincreased by ≈20% in WT but decreased by ≈24% in R67Q (<0.01). R67Q myocytes (n=5) demonstrated prolonged action potential duration at 90% repolarization and after 10 nmol/L isoproterenol compared with WT (n=7; <0.05). Ca transient amplitude, 50% decay rate, and sarcoplasmic reticulum Ca content were not different between WT (n=18) and R67Q (n=16) myocytes. R67Q myocytes (n=10) under adrenergic stimulation showed frequent spontaneous development of early afterdepolarizations that occurred at phase 3 of action potential repolarization.
Conclusions
mutation R67Q causes adrenergic-dependent loss ofduring terminal repolarization and vulnerability to phase 3 early afterdepolarizations. This model clarifies a heretofore unknown arrhythmia mechanism and extends our understanding of treatment implications for patients withmutation.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008638
Reilly L, Alvarado FJ, Lang D, Abozeid S, ... Glukhov AV, Eckhardt LL
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008638 | PMID: 32931337
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Abstract

Office, central and ambulatory blood pressure for predicting incident atrial fibrillation in older adults.

Matsumoto K, Jin Z, Homma S, Elkind MSV, ... Sacco RL, Di Tullio MR
Objectives
Recently, more sophisticated blood pressure (BP) measurements, such as central and ambulatory BP (ABP), have proven to be stronger predictors of future cardiovascular disease than conventional office BP. Their predictive value for atrial fibrillation development is not established. We investigated the prognostic impact for incident atrial fibrillation of office, central and ambulatory BP measurements in a predominantly older population-based cohort.
Methods
Of 1004 participants in the Cardiovascular Abnormalities and Brain Lesions (CABL) study, 769 in sinus rhythm with no history of atrial fibrillation or stroke (mean age 70.5 years) underwent ABP and arterial wave reflection analysis for central BP determination. Fine and Gray\'s proportional subdistribution hazards models were used to assess the association of BP parameters with incident atrial fibrillation.
Results
During 9.5 years, atrial fibrillation occurred in 83 participants. No office BP variable showed a significant association with incident atrial fibrillation. Central SBP and central pulse pressure were marginally associated with incident atrial fibrillation in multivariate analysis. Among ABP variables, 24-h SBP [adjusted hazard ratio per 10 mmHg, 1.24; 95% confidence interval (CI) 1.07--1.44; P = 0.004], daytime SBP (adjusted hazard ratio per 10 mmHg, 1.21; 95% CI 1.04--1.40; P = 0.011) and night-time SBP (adjusted hazard ratio per 10 mmHg, 1.22; 95% CI 1.07--1.39; P = 0.002) were significantly associated with incident atrial fibillation.
Conclusion
In a predominantly older, stroke-free community-based cohort, ABP was a better independent predictor of incident atrial fibrillation than central BP, whereas office BP was inadequate for this purpose.



J Hypertens: 05 Oct 2020; epub ahead of print
Matsumoto K, Jin Z, Homma S, Elkind MSV, ... Sacco RL, Di Tullio MR
J Hypertens: 05 Oct 2020; epub ahead of print | PMID: 33031165
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Abstract

A Superior-type Fast-slow Atrioventricular Nodal Reentrant Tachycardia Phenotype Mimicking the Slow-fast Type.

Kaneko Y, Nakajima T, Tamura S, Hasegawa H, ... Iizuka T, Kurabayashi M

- Superior-type fast-slow (sup-F/S-) atrioventricular nodal reentrant tachycardia (AVNRT) is a rare AVNRT variant using a superior (sup-) slow pathway (SP) as the retrograde limb. Its intracardiac appearance, characterized by a short atrio-His (AH) interval and the earliest site of atrial activation in the His-bundle (HB; EAA-HB), is an initial indicator for making a diagnosis.- Among 22 consecutive patients with sup-F/S-AVNRT, three (age, 68-81 years) patients had an apparent but not typical slow-fast (S/F) AVNRT characterized by a long AH interval and EAA-HB (tachy-long-AH).- The diagnosis of sup-F/S-AVNRT was based on the standard criteria in two patients and on the occurrence of Wenckebach-type AV block during tachycardia, which was attributable to a block at the lower common pathway (LCP) below the circuit of the AVNRT, detected owing to the LCP potentials, in one patient. As with the typical S/F-AVNRT, tachy-long-AH was induced after a jump in the AH interval. In contrast to typical S/F-AVNRT, fluctuation in the ventriculoatrial interval was observed during the tachy-long-AH. Ventricular overdrive pacing was unable to entrain or terminate the tachy-long-AH. Moreover, the tachy-long-AH reciprocally transited to/from sup-F/S-AVNRT spontaneously or was triggered by ventricular contractions while the atrial cycle length and EAA remained unchanged. Both tachycardias were cured by ablation at a single site in the right-side parahisian region of two patients and the non-coronary aortic cusp of one patient. Collectively, the essential circuit of both tachycardias was identical, and the tachy-long-AH was diagnosed as another phenotype of sup-F/S-AVNRT accompanied by sustained antegrade conduction via another bystander SP breaking through the HB owing to the repetitive antegrade block at the LCP, thus representing a long AH interval during the ongoing sup-F/S-AVNRT.- An unknown sup-F/S-AVNRT phenotype exists that apparently mimics the typical S/F-AVNRT and is also an unknown subtype of apparent S/F-AVNRT.



Circ Arrhythm Electrophysiol: 30 Sep 2020; epub ahead of print
Kaneko Y, Nakajima T, Tamura S, Hasegawa H, ... Iizuka T, Kurabayashi M
Circ Arrhythm Electrophysiol: 30 Sep 2020; epub ahead of print | PMID: 33000970
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Abstract

Long-term Outcome of the Randomized Defibrillator After Primary Angioplasty (DAPA) Trial.

Haanschoten DM, Elvan A, Ramdat Misier AR, Delnoy PPHM, ... Verheugt FWA, Ottervanger JP

- The randomized Defibrillator After Primary Angioplasty (DAPA) trial aimed to evaluate the survival benefit of prophylactic implantable cardioverter defibrillator (ICD) implantation in early selected high-risk patients after primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI).- A randomized, multicenter, controlled trial compared ICD versus conventional medical therapy in high risk primary PCI patients, based on one of the following factors: left ventricular ejection fraction (LVEF) < 30% within 4 days after STEMI, primary ventricular fibrillation, Killip class ≥2 and/or TIMI flow < 3 after PCI. ICD was implanted 30-60 days after MI. Primary endpoint was all-cause mortality at 3 years follow-up. The trial prematurely ended after inclusion of 266 patients (38% of the calculated sample size). Additional survival assessment was performed in February 2019 for the primary endpoint.- A total of 266 patients, 78.2% males, with a mean age of 60.8 ± 11.3 years, were enrolled. 131 patients were randomized to the ICD arm and 135 patients to the control arm. All-cause mortality was significant lower in the ICD group (5% vs 13%, HR 0.37; 95% CI 0.15-0.95) after 3 years follow-up. Appropriate ICD therapy occurred in 9 patients at 3 years follow-up (5 within the first 8 months after implantation). After median long-term follow-up of 9 years (IQR, 3-11), total mortality (18% vs 38%, HR 0.58; 95% CI 0.37-0.91) and cardiac mortality (HR 0.52; 95% CI 0.28-0.99) was significant lower in the ICD group. Non-cardiac death was not significantly different between groups. LVEF increased ≥10% in 46.5% of the patients during follow up and the extent of improvement was similar in both study groups.- In this prematurely terminated and thus underpowered randomized trial, early prophylactic ICD implantation demonstrated lower total and cardiac mortality in high-risk STEMI patients treated with primary PCI.



Circ Arrhythm Electrophysiol: 30 Sep 2020; epub ahead of print
Haanschoten DM, Elvan A, Ramdat Misier AR, Delnoy PPHM, ... Verheugt FWA, Ottervanger JP
Circ Arrhythm Electrophysiol: 30 Sep 2020; epub ahead of print | PMID: 33003972
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Abstract

Safely Administering Potential QTc Prolonging Therapy Across a Large Healthcare System in the COVID-19 Era.

Saleh M, Gabriels J, Chang D, Fishbein J, ... Mountantonakis SE, Epstein LM

- The SARs-CoV-2 coronavirus has resulted in a global pandemic. Hydroxychloroquine ± azithromycin have been widely used to treat COVID-19 despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes (TdP) remains unknown. Widespread use of these medications forced overwhelmed healthcare systems to search for ways to effectively monitor these patients while simultaneously trying to minimize healthcare provider (HCP) exposure and use of personal protective equipment (PPE).- COVID-19 positive patients that received hydroxychloroquine ± azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest.- The primary outcome of TdP was observed in 1 (0.015%) out of 6,476 hospitalized COVID-19 patients receiving hydroxychloroquine ± azithromycin. Sixty-seven (1.03%) had hydroxychloroquine ± azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5ms from a baseline QTc of 473.7±35.9ms to a peak QTc of 532.6±31.6ms. Of these patients, hydroxychloroquine ± azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and HCP exposure was reduced.- The risk of torsade de pointes is low in hospitalized COVID-19 patients receiving hydroxychloroquine ± azithromycin therapy.



Circ Arrhythm Electrophysiol: 30 Sep 2020; epub ahead of print
Saleh M, Gabriels J, Chang D, Fishbein J, ... Mountantonakis SE, Epstein LM
Circ Arrhythm Electrophysiol: 30 Sep 2020; epub ahead of print | PMID: 33003964
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Abstract

Cardiac Inflammation Impedes Response to Cardiac Resynchronization Therapy in Patients with Idiopathic Dilated Cardiomyopathy.

Verdonschot JAJ, Merken JJ, van Stipdonk AMW, Pliger P, ... Heymans SRB, Hazebroek MR

- Cardiac resynchronization therapy (CRT) is an established therapy in patients with dilated cardiomyopathy (DCM) and conduction disorders. Still, one-third of the patients with DCM do not respond to CRT. This study aims to depict the underlying cardiac pathophysiological processes of non-response to CRT in DCM patients using endomyocardial biopsies (EMB).- Within the Maastricht and Innsbruck registries of DCM patients, 99 patients underwent EMB before CRT implantation, with histological quantification of fibrosis and inflammation, where inflammation was defined as >14 infiltrating cells/mm2. Echocardiographic left ventricular end-systolic volume (LVESV) reduction ≥15% after 6 months was defined as response to CRT. RNA was isolated from cardiac biopsies of a representative subset of responders and non-responders.- Sixty-seven patients responded (68%), whereas 32 (32%) did not respond to CRT. Cardiac inflammation prior to implantation was negatively associated with response to CRT (25% of responders, 47% of non-responders; odds ratio 0.3 [0.12-0.76]; p=0.01). EMB fibrosis did not relate to CRT response. Cardiac inflammation improved the robustness of prediction beyond well-known clinical predictors of CRT response (likelihood ratio test p<0.001). Cardiac transcriptomic profiling of EMB reveals a strong pro-inflammatory and pro-fibrotic signature in the hearts of non-responders compared to responders. In particular, , , , , , , , , , ,andwere significantly higher expressed in the hearts of non-responders.- Cardiac inflammation along with a transcriptomic profile of high expression of combined pro-inflammatory and pro-fibrotic genes are associated with a poor response to CRT in DCM patients.



Circ Arrhythm Electrophysiol: 29 Sep 2020; epub ahead of print
Verdonschot JAJ, Merken JJ, van Stipdonk AMW, Pliger P, ... Heymans SRB, Hazebroek MR
Circ Arrhythm Electrophysiol: 29 Sep 2020; epub ahead of print | PMID: 32997547
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Abstract

Risk Factors for Early Recurrence following Ablation for Accessory Pathways: The Role of Consolidation Lesions.

Dionne A, Gauvreau K, O\'Leary E, Mah DY, ... Triedman JK, Walsh EP

- Atrioventricular reentrant tachycardia is common in children. Catheter ablation is increasingly used as a first line therapy with a high acute success rate, but recurrence during follow-up remains a concern. The aim of this study was to identify risk factors for recurrence after accessory pathway (AP) ablation.- Retrospective cohort study including patients who underwent AP ablation between 2013-2018. Cox proportional hazards model were used to examine the association between patient and procedural characteristics and recurrence during follow-up.- From 558 AP ablation procedure, 542 (97%) were acutely successful. During a median follow-up of 0.4 [IQR 0.1, 1.4] years, there were 42 (8%) patients with documented recurrence. On univariate analysis, early recurrence was associated with younger age, congenital heart disease, multiple AP, AP location (right sided and postero-septal versus left sided), cryoablation (versus RF), empiric ablation, the lack of full power RF lesions (<50W), RF consolidation time < 90 seconds and the use of fluoroscopy without a 3-dimensional electroanatomic mapping system. On multivariable analysis, only multiple AP (HR 2.78 [95% CI 1.063, 4.74]) and RF consolidation time < 90 seconds (HR 4.38 [95% CI 1.92, 9.51]) remained significantly associated with early recurrence; this association remained true when analyzed in subgroups by pathway location for right and left free wall AP.- In our institutional experience, RF consolidation time < 90 seconds after ablation of AP was associated with an increased risk of early recurrence.



Circ Arrhythm Electrophysiol: 04 Oct 2020; epub ahead of print
Dionne A, Gauvreau K, O'Leary E, Mah DY, ... Triedman JK, Walsh EP
Circ Arrhythm Electrophysiol: 04 Oct 2020; epub ahead of print | PMID: 33017181
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Abstract

3D Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Predicts Inducibility of Ventricular Tachycardia in Adults with Repaired Tetralogy of Fallot.

Ghonim S, Ernst S, Keegan J, Giannakidis A, ... Gatzoulis MA, Babu-Narayan SV

- Adults with repaired tetralogy of Fallot (rTOF) die prematurely from ventricular tachycardia (VT) and sudden cardiac death. Inducible VT predicts mortality. Ventricular scar, the key substrate for VT, can be non-invasively defined with late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) but whether this relates to inducible VT is unknown.- Sixty-nine consecutive rTOF patients (43 male, mean 40{plus minus}15 years) clinically scheduled for invasive programmed VT-stimulation were prospectively recruited for prior 3D LGE CMR. Ventricular LGE was segmented and merged with reconstructed cardiac chambers and LGE volume measured.- VT was induced in 22(31%) patients. Univariable predictors of inducible VT included increased RV LGE (OR 1.15;p=0.001 per cm), increased non-apical vent LV LGE (OR 1.09;p=0.008 per cm), older age (OR 1.6;p=0.01 per decile), QRS duration ≥180ms (OR 3.5;p=0.02), history of non-sustained VT (OR 3.5; p=0.02) and previous clinical sustained VT (OR 12.8;p=0.003); only prior sustained VT (OR 8.02;p=0.02) remained independent in bivariable analyses after controlling for RV LGE volume (OR 1.14;p=0.003). An RV LGE volume of 25cm had 72% sensitivity and 81% specificity for predicting inducible VT (AUC 0.81;p<0.001). At the extreme cutoffs for \'ruling-out\' and \'ruling-in\' inducible VT, RV LGE >10cm was 100% sensitive and >36cm was 100% specific for predicting inducible VT.- 3D LGE CMR-defined scar burden is independently associated with inducible VT and may help refine patient selection for programmed VT-stimulation when applied to an at least intermediate clinical risk cohort.



Circ Arrhythm Electrophysiol: 05 Oct 2020; epub ahead of print
Ghonim S, Ernst S, Keegan J, Giannakidis A, ... Gatzoulis MA, Babu-Narayan SV
Circ Arrhythm Electrophysiol: 05 Oct 2020; epub ahead of print | PMID: 33022183
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Abstract

Digital Health and the Care of the Arrhythmia Patient; What Every Electrophysiologist Needs to Know.

Tarakji KG, Silva JNA, Chen LY, Turakhia MP, ... Wan EY, Chung MK

The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and healthcare apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.



Circ Arrhythm Electrophysiol: 05 Oct 2020; epub ahead of print
Tarakji KG, Silva JNA, Chen LY, Turakhia MP, ... Wan EY, Chung MK
Circ Arrhythm Electrophysiol: 05 Oct 2020; epub ahead of print | PMID: 33021815
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Abstract

The Clinical Application of the Deep Learning Technique for Predicting Trigger Origins in Paroxysmal Atrial Fibrillation Patients with Catheter Ablation.

Liu CM, Chang SL, Chen HH, Chen WS, ... Lu HH, Chen SA

- Non-pulmonary vein (NPV) trigger has been reported as an important predictor of recurrence post-atrial fibrillation (AF) ablation. Elimination of NPV triggers can reduce the recurrence of post-ablation AF. Deep learning was applied to pre-ablation pulmonary vein computed tomography (PVCT) geometric slices to create a prediction model for NPV triggers in patients with paroxysmal atrial fibrillation (PAF).- We retrospectively analyzed 521 PAF patients who underwent catheter ablation of PAF. Among them, PVCT geometric slices from 358 non-recurrent AF patients (1-3 mm interspace per slice, 20-200 slices for each patient, ranging from the upper border of the left atrium to the bottom of the heart, for a total of 23683 images of slices) were used in the deep learning process, the ResNet34 of the neural network, to create the prediction model of the NPV trigger. There were 298 (83.2%) patients with only pulmonary vein (PV) triggers and 60 (16.8%) patients with NPV triggers +/- PV triggers. The patients were randomly assigned to either training, validation or test groups and their data was allocated according to those sets. The image datasets were split into training (n=17340), validation (n=3491), and testing (n=2852) groups, which had completely independent sets of patients.- The accuracy of prediction in each PVCT image for NPV trigger was up to 82.4±2.0%. The sensitivity and specificity were 64.3±5.4% and 88.4±1.9%, respectively. For each patient, the accuracy of prediction for a NPV trigger was 88.6±2.3%. The sensitivity and specificity were 75.0±5.8% and 95.7±1.8%, respectively. The area under the curve (AUC) for each image and patient were 0.82±0.01 and 0.88±0.07, respectively.- The deep learning model using pre-ablation PVCT can be applied to predict the trigger origins in PAF patients receiving catheter ablation. The application of this model may identify patients with a high risk of NPV trigger before ablation.



Circ Arrhythm Electrophysiol: 05 Oct 2020; epub ahead of print
Liu CM, Chang SL, Chen HH, Chen WS, ... Lu HH, Chen SA
Circ Arrhythm Electrophysiol: 05 Oct 2020; epub ahead of print | PMID: 33021404
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Abstract

Long-term Outcomes of Left Atrial Appendage Electrical Isolation in Patients with Non-Paroxysmal Atrial Fibrillation: A Propensity Score-Matched Analysis.

Romero J, Di Biase L, Mohanty S, Trivedi C, ... Lakkireddy D, Natale A

- Left atrial appendage electrical isolation (LAAEI) has been proposed for the treatment of non-paroxysmal atrial fibrillation (AF). The long-term clinical outcomes and safety of this approach remain unclear. The objective of our study was to investigate the incremental benefit of LAAEI in patients undergoing catheter ablation (CA) for non-paroxysmal AF.- Propensity score-matched analysis was performed using a prospective registry database from 2010-2014. All patients in the LAAEI group were matched based on baseline characteristics, echocardiographic parameters, and procedural ablation techniques.- We identified 1842 patients who underwent CA for non-paroxysmal AF. Propensity score matching yielded 1092 patients, 546 patients with LAAEI and 546 patients without LAAEI. At 5-year follow-up, overall freedom from all-atrial arrhythmia recurrence, off-anti-arrhythmic drugs, in patients who underwent LAAEI was 68.9% vs. 50.2% in those who underwent standard ablation alone (p <0.001). Acute complication rates were similar between groups (LAAEI 1.3% vs. non-LAAEI 0.73%, p=0.36). At 5-year follow-up, 382 (70%) patients in the LAAEI group remained on oral anticoagulation (OAC) vs. 217 (39.7%) in the non-LAAEI group. No thromboembolic events occurred in either group on-OAC. In patients that were off-OAC, at 5-year follow-up, thromboembolic events occurred in 15/164 (9.1%) in the LAAEI group, and 4/329 (1.2%) in the non-LAAEI group (p < 0.001).- At 5-year follow-up, LAAEI was associated with significantly higher freedom from all-atrial arrhythmia recurrence in patients with persistent and long-standing persistent AF without increasing acute procedural complication rate. In patients off-OAC, there appears to be a higher risk of thromboembolic events in the LAAEI group.



Circ Arrhythm Electrophysiol: 29 Sep 2020; epub ahead of print
Romero J, Di Biase L, Mohanty S, Trivedi C, ... Lakkireddy D, Natale A
Circ Arrhythm Electrophysiol: 29 Sep 2020; epub ahead of print | PMID: 32998529
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Abstract

Magnetic Resonance Imaging-Guided Fibrosis Ablation for the Treatment of Atrial Fibrillation: The ALICIA Trial.

Bisbal F, Benito E, Teis A, Alarcón F, ... Bayés-Genis A, Mont L

Myocardial fibrosis is key for atrial fibrillation (AF) maintenance. We aimed to test the efficacy of ablating cardiac magnetic resonance (CMR)-detected atrial fibrosis plus pulmonary vein isolation (PVI).- This was an open label, parallel-group, randomized, controlled trial. Patients with symptomatic drug-refractory AF (paroxysmal and persistent) undergoing first or repeat ablation were randomized in a 1:1 basis to receive PVI plus CMR-guided fibrosis ablation (CMR group) or PVI alone (PVI-alone group). The primary endpoint was the rate of recurrence (>30 seconds) at 12 months of follow-up using a 12-lead ECG and Holter monitoring at 3, 6, and 12 months. The analysis was conducted by intention-to-treat.- In total, 155 patients (71% male, age 59±10, CHA2DS2-VASc 1.3±1.1, 54% Paroxysmal AF) were allocated to the PVI-alone group (N=76) or CMR group (N=79). First ablation was performed in 80% and 71% of patients in the PVI-alone and CMR groups, respectively. The mean atrial fibrosis burden was 12% (only 〜50% of patients had fibrosis outside the pulmonary vein area). 100% and 99% of patients received the assigned intervention in the PVI-alone and CMR group, respectively. The primary outcome was achieved in 21 patients (27.6%) in the PVI-alone group and 22 patients (27.8%) in the CMR group (odds ratio[OR]: 1.01, 95% confidence interval [CI] 0.50-2.04; p=0.976). There were no differences in the rate of adverse events (3 in the CMR group and 2 in the PVI-alone group; p=0.68).- A pragmatic ablation approach targeting CMR-detected atrial fibrosis plus PVI was not more effective than PVI alone in an unselected population undergoing AF ablation with low fibrosis burden.



Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print
Bisbal F, Benito E, Teis A, Alarcón F, ... Bayés-Genis A, Mont L
Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print | PMID: 33031713
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Abstract

A Cross-Center Virtual Education Fellowship Program for Early-Career Researchers in Atrial Fibrillation.

Ajayi TB, Remein CD, Stafford RS, Fagerlin A, ... Childs E, Benjamin EJ

- It is estimated that over 46 million individuals have atrial fibrillation (AF) worldwide, and the incidence and prevalence of AF are increasing globally. There is an urgent need to accelerate the academic development of scientists possessing the skills to conduct innovative, collaborative AF research.- We designed and implemented a virtual AF Strategically Focused Research Network (SFRN) Cross-Center Fellowship program to enhance the competencies of early-stage AF basic, clinical, and population health researchers through experiential education and mentorship. The pedagogical model involves significant cross-Center collaboration to produce a curriculum focused on enhancing AF scientific competencies, fostering career/professional development, and cultivating grant writing skills. Outcomes for success involve clear expectations for fellows to produce manuscripts, presentations, and-for those at the appropriate career stage-grant applications. We evaluated the effectiveness of the fellowship model via mixed methods formative and summative surveys.- In two years of the fellowship, fellows generally achieved the productivity metrics sought by our pedagogical model, with outcomes for the twelve fellows including 50 AF-related manuscripts, 7 publications, 28 presentations, and 3 grant awards applications. Participant evaluations reported that the fellowship effectively met its educational objectives. All fellows reported medium to high satisfaction with the overall fellowship, webinar content and facilitation, staff communication and support, and program organization.- The fellowship model represents an innovative educational strategy by providing a virtual AF training and mentoring curriculum for early-career basic, clinical, and population health scientists working across multiple institutions, which is particularly valuable in the pandemic era.



Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print
Ajayi TB, Remein CD, Stafford RS, Fagerlin A, ... Childs E, Benjamin EJ
Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print | PMID: 33031707
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Abstract

Histopathologic and Ultrastructural Findings in Human Myocardium after Stereotactic Body Radiation Therapy for Recalcitrant Ventricular Tachycardia.

Kiani S, Kutob L, Schneider F, Higgins KA, Lloyd MS

- Stereotactic body radiation therapy (SBRT) is a novel treatment for refractory ventricular tachycardia (VT). While outcomes have been described in small studies, histological findings after SBRT for VT are unknown.- We identified four explanted hearts in the context of transplant who received prior SBRT as part of an 11-patient compassionate use series at our institution. Clinical VTs and CT-defined target volume areas of SBRT were correlated to the anatomic specimens. Gross pathologic, histologic and ultrastructural examination of tissue in the target area of SBRT were performed.- All four patients had NICM, and three had left ventricular assist devices. In all cases, patients had recurrent sustained VT and had failed multiple antiarrhythmics and radiofrequency ablations. Four patients underwent 5 total SBRT therapy session with 25 Gy single fraction dose delivered to the area of culprit scar. The time from SBRT to explant ranged from 12-250 days. Histopathologic features following radiation were comparable in all patients and were characterized by areas of subendocardial necrosis surrounded by a rim of fibrosis. In one patient, the surrounding myocardium showed cytoplasmic vacuolization in myocytes and in another patchy interstitial fibrosis. Vascular changes consisted of myointimal thickening with prominence of endothelial cells. Electron microscopy (EM) of myocardium showed irregular, convoluted intercalated disc regions, loss of contractile elements with disrupted and haphazardly arranged myofibrils and edematous mitochondria with loss of cisternae.- Here, we report the first series of findings in human tissue in four patients after SBRT. Histopathologic features were consistent across all four patients, and were indicative of cell injury, death, and to a lesser extent, fibrosis. EM demonstrated features consistent with acute injury. These specimens provide radiobiological mechanisms of acute cellular injury during SBRT for VT which may have an antiarrhythmic effect prior to the onset of fibrosis.



Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print
Kiani S, Kutob L, Schneider F, Higgins KA, Lloyd MS
Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print | PMID: 33031001
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Abstract

Social Media Influence Does Not Reflect Scholarly or Clinical Activity in Real Life.

Zenger B, Swink JM, Turner JL, Bunch TJ, ... Piccini JP, Steinberg BA

- Social media has become a major source of communication in medicine. We aimed to understand the relationship between physicians\' social media influence and their scholarly and clinical activity.- We identified attending, US electrophysiologists on Twitter. We compared physician Twitter activity to (a) scholarly publication record (h-index) and (b) clinical volume according to CMS. The ratio of observed vs. expected Twitter followers (obs/exp) was calculated based on each scholarly (K-index) and clinical activity.- We identified 284 physicians, with mean Twitter age of 5.0 (SD 3.1) years and median 568 followers (25, 75: 195, 1146). They had a median 34.5 peer-reviewed papers (25, 75: 14, 105), 401 citations (25, 75: 102, 1677), and h-index 9 (25, 75: 4, 19.8). The median K-index was 0.4 (25, 75: 0.15, 1.0), ranging 0.0008 - 29.2. The median EP procedures was 77 (25, 75: 0, 160) and E&M visits 264 (25, 75: 59, 516) in 2017. The top 1% electrophysiologists for followers accounted for 20% of all followers, 17% of status updates, had a mean h-index of 6 (vs. 15 for others, p=0.3), and accounted for 1% of procedural and E&M volumes. They had a mean K-index of 21 (vs. 0.77 for others, p<0.0001), and clinical obs/exp follower ratio of 17.9 and 18.1 for procedures and E&M (p<0.001 each, vs. others [0.81 for each]).- Electrophysiologists are active on Twitter, with modest influence often representative of scholarly and clinical activity. However, the most influential physicians appear to have relatively modest scholarly and clinical activity.



Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print
Zenger B, Swink JM, Turner JL, Bunch TJ, ... Piccini JP, Steinberg BA
Circ Arrhythm Electrophysiol: 07 Oct 2020; epub ahead of print | PMID: 33030380
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Abstract

Left Ventricular Enlargement, CRT Response and Impact of MultiPoint Pacing.

Varma N, Baker Ii J, Tomassoni G, Love CJ, ... Lee K, Corbisiero R

- Left ventricular (LV) epicardial pacing results in slowly propagating paced wavefronts. We postulated that this effect might limit cardiac resynchronization therapy (CRT) efficacy in patients with LV enlargement using conventional biventricular (BiV) pacing with single-site LV pacing, but be mitigated by LV stimulation from 2 widely spaced sites using MultiPoint™ Pacing (MPP-AS: anatomical separation ≥ 30mm). We tested this hypothesis in the multicenter randomized MPP IDE trial.- Following implant, quadripolar BiV pacing was activated in all patients (n=506). From 3 to 9 months postimplant, among patients with available baseline LV end-diastolic volume (LVEDV) measures, 188 received BiV pacing, and 43 received MPP-AS. Patients were dichotomized by median baseline LVEDV indexed to height (LVEDVI). Outcomes were measured by the clinical composite score (CCS, primary efficacy endpoint), quality of life (QOL), LV structural remodeling (↑EF>5% and ↓ESV 10%) and heart failure (HF) event/ cardiovascular death.- LVEDVI was 1.1 mL/cm. Baseline characteristics differed in patients with LVEDVI vs. LVEDVI. Among patients with LVEDVI, BiV was less efficacious compared to patients with LVEDVI (CCS 65% vs. 79%). In contrast, MPP-AS programming generated greater CCS response (92% vs. 65%, p=0.023) and improved QOL (-31.0±29.7 vs. -15.7±22.1, p=0.038) vs. BiV in patients with LVEDVI. Reverse remodeling trended better with MPP-AS programming. When LVEDVI, HF event rate increased following the 3-month randomization point (0.0150±0.1725 in LVEDVI vs. -0.0190±0.0808 in LVEDVI, p=0.012) in BiV, but no heart failure event occurred in patients with MPP-AS programming between 3 and 9 months in LVEDVI. All measured outcomes did not differ in patients receiving MPP-AS and BiV pacing with LVEDVI.- Conventional BiV pacing, even with a quadripolar lead, has reduced efficacy in patients with LV enlargement. However, in patients with larger hearts and programmed to MPP-AS the greatest response rate was observed.



Circ Arrhythm Electrophysiol: 06 Oct 2020; epub ahead of print
Varma N, Baker Ii J, Tomassoni G, Love CJ, ... Lee K, Corbisiero R
Circ Arrhythm Electrophysiol: 06 Oct 2020; epub ahead of print | PMID: 33028082
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Abstract

Malignant Arrhythmias in Patients with COVID-19: Incidence, Mechanisms and Outcomes.

Turagam MK, Musikantow D, Goldman ME, Bassily-Marcus A, ... Kohli-Seth R, Reddy VY

- Patients with coronavirus disease 2019 (COVID-19) who develop cardiac injury are reported to experience higher rates of malignant cardiac arrhythmias. However, little is known about these arrhythmias - their frequency, the underlying mechanisms, and their impact on mortality.- We extracted data from a registry (NCT04358029) regarding consecutive inpatients with confirmed COVID-19, were receiving continuous telemetric ECG monitoring, and had a definitive disposition of hospital discharge or death. Between patients who died versus discharged, we compared a primary composite endpoint of cardiac arrest from ventricular tachycardia/fibrillation or bradyarrhythmias such as atrio-ventricular block.- Among 800 COVID-19 patients at Mount Sinai Hospital with definitive dispositions, 140 patients had telemetric monitoring and either died (52) or were discharged (88). The median (IQR) age was 61 years (48 - 74); 73% men; and ethnicity was Caucasian in 34%. Comorbidities included hypertension in 61%, coronary artery disease in 25%, ventricular arrhythmia history in 1.4%, and no significant comorbidities in 16%. Compared to discharged patients, those who died had elevated peak troponin I levels (0.27 vs 0.02 ng/mL), and more primary endpoint events (17% vs 4%, p = 0.01), a difference driven by tachyarrhythmias. Fatal tachyarrhythmias invariably occurred in the presence of severe metabolic imbalance, while atrioventricular block was largely an independent primary event.- Hospitalized COVID-19 patients who die experience malignant cardiac arrhythmias more often than those surviving to discharge. However, these events represent a minority of cardiovascular deaths, and ventricular tachyarrhythmias are mainly associated with severe metabolic derangement.



Circ Arrhythm Electrophysiol: 06 Oct 2020; epub ahead of print
Turagam MK, Musikantow D, Goldman ME, Bassily-Marcus A, ... Kohli-Seth R, Reddy VY
Circ Arrhythm Electrophysiol: 06 Oct 2020; epub ahead of print | PMID: 33026892
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Abstract

Automated blood pressure measurement in atrial fibrillation: validation process modification and evaluation of a novel professional device which detects atrial fibrillation and adapts its blood pressure measurement algorithm.

Stergiou GS, Kyriakoulis KG, Bountzona I, Menti A, ... Kalogeropoulos P, Kollias A
Objectives
Blood pressure (BP) measurement in atrial fibrillation (AF) patients is problematic and automated monitors are regarded as inaccurate. The optimal procedure for validating BP monitors in AF is questionable. This study evaluated the accuracy of a novel professional oscillometric upper-arm cuff device (Microlife WatchBP Office), which has an algorithm for detecting AF and then applies an AF-specific BP measurement algorithm. BP variability, which is inherently increased in AF patients, was considered in the analysis.
Methods
Subjects with sustained AF were included in a validation study using the same arm sequential measurement method of the Universal Standard (ISO 81060-2:2018) for special populations. Analysis was performed in all subjects and separately in those with and without high reference BP variability (>12/8 mmHg SBP/DBP).
Results
Thirty-five subjects with 105 paired test/reference BP measurements were included (mean age 76.3 ± 8.4 years, reference SBP/DBP 128.2 ± 19.5/72.5 ± 12.1 mmHg, pulse rate 68.3 ± 14.9 bpm). Validation Criterion 1 (mean difference ± SD) was 0.0 ± 7.7/0.2 ± 7.0 mmHg in all 105 BP pairs (threshold ≤5 ± 8 mmHg). Criterion 1 was 0.5 ± 6.1/-0.2 ± 6.8 mmHg in 18 subjects (54 BP pairs) with low reference BP variability and -0.6 ± 9.2/0.6 ± 7.3 mmHg in 17 (51 pairs) with high variability. Criterion 1 did not differ in pulse rate < 70 vs. ≥ 70 bpm Validation Criterion 2 (SD of differences for 35 individuals) was 5.38/6.20 mmHg (SBP/DBP; threshold ≤6.95/6.95).
Conclusion
A technology which detects AF and activates an AF-specific BP measurement algorithm introduces a challenging solution for clinical practice. Validation of BP monitors in AF patients should not ignore their inherently high BP variability.



J Hypertens: 15 Oct 2020; epub ahead of print
Stergiou GS, Kyriakoulis KG, Bountzona I, Menti A, ... Kalogeropoulos P, Kollias A
J Hypertens: 15 Oct 2020; epub ahead of print | PMID: 33060450
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Abstract

Reduction in Pulmonary Vein Stenosis and Collateral Damage With Pulsed Field Ablation Compared With Radiofrequency Ablation in a Canine Model.

Howard B, Haines DE, Verma A, Packer D, ... Miklavčič D, Stewart MT
Background
Pulmonary vein (PV) stenosis is a highly morbid condition that can result after catheter ablation for PV isolation. We hypothesized that pulsed field ablation (PFA) would reduce PV stenosis risk and collateral injury compared with irrigated radiofrequency ablation (IRF).
Methods
IRF and PFA deliveries were randomized in 8 dogs with 2 superior PVs ablated using one technology and 2 inferior PVs ablated using the other technology. IRF energy (25-30 W) or PFA was delivered (16 pulse trains) at each PV in a proximal and in a distal site. Contrast computed tomography scans were collected at 0, 2, 4, 8, and 12-week (termination) time points to monitor PV cross-sectional area at each PV ablation site.
Results
Maximum average change in normalized cross-sectional area at 4-weeks was -46.1±45.1% post-IRF compared with -5.5±20.5% for PFA (≤0.001). PFA-treated targets showed significantly fewer vessel restrictions compared with IRF (≤0.023). Necropsy showed expansive PFA lesions without stenosis in the proximal PV sites, compared with more confined and often incomplete lesions after IRF. At the distal PV sites, only IRF ablations were grossly identified based on focal fibrosis. Mild chronic parenchymal hemorrhage was noted in 3 left superior PV lobes after IRF. Damage to vagus nerves as well as evidence of esophagus dilation occurred at sites associated with IRF. In contrast, no lung, vagal nerve, or esophageal injury was observed at PFA sites.
Conclusions
PFA significantly reduced risk of PV stenosis compared with IRF postprocedure in a canine model. IRF also caused vagus nerve, esophageal, and lung injury while PFA did not.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008337
Howard B, Haines DE, Verma A, Packer D, ... Miklavčič D, Stewart MT
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008337 | PMID: 32877256
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Abstract

Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation.

McCauley MD, Hong L, Sridhar A, Menon A, ... Rehman J, Darbar D
Background
Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing , and enhancing susceptibility to AF.
Methods
To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F-isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes.
Results
Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls (<0.01) with increased AF burden. Cardiac sodium channel expression,and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current () and F-isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored , , , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls.
Conclusions
Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008296
McCauley MD, Hong L, Sridhar A, Menon A, ... Rehman J, Darbar D
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008296 | PMID: 32654503
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Abstract

Complete Electroanatomic Imaging of the Diastolic Pathway Is Associated With Improved Freedom From Ventricular Tachycardia Recurrence.

Hadjis A, Frontera A, Limite LR, Bisceglia C, ... Calore F, Della Bella P
Background
The development of multielectrode mapping catheters has expanded the spectrum of mappable ventricular tachycardias (VTs). Full diastolic pathway recording has been associated with a high rate of VT termination during radiofrequency ablation as well as noninducibility at study end. However, the role of diastolic pathway mapping on VT recurrence has yet to be clearly elucidated. We aimed to explore the role of complete diastolic pathway activation mapping on VT recurrence.
Methods
Eighty-five consecutive patients who underwent VT ablation guided by high-density mapping were enrolled. During activation mapping, the presence of electrical activity in all segments of diastole defined the evidence of having had recorded the whole diastolic interval. Patients were categorized as having recorded the full diastolic pathway, partial diastolic pathway, or no diastolic pathway map performed. Recurrences of VT were defined as appropriate implantable cardioverter defibrillator therapies or on the basis of ECG-documented arrhythmia.
Results
Eighty-five patients were included. Complete recording of the diastolic pathway was achieved in 36/85 (42.4%) patients. Partial recording of the diastolic pathway of the clinical VT was achieved in 24/85 (28.2%) patients. No recording of the diastolic pathway of the clinical VT was feasible in 25/85 patients (29.4%). At a mean of 12.8 months, freedom from VT recurrence was 67% in the overall cohort. At a mean of 12.8 months, freedom from VT recurrence was 88%, 50%, and 55% in patients who had full diastolic activity recorded, partial diastolic activity recorded, or underwent substrate modification, respectively; the observed differences were statistically significant (=0.02).
Conclusions
Mapping of the entire diastolic pathway was associated with a higher freedom from VT recurrence as compared with partial diastolic pathway recording and substrate modification. The use of multielectrode mapping catheters in recording diastolic activity may help predict those VTs employing intramural circuits and further optimize ablation strategies.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008651
Hadjis A, Frontera A, Limite LR, Bisceglia C, ... Calore F, Della Bella P
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008651 | PMID: 32755381
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Abstract

Novel CineECG Derived From Standard 12-Lead ECG Enables Right Ventricle Outflow Tract Localization of Electrical Substrate in Patients With Brugada Syndrome.

van Dam PM, Locati ET, Ciconte G, Borrelli V, ... Anastasia L, Pappone C
Background
In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS.
Methods
The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined.
Results
In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results.
Conclusions
In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008524
van Dam PM, Locati ET, Ciconte G, Borrelli V, ... Anastasia L, Pappone C
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008524 | PMID: 32755392
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Abstract

Cardiac Emerinopathy: A Non-syndromic Nuclear Envelopathy with Increased Risk of Thromboembolic Stroke due to Progressive Atrial Standstill and Left Ventricular Non-compaction.

Ishikawa T, Mishima H, Barc J, Takahashi MP, ... Schott JJ, Makita N

- Mutations in the nuclear envelope genes encoding lamin A/C () and emerin () are responsible for Emery-Dreifuss muscular dystrophy. However,mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the other hand, the phenotypic spectrums ofmutations are less clear. Our aims were to determine the prevalence of non-syndromic forms of emerinopathy which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated withmutations.- Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51).- We identified three X-linked recessivemutations (start-loss, splicing, missense) in families with cardiac conduction disease. All three probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular non-compaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC withhas never been reported, we further genetically screened 102 LVNC patients, and found a frameshiftmutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All six malemutation carriers of four families underwent pacemaker or defibrillator implantation, whereas two female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC.- Cardiac emerinopathy is a novel non-syndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.



Circ Arrhythm Electrophysiol: 28 Jul 2020; epub ahead of print
Ishikawa T, Mishima H, Barc J, Takahashi MP, ... Schott JJ, Makita N
Circ Arrhythm Electrophysiol: 28 Jul 2020; epub ahead of print | PMID: 32755394
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Abstract

Electrical Posterior Box Isolation in Persistent Atrial Fibrillation Changed to Paroxysmal Atrial Fibrillation: A Multicenter, Prospective, Randomized Study.

Pak HN, Park J, Park JW, Yang SY, ... Kim YH, Shim J
Background
Persistent atrial fibrillation (AF) can change to paroxysmal AF after antiarrhythmic drug medication and cardioversion. We investigated whether electrical posterior box isolation (POBI) may improve rhythm outcome of catheter ablation in those patient groups.
Methods
We prospectively randomized 114 patients with persistent AF to paroxysmal AF (men, 75%; 59.8±9.9 years old) to circumferential pulmonary vein isolation (CPVI) alone group (n=57) and additional POBI group (n=57). Primary end point was AF recurrence after a single procedure, and secondary end points were recurrence pattern, cardioversion rate, and response to antiarrhythmic drugs.
Results
After a mean follow-up of 23.8±10.2 months, the clinical recurrence rate did not significantly differ between the CPVI alone and additional POBI group (31.6% versus 28.1%; =0.682; log-rank =0.729). The recurrences as atrial tachycardias (5.3% versus 12.3%; =0.134) and cardioversion rates (5.3% versus 10.5%; =0.250) were not significantly different between the CPVI and POBI groups. At the final follow-up, sinus rhythm was maintained without antiarrhythmic drug in 52.6% of CPVI group and 59.6% of POBI group (=0.450). No significant difference was found in major complication rates between the two groups (5.3% versus 1.8%; =0.618), but the total ablation time was significantly longer in the POBI group (4187±952 versus 5337±1517 s; <0.001).
Conclusions
In patients with persistent AF converted to paroxysmal AF by antiarrhythmic drug, the addition of POBI to CPVI did not improve the rhythm outcome of catheter ablation or influence overall safety, while leading to longer ablation time. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02176616.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008531
Pak HN, Park J, Park JW, Yang SY, ... Kim YH, Shim J
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008531 | PMID: 32755396
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Abstract

Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates.

Sattayaprasert P, Vasireddi SK, Bektik E, Jeon O, ... Fu J, Laurita KR

- The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac hMSCs remodels and can regulate arrhythmia substrates.- Human cardiac MSCs (hMSCs) were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or non-failing hMSCs were co-cultured with normal human myocytes (hCM) derived from induced pluripotent stem cells. Using fluorescent indicators, APD, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined.- Failing and non-failing hMSCs from both sources exhibited similar tri-lineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared to non-failing hMSCs, failing hMSCs prolonged APD by 24% (p<0.001, n=15), increased Ca2+ alternans by 300% (p<0.001, n=18), and promoted SCR activity (n=14, p <0.013) in hCM. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL-1β (98%, p<0.0001) and IL-6 (460%, p <0.02) compared to non-failing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged APD but only IL-6 increased Ca2+ alternans and promoted SCR activity in hCM, replicating the effects of failing hMSCs. In contrast, non-failing hMSCs prevented Ca2+ alternans in hCM during oxidative stress. Finally, non-failing hMSCs exhibited >25 times higher secretion of IGF-1 compared to failing hMSCs. Importantly, IGF-1 supplementation or anti-IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs.- We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti-IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.



Circ Arrhythm Electrophysiol: 28 Jul 2020; epub ahead of print
Sattayaprasert P, Vasireddi SK, Bektik E, Jeon O, ... Fu J, Laurita KR
Circ Arrhythm Electrophysiol: 28 Jul 2020; epub ahead of print | PMID: 32755466
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Abstract

Stabilizer Cell Gene Therapy: A Less-Is-More Strategy to Prevent Cardiac Arrhythmias.

Liu MB, Priori SG, Qu Z, Weiss JN
Background
In cardiac gene therapy to improve contractile function, achieving gene expression in the majority of cardiac myocytes is essential. In preventing cardiac arrhythmias, however, this goal may not be as important since transduction efficiencies as low as 40% suppressed ventricular arrhythmias in genetically modified mice with catecholaminergic polymorphic ventricular tachycardia.
Methods
Using computational modeling, we simulated 1-, 2-, and 3-dimensional tissue under a variety of conditions to test the ability of genetically engineered nonarrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarizations.
Results
Due to source-sink relationships in cardiac tissue, a minority (20%-50%) of randomly distributed stabilizer cells engineered to be nonarrhythmogenic can suppress the ability of arrhythmogenic cells to generate delayed and early afterdepolarizations-related arrhythmias. Stabilizer cell gene therapy strategy can be designed to correct a specific arrhythmogenic mutation, as in the catecholaminergic polymorphic ventricular tachycardia mice studies, or more generally to suppress delayed or early afterdepolarizations from any cause by overexpressing the inward rectifier K channel Kir2.1 in stabilizer cells.
Conclusions
This promising antiarrhythmic strategy warrants further testing in experimental models to evaluate its clinical potential.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008420
Liu MB, Priori SG, Qu Z, Weiss JN
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008420 | PMID: 32718183
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Abstract

Flutter Wave Morphology of Peri-Mitral Atrial Flutters Is Mainly Determined by Right Atrial Activation: Insights From High-Resolution Mapping.

Hu W, Zhou D, Hua B, Yang G, ... Zheng L, Chen M
Background
Peri-mitral atrial flutters frequently develop post-atrial fibrillation ablation or postcardiac surgery. The determinants of the flutter wave morphology on surface ECG have been less studied.
Methods
We retrospectively reviewed 24 patients with peri-mitral atrial flutters who underwent biatrial high-resolution mapping at 3 institutions with LUMIPOINT software. We analyzed the overlap between the right atrial (RA) activation time and flutter wave duration and compared the proportion of the endocardial area that was activated in both atria during the flutter wave duration. Biatrial activation patterns and interatrial conductions were also identified.
Results
The mean tachycardia cycle length was 264±60 ms, with RA activation time 155±45 ms (60.8±20.6% of the tachycardia cycle length), and the flutter wave duration 107±31 ms (41.6±11.7% of the tachycardia cycle length). The overlap between the RA activation time and the flutter wave duration was 102±29 ms, which takes 68.5±17.2% of the RA activation time and 95.7±9.1% of the flutter wave duration, respectively. Quantitative analysis also showed that during the flutter wave duration, more percentage of the endocardial area was activated in the RA than in the left atrium (73.0±12.7% versus 45.2±13.0%, <0.001). We consistently observed that the RA anterior wall rightward activation corresponded to the positive component in V1 in both flutter patterns, and the RA downward activation corresponded to the positive component in the counterclockwise group or the upward activation corresponded to the negative component in the clockwise group in the inferior leads. The passive RA activation patterns were varied with spontaneous atrial scarring or previous linear ablation.
Conclusions
ECG flutter wave morphology of peri-mitral atrial flutters is mainly dependent on RA activation patterns.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008446
Hu W, Zhou D, Hua B, Yang G, ... Zheng L, Chen M
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008446 | PMID: 32718185
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Abstract

Family History of Atrial Fibrillation and Risk of Cardiovascular Events: A Multicenter Prospective Cohort Study.

Pastori D, Menichelli D, Lip GYH, Sciacqua A, ... Pignatelli P,
Background
To investigate the association between family history of atrial fibrillation (AF) with cardiovascular events (CVEs), major adverse cardiac events (MACE), and cardiovascular mortality.
Methods
Multicenter prospective observational cohort study including 1722 nonvalvular AF patients from February 2008 to August 2019 in Italy. Family history of AF was defined as the presence of AF in a first-degree relative: mother, father, sibling, or children. Primary outcome was a composite of CVEs including fatal/nonfatal ischemic stroke and myocardial infarction, and cardiovascular death. Second, we analyzed the association with major adverse cardiac event.
Results
Mean age was 74.6±9.4 years; 44% of women. Family history of AF was detected in 368 (21.4%) patients, and 3.5% had ≥2 relatives affected by AF. Age of AF onset progressively decreased from patients without family history of AF, compared with those with single and multiple first-degree affected relatives (<0.001). During a mean follow-up of 23.7 months (4606 patients/y) 145 CVEs (3.15%/y), 98 major adverse cardiac event (2.13%/y), and 57 cardiovascular deaths (0.97%/y) occurred. After adjustment for cardiovascular risk factors, family history of AF was associated with a higher risk of CVEs (hazard ratio, 1.524 [95% CI, 1.021-2.274], =0.039), major adverse cardiac event (hazard ratio, 1.917 [95% CI, 1.207-3.045], =0.006), and cardiovascular mortality (hazard ratio, 2.008 [95% CI, 1.047-3.851], =0.036). Subgroup analysis showed that this association was modified by age, sex, and prior ischemic heart disease.
Conclusions
In a cohort of elderly patients with a high atherosclerotic burden, family history of AF is evident in >20% of patients and was associated with an increased risk for CVEs and mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01882114.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008477
Pastori D, Menichelli D, Lip GYH, Sciacqua A, ... Pignatelli P,
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008477 | PMID: 32718257
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Abstract

Incidence and Predictors of Very Late Recurrence of Atrial Fibrillation Following Cryoballoon Pulmonary Vein Isolation.

Musat DL, Milstein NS, Bhatt A, Sichrovsky TC, ... Shaw RE, Mittal S
Background
A very late recurrence (VLR) of atrial fibrillation (AF) is considered present when the first recurrence of AF occurs ≥12 months following ablation. Prior studies characterizing VLR have not used an implantable loop recorder for ECG monitoring. Thus, it is unknown whether VLR truly occurs or whether these patients have simply had unrecognized AF. Our objective was to assess the incidence and predictors of VLR in patients who underwent cryoballoon pulmonary vein isolation alone, had an implantable loop recorder, and were confirmed AF free for at least 1 year.
Methods
We enrolled consecutive patients with paroxysmal or persistent AF who underwent cryoballoon pulmonary vein isolation and had an implantable loop recorder implanted <3 months post-ablation. Patients free of AF 1 year post-ablation were followed prospectively for recurrent AF. All AF episodes were adjudicated.
Results
We included 188 patients (66±10 years; 116 [62%] men; 102 [54%] paroxysmal AF; CHADS-VASc, 2.6±1.7). After 1 year post-pulmonary vein isolation, 93 (49%) patients remained AF free. During subsequent follow-up, 30 (32%) patients had VLR of AF. The only independent risk factor for VLR was an elevated CHADS-VASc score (hazard ratio, 1.317 [95% CI, 1.033-1.6979]; =0.026). Patients with CHADS-VASc score ≥4 represented a quarter of the population and were at the highest risk.
Conclusions
Our data using implantable loop recorders for continuous ECG monitoring post-AF ablation show that VLR occurs in a third of patients after an apparently successful cryoballoon pulmonary vein isolation procedure. Additional strategies are needed to ensure long-term freedom from AF recurrences in these high-risk patients.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008646
Musat DL, Milstein NS, Bhatt A, Sichrovsky TC, ... Shaw RE, Mittal S
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008646 | PMID: 32703009
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Abstract

Procedural Patterns and Safety of Atrial Fibrillation Ablation: Findings From Get With The Guidelines-Atrial Fibrillation.

Loring Z, Holmes DN, Matsouaka RA, Curtis AB, ... Lewis WR, Piccini JP
Background
Catheter ablation is an increasingly used treatment for symptomatic atrial fibrillation (AF). However, there are limited prospective, nationwide data on patient selection and procedural characteristics. This study describes patient characteristics, techniques, treatment patterns, and safety outcomes of patients undergoing AF ablation.
Methods
A total of 3139 patients undergoing AF ablation between 2016 and 2018 in the Get With The Guidelines-Atrial Fibrillation registry from 24 US centers were included. Patient demographics, medical history, procedural details, and complications were abstracted. Differences between paroxysmal and patients with persistent AF were compared using Pearson χ and Wilcoxon rank-sum tests.
Results
Patients undergoing AF ablation were predominantly male (63.9%) and White (93.2%) with a median age of 65. Hypertension was the most common comorbidity (67.6%), and patients with persistent AF had more comorbidities than patients with paroxysmal AF. Drug refractory, paroxysmal AF was the most common ablation indication (class I, 53.6%) followed by drug refractory, persistent AF (class I, 41.8%). Radiofrequency ablation with contact force sensing was the most common ablation modality (70.5%); 23.7% of patients underwent cryoballoon ablation. Pulmonary vein isolation was performed in 94.6% of de novo ablations; the most common adjunctive lesions included left atrial roof or posterior/inferior lines, and cavotricuspid isthmus ablation. Complications were uncommon (5.1%) and were life-threatening in 0.7% of cases.
Conclusions
More than 98% of AF ablations among participating sites are performed for class I or class IIA indications. Contact force-guided radiofrequency ablation is the dominant technique and pulmonary vein isolation the principal lesion set. In-hospital complications are uncommon and rarely life-threatening.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e007944
Loring Z, Holmes DN, Matsouaka RA, Curtis AB, ... Lewis WR, Piccini JP
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e007944 | PMID: 32703018
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Abstract

Aging Disrupts Normal Time-of-Day Variation in Cardiac Electrophysiology.

Wang Z, Tapa S, Francis Stuart SD, Wang L, ... Delisle BP, Ripplinger CM
Background
Cardiac gene expression and arrhythmia occurrence have time-of-day variation; however, daily changes in cardiac electrophysiology, arrhythmia susceptibility, and Ca handling have not been characterized. Furthermore, how these patterns change with age is unknown.
Methods
Hearts were isolated during the light (zeitgeber time [ZT] 4 and ZT9) and dark cycle (ZT14 and ZT21) from adult (12-18 weeks) male mice. Hearts from aged (18-20 months) male mice were isolated at ZT4 and ZT14. All hearts were Langendorff-perfused for optical mapping with voltage- and Ca-sensitive dyes (n=4-7/group). Cardiac gene and protein expression were assessed with real-time polymerase chain reaction (n=4-6/group) and Western blot (n=3-4/group).
Results
Adult hearts had the shortest action potential duration (APD) and Ca transient duration (CaTD) at ZT14 (APD: ZT4: 45.4±4.1 ms; ZT9: 45.1±8.6 ms; ZT14: 34.7±4.2 ms; ZT21: 49.2±7.6 ms, <0.05 versus ZT4 and ZT21; and CaTD: ZT4: 70.1±3.3 ms; ZT9: 72.7±2.7 ms; ZT14: 64.3±3.3 ms; ZT21: 74.4±1.2 ms, <0.05 versus other time points). The pacing frequency at which CaT alternans emerged was faster, and average CaT alternans magnitude was significantly reduced at ZT14 compared with the other time points. There was a trend for decreased spontaneous premature ventricular complexes and pacing-induced ventricular arrhythmias at ZT14, and the hearts at ZT14 had diminished responses to isoproterenol compared with ZT4 (ZT4: 49.5.0±5.6% versus ZT14: 22.7±9.5% decrease in APD, <0.01). In contrast, aged hearts exhibited no difference between ZT14 and ZT4 in nearly every parameter assessed (except APD: ZT4: 39.7±1.9 ms versus ZT14: 33.8±3.1 ms, <0.01). Gene expression of(potassium voltage-gated channel subfamily A member 5; encoding Kv1.5) was increased, whereas gene expression of(encoding β1-adrenergic receptors) was decreased at ZT14 versus ZT4 in adult hearts. No time-of-day changes in expression or phosphorylation of Ca handling proteins (SERCA2 [sarco/endoplasmic reticulum Ca-ATPase], RyR2 [ryanodine receptor 2], and PLB [phospholamban]) was found in ex vivo perfused adult isolated hearts.
Conclusions
Isolated adult hearts have strong time-of-day variation in cardiac electrophysiology, Ca handling, and adrenergic responsiveness, which is disrupted with age.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008093
Wang Z, Tapa S, Francis Stuart SD, Wang L, ... Delisle BP, Ripplinger CM
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008093 | PMID: 32706628
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Abstract

Ablation of Atrial Fibrillation Without Left Atrial Appendage Imaging in Patients Treated With Direct Oral Anticoagulants.

Diab M, Wazni OM, Saliba WI, Tarakji KG, ... Kanj M, Hussein AA
Background
Many centers continue to routinely perform transesophageal echocardiograms before atrial fibrillation (AF) ablation procedures in patients treated with direct oral anticoagulants (DOACs). One study suggested that the procedures could be done without transesophageal echocardiogram but used intracardiac echocardiography imaging of the appendage from the right ventricular outflow. This study aimed to assess the safety of ablation for AF without transesophageal echocardiogram screening or intracardiac echocardiography imaging of the appendage in DOAC compliant patients.
Methods
All patients undergoing AF ablation at the Cleveland Clinic (2011-2018) were enrolled in a prospectively maintained data registry. All consecutive patients presenting with AF or atrial flutter on DOAC were included. Periprocedural thromboembolic complications were assessed.
Results
A total of 900 patients were included. Their median CHADS-VASc score was 2 (interquartile range 1-3). All were on DOACs (333 rivaroxaban, 285 dabigatran, 281 apixaban, and 1 edoxaban). Thromboembolic complications occurred in 4 patients (0.3%): 2 ischemic strokes, 1 transient ischemic attack without residual deficit, and 1 splenic infarct; all with no further complications. Bleeding complications occurred in 5 patients (0.4%): 2 pericardial effusions (1 intraoperative, 1 after 30 days, both drained), 3 groin hematomas (1 of them due to needing heparin for venous thrombosis, none required interventions). No patients required emergent surgeries.
Conclusions
In DOAC compliant patients who present for ablation in AF/atrial flutter, the procedures could be performed without transesophageal echocardiogram screening or intracardiac echocardiography imaging of the appendage; with low risk of complications.



Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008301
Diab M, Wazni OM, Saliba WI, Tarakji KG, ... Kanj M, Hussein AA
Circ Arrhythm Electrophysiol: 30 Aug 2020; 13:e008301 | PMID: 32706992
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Abstract

Bilateral Bundle Branch Area Pacing to Achieve Physiological Conduction System Activation.

Lin J, Chen K, Dai Y, Sun Q, ... Gold MR, Zhang S
Background
Left bundle branch pacing (LBBP) is a technique for conduction system pacing, but it often results in right bundle branch block morphology on the ECG. This study was designed to assess simultaneous pacing of the left and right bundle branch areas to achieve more synchronous ventricular activation.
Methods
In symptomatic bradycardia patients, the distal electrode of a bipolar pacing lead was placed at the left bundle branch area via a transventricular-septal approach. This was used to pace the left bundle branch area, while the ring electrode was used to pace the right bundle branch area. Bilateral bundle branch area pacing (BBBP) was achieved by stimulating the cathode and anode in various pacing configurations. QRS duration, delayed right ventricular activation time, left ventricular activation time, and interventricular conduction delay were measured. Pacing stability and short-term safety were assessed at 3-month follow-up.
Results
BBBP was successfully performed in 22 of 36 patients. Compared with LBBP, BBBP resulted in greater shortening of QRS duration (109.3±7.1 versus 118.4±5.7 ms, <0.001). LBBP resulted in a paced right bundle branch block configuration, with a delayed right ventricular activation time of 115.0±7.5 ms and interventricular conduction delay of 34.0±8.8 ms. BBBP fully resolved the right bundle branch block morphology in 18 patients. In the remaining 4 patients, BBBP partially corrected the right bundle branch block with delayed right ventricular activation time decreasing from 120.5±4.7 ms during LBBP to 106.1±4.2 ms during BBBP (=0.005).
Conclusions
LBBP results in a relatively narrow QRS complex but with an interventricular activation delay. BBBP can diminish the delayed right ventricular activation, producing more physiological ventricular activation. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008267
Lin J, Chen K, Dai Y, Sun Q, ... Gold MR, Zhang S
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008267 | PMID: 32701363
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Abstract

Efficacy of an Adjunctive Electrophysiological Test-Guided Left Atrial Posterior Wall Isolation in Persistent Atrial Fibrillation Without a Left Atrial Low-Voltage Area.

Yamaji H, Higashiya S, Murakami T, Hina K, ... Hirohata S, Kusachi S
Background
Electrical remodeling precedes structural remodeling. In adjunctive left atrial (LA) low-voltage area (LVA) ablation to pulmonary vein isolation of atrial fibrillation (AF), LA areas without LVA have not been targeted for ablation. We studied the effect of adjunctive LA posterior wall isolation (PWI) on persistent AF without LA-LVA according to electrophysiological testing (EP test).
Methods
We examined consecutive patients with persistent AF with (n=33) and without (n=111) LA-LVA. Patients without LA-LVA were randomly assigned to EP test-guided (n=57) and control (n=54) groups. In the EP test-guided group, an adjunctive PWI was performed in those with positive results (PWI subgroup; n=24), but not in those with negative results (n=33). The criteria for positive EP tests were an effective refractory period ≤180 ms, effective refractory period>20 ms shorter than the other sites, and/or induction of AF/atrial tachycardia (AT) during measurements. LVA ablation was performed in the patients with LA-LVA.
Results
During the follow-up period (62±33 weeks), the EP test-guided group had significantly lower recurrence rates (19%,11/57 versus 41%, 22/54, =0.012) and higher Kaplan-Meier AF/AT-free survival curve rates than the control group (=0.01). No significant differences in the recurrence and AF/AT-free survival curve rates between the PWI (positive EP test) and non-PWI (negative EP test) subgroups were observed. Therefore, PWI for positive EP tests reduced the AF/AT recurrence in the EP test-guided group. A stepwise Cox proportional hazard analyses identified EP test-guided ablation as a factor reducing the recurrence rate. The recurrence rates in the LA-LVA ablation group and EP test-guided group were similar.
Conclusions
This pilot study proposed that an EP test-guided adjunctive PWI of persistent AF without LA-LVA potentially reduced AF/AT recurrences. The results suggest that there is an AF substrate in the LA with altered electrophysiological function even when there is no LA-LVA. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008191
Yamaji H, Higashiya S, Murakami T, Hina K, ... Hirohata S, Kusachi S
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008191 | PMID: 32660260
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Abstract

Prospective Evaluation of Clinico-Pathological Predictors of Postoperative Atrial Fibrillation: An Ancillary Study From the OPERA Trial.

Corradi D, Saffitz JE, Novelli D, Asimaki A, ... Gregorini R, Mozaffarian D
Background
Postoperative atrial fibrillation (POAF) occurs in 30% to 50% of patients undergoing cardiac surgery and is associated with increased morbidity and mortality. Prospective identification of structural/molecular changes in atrial myocardium that correlate with myocardial injury and precede and predict risk of POAF may identify new molecular pathways and targets for prevention of this common morbid complication.
Methods
Right atrial appendage samples were prospectively collected during cardiac surgery from 239 patients enrolled in the OPERA trial (Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation), fixed in 10% buffered formalin, and embedded in paraffin for histology. We assessed general tissue morphology, cardiomyocyte diameters, myocytolysis (perinuclear myofibril loss), accumulation of perinuclear glycogen, interstitial fibrosis, and myocardial gap junction distribution. We also assayed NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT, CRP (C-reactive protein), and circulating oxidative stress biomarkers (F2-isoprostanes, F3-isoprostanes, isofurans) in plasma collected before, during, and 48 hours after surgery. POAF was defined as occurrence of postcardiac surgery atrial fibrillation or flutter of at least 30 seconds duration confirmed by rhythm strip or 12-lead ECG. The follow-up period for all arrhythmias was from surgery until hospital discharge or postoperative day 10.
Results
Thirty-five percent of patients experienced POAF. Compared with the non-POAF group, they were slightly older and more likely to have chronic obstructive pulmonary disease or heart failure. They also had a higher European System for Cardiac Operative Risk Evaluation and more often underwent valve surgery. No differences in left atrial size were observed between patients with POAF and patients without POAF. The extent of atrial interstitial fibrosis, cardiomyocyte myocytolysis, cardiomyocyte diameter, glycogen score or Cx43 distribution at the time of surgery was not significantly associated with incidence of POAF. None of these histopathologic abnormalities were correlated with levels of NT-proBNP, hs-cTnT, CRP, or oxidative stress biomarkers.
Conclusions
In sinus rhythm patients undergoing cardiac surgery, histopathologic changes in the right atrial appendage do not predict POAF. They also do not correlate with biomarkers of cardiac function, inflammation, and oxidative stress. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008382
Corradi D, Saffitz JE, Novelli D, Asimaki A, ... Gregorini R, Mozaffarian D
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008382 | PMID: 32654517
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Abstract

Machine Learning to Classify Intracardiac Electrical Patterns During Atrial Fibrillation: Machine Learning of Atrial Fibrillation.

Alhusseini MI, Abuzaid F, Rogers AJ, Zaman JAB, ... Rappel WJ, Narayan SM
Background
Advances in ablation for atrial fibrillation (AF) continue to be hindered by ambiguities in mapping, even between experts. We hypothesized that convolutional neural networks (CNN) may enable objective analysis of intracardiac activation in AF, which could be applied clinically if CNN classifications could also be explained.
Methods
We performed panoramic recording of bi-atrial electrical signals in AF. We used the Hilbert-transform to produce 175 000 image grids in 35 patients, labeled for rotational activation by experts who showed consistency but with variability (kappa [κ]=0.79). In each patient, ablation terminated AF. A CNN was developed and trained on 100 000 AF image grids, validated on 25 000 grids, then tested on a separate 50 000 grids.
Results
In the separate test cohort (50 000 grids), CNN reproducibly classified AF image grids into those with/without rotational sites with 95.0% accuracy (CI, 94.8%-95.2%). This accuracy exceeded that of support vector machines, traditional linear discriminant, and k-nearest neighbor statistical analyses. To probe the CNN, we applied gradient-weighted class activation mapping which revealed that the decision logic closely mimicked rules used by experts (C statistic 0.96).
Conclusions
CNNs improved the classification of intracardiac AF maps compared with other analyses and agreed with expert evaluation. Novel explainability analyses revealed that the CNN operated using a decision logic similar to rules used by experts, even though these rules were not provided in training. We thus describe a scaleable platform for robust comparisons of complex AF data from multiple systems, which may provide immediate clinical utility to guide ablation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02997254. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008160
Alhusseini MI, Abuzaid F, Rogers AJ, Zaman JAB, ... Rappel WJ, Narayan SM
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008160 | PMID: 32631100
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Abstract

Endocardial-Epicardial Phase Mapping of Prolonged Persistent Atrial Fibrillation Recordings: High Prevalence of Dissociated Activation Patterns.

Parameswaran R, Kalman JM, Royse A, Goldblatt J, ... Gerstenfeld EP, Lee G
Background
Endocardial-epicardial dissociation and focal breakthroughs in humans with atrial fibrillation (AF) have been recently demonstrated using activation mapping of short 10-second AF segments. In the current study, we used simultaneous endo-epi phase mapping to characterize endo-epi activation patterns on long segments of human persistent AF.
Methods
Simultaneous intraoperative mapping of endo- and epicardial lateral right atrium wall was performed in patients with persistent AF using 2 high-density grid catheters (16 electrodes, 3 mm spacing). Filtered unipolar and bipolar electrograms of continuous 2-minute AF recordings and electrodes locations were exported for phase analyses. We defined endocardial-epicardial dissociation as phase difference of ≥20 ms between paired endo-epi electrodes. Wavefronts were classified as rotations, single wavefronts, focal waves, or disorganized activity as per standard criteria. Endo-Epi wavefront patterns were simultaneously compared on dynamic phase maps. Complex fractionated electrograms were defined as bipolar electrograms with ≥5 directional changes occupying at least 70% of sample duration.
Results
Fourteen patients with persistent AF undergoing cardiac surgery were included. Endocardial-epicardial dissociation was seen in 50.3% of phase maps with significant temporal heterogeneity. Disorganized activity (Endo: 41.3% versus Epi: 46.8%, =0.0194) and single wavefronts (Endo: 31.3% versus Epi: 28.1%, =0.129) were the dominant patterns. Transient rotations (Endo: 22% versus Epi: 19.2%, =0.169; mean duration: 590±140 ms) and nonsustained focal waves (Endo: 1.2% versus Epi: 1.6%, =0.669) were also observed. Apparent transmural migration of rotational activations (n=6) from the epi- to the endocardium was seen in 2 patients. Electrogram fractionation was significantly higher in the epicardium than endocardium (61.2% versus 51.6%, <0.0001).
Conclusions
Simultaneous endo-epi phase mapping of prolonged human persistent AF recordings shows significant Endocardial-epicardial dissociation marked temporal heterogeneity, discordant and transitioning wavefronts patterns and complex fractionations. No sustained focal activity was observed. Such complex 3-dimensional interactions provide insight into why endocardial mapping alone may not fully characterize the AF mechanism and why endocardial ablation may not be sufficient. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008512
Parameswaran R, Kalman JM, Royse A, Goldblatt J, ... Gerstenfeld EP, Lee G
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008512 | PMID: 32634027
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Abstract

Late I Blocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2.

Hwang J, Kim TY, Terentyev D, Zhong M, ... Koren G, Choi BR
Background
Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs.
Methods
We tested the effects of the selective I blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca imaging, and computer modeling.
Results
GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca-mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca transient duration via accelerating Na/Ca exchanger (I)-mediated Ca efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I potentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na (Na) that decreases the depolarizing I thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K channels (I), suggesting important roles of I in regulating Na.
Conclusions
Selective I blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e006875
Hwang J, Kim TY, Terentyev D, Zhong M, ... Koren G, Choi BR
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e006875 | PMID: 32628505
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Abstract

Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology.

Feeny AK, Chung MK, Madabhushi A, Attia ZI, ... Turakhia MP, Wang PJ

Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e007952
Feeny AK, Chung MK, Madabhushi A, Attia ZI, ... Turakhia MP, Wang PJ
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e007952 | PMID: 32628863
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Abstract

Characterization of Lead Adherence Using Intravascular Ultrasound to Assess Difficulty of Transvenous Lead Extraction.

Beaser AD, Aziz Z, Besser SA, Jones CI, ... Tung R, Nayak HM
Background
Clinical factors associated with development of intravascular lead adherence (ILA) are unreliable predictors. Because vascular injury in the superior vena cava-right atrium during transvenous lead extraction is more likely to occur in segments with higher degrees of ILA, reliable and accurate assessment of ILA is warranted. We hypothesized that intravascular ultrasound (IVUS) could accurately visualize and quantify ILA and degree of ILA correlates with transvenous lead extraction difficulty.
Methods
Serial imaging of leads occurred before transvenous lead extraction using IVUS. ILA areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with ILA grade. Lead extraction difficulty was calculated for each patient and compared with IVUS findings.
Results
One hundred fifty-eight vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low=0 versus high grade=97 seconds, <0.001) and median laser pulsations delivered (low=0 versus high grade=5852, <0.001) were significantly higher in high-grade segments. Most patients with low lead extraction difficulty score had low ILA grades. Eighty-six percentage of patients with high lead extraction difficulty score had low IVUS grade, and the degree of transvenous lead extraction difficulty was similar to patients with low IVUS grades and lead extraction difficulty scores.
Conclusions
IVUS is a feasible imaging modality that may be useful in characterizing ILA in the superior vena cava-right atrium region. An ILA grading system using imaging correlates with extraction difficulty. Most patients with clinical factors associated with higher extraction difficulty may exhibit lower ILA and extraction difficulty based on IVUS imaging. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e007726
Beaser AD, Aziz Z, Besser SA, Jones CI, ... Tung R, Nayak HM
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e007726 | PMID: 32628867
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Abstract

Long-Term Outcome After Ventricular Tachycardia Ablation in Nonischemic Cardiomyopathy: Late Potential Abolition and VT Noninducibility.

Okubo K, Gigli L, Trevisi N, Foppoli L, ... Mazzone P, Della Bella P
Background
In patients with an ischemic cardiomyopathy (ICM), the combination of late potential (LP) abolition and postprocedural ventricular tachycardia (VT) noninducibility is known to be the desirable end point for a successful long-term outcome after VT ablation. We investigated whether LP abolition and VT noninducibilty have a similar impact on the outcomes of patients with non-ICMs (NICM) undergoing VT ablation.
Methods
A total of 403 patients with NICM (523 procedures) who underwent a VT ablation from 2010 to 2016 were included. The procedure end points were the LP abolition (if the LPs were absent, other ablation strategies were undertaken) and the VT noninducibilty.
Results
The underlying structural heart disease consisted of dilated cardiomyopathy (DCM, 49%), arrhythmogenic right ventricular dysplasia (ARVD, 17%), postmyocarditis (14%), valvular heart disease (8%), congenital heart disease (2%), hypertrophic cardiomyopathy (2%), and others (5%). The epicardial access was performed in 57% of the patients. At baseline, the LPs were present in 60% of the patients and a VT was either inducible or sustained/incessant in 85% of the cases. At the end of the procedure, the LP abolition was achieved in 79% of the cases and VT noninducibility in 80%. After a multivariable analysis, the combination of LP abolition and VT noninducibilty was independently associated with free survival from VT (hazard ratio, 0.45 [95% CI, 0.29-0.69], =0.0002) and cardiac death (hazard ratio, 0.38 [95% CI, 0.18-0.74], =0.005). The benefit of the LP abolition on preventing the VT recurrence in patients with ARVD and postmyocarditis appeared superior to that observed for those with DCM.
Conclusions
In patients with NICM undergoing VT ablation, the strategy of LP abolition and VT noninducibilty were associated with better outcomes in terms of long-term VT recurrences and cardiac survival. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008307
Okubo K, Gigli L, Trevisi N, Foppoli L, ... Mazzone P, Della Bella P
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008307 | PMID: 32657137
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Abstract

Artificial Intelligence-Enabled ECG Algorithm to Identify Patients With Left Ventricular Systolic Dysfunction Presenting to the Emergency Department With Dyspnea.

Adedinsewo D, Carter RE, Attia Z, Johnson P, ... Lopez-Jimenez F, Noseworthy PA
Background
Identification of systolic heart failure among patients presenting to the emergency department (ED) with acute dyspnea is challenging. The reasons for dyspnea are often multifactorial. A focused physical evaluation and diagnostic testing can lack sensitivity and specificity. The objective of this study was to assess the accuracy of an artificial intelligence-enabled ECG to identify patients presenting with dyspnea who have left ventricular systolic dysfunction (LVSD).
Methods
We retrospectively applied a validated artificial intelligence-enabled ECG algorithm for the identification of LVSD (defined as LV ejection fraction ≤35%) to a cohort of patients aged ≥18 years who were evaluated in the ED at a Mayo Clinic site with dyspnea. Patients were included if they had at least one standard 12-lead ECG acquired on the date of the ED visit and an echocardiogram performed within 30 days of presentation. Patients with prior LVSD were excluded. We assessed the model performance using area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity.
Results
A total of 1606 patients were included. Median time from ECG to echocardiogram was 1 day (Q1: 1, Q3: 2). The artificial intelligence-enabled ECG algorithm identified LVSD with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.86-0.91) and accuracy of 85.9%. Sensitivity, specificity, negative predictive value, and positive predictive value were 74%, 87%, 97%, and 40%, respectively. To identify an ejection fraction <50%, the area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity were 0.85 (95% CI, 0.83-0.88), 86%, 63%, and 91%, respectively. NT-proBNP (N-terminal pro-B-type natriuretic peptide) alone at a cutoff of >800 identified LVSD with an area under the receiver operating characteristic curve of 0.80 (95% CI, 0.76-0.84).
Conclusions
The ECG is an inexpensive, ubiquitous, painless test which can be quickly obtained in the ED. It effectively identifies LVSD in selected patients presenting to the ED with dyspnea when analyzed with artificial intelligence and outperforms NT-proBNP. Graphic Abstract: A graphic abstract is available for this article.



Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008437
Adedinsewo D, Carter RE, Attia Z, Johnson P, ... Lopez-Jimenez F, Noseworthy PA
Circ Arrhythm Electrophysiol: 30 Jul 2020; 13:e008437 | PMID: 32986471
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Abstract

What is the optimal blood pressure level for patients with atrial fibrillation treated with direct oral anticoagulants?

Minhas JS, Coles B, Mistri AK, Eveson DJ, ... Khunti K, Robinson TG
Objective
Limited data exist to inform blood pressure (BP) thresholds for patients with atrial fibrillation prescribed direct oral anticoagulants (DOAC) therapy in the real world setting.
Methods
SBP was measured in 9051 primary care patients in England on DOACs for atrial fibrillation with postinitiation BP levels available within the Clinical Practice Research Datalink. The incidence rate for the primary outcome of the first recorded event (defined as a diagnosis of first stroke, recurrent stroke, myocardial infarction, symptomatic intracranial bleed, or significant gastrointestinal bleed) and of secondary outcomes all-cause mortality and cardiovascular mortality were calculated by postinitiation BP groups.
Results
The Cox proportional hazard ratio of an event [crude and adjusted hazard ratio 1.04 (95% confidence interval (CI) 1.00-1.08), P = 0.077 and 0.071, respectively] did not differ significantly with a 10 mmHg increase in SBP. The hazard of all-cause mortality [crude hazard ratio 0.83 (95% CI 0.80-0.86), P = 0.000; adjusted hazard ratio 0.84 (95% CI 0.81-0.87), P = 0.000] and cardiovascular mortality [crude hazard ratio 0.92 (95% CI 0.85-0.99), P = 0.021; adjusted hazard ratio 0.93 (95% CI 0.86-1.00), P = 0.041] demonstrated a significant inverse relationship with a 10 mmHg increase in SBP. Patients with a SBP within 161-210 mmHg had the lowest all-cause death rate, while patients with SBP within 121-140 mmHg had the lowest cardiovascular death rate.
Conclusion
SBP values below 161 mmHg are associated higher all-cause mortality, but lower event risk in patients with atrial fibrillation on DOAC therapy. The nadir SBP for lowest event rate was 120 mmHg, for lowest cardiovascular mortality was 130 mmHg and for lowest all-cause mortality was 160 mmHg. This demonstrates a need for a prospective interventional study of BP control after initiation of anticoagulation.



J Hypertens: 30 Aug 2020; 38:1820-1828
Minhas JS, Coles B, Mistri AK, Eveson DJ, ... Khunti K, Robinson TG
J Hypertens: 30 Aug 2020; 38:1820-1828 | PMID: 32453015
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Abstract

Changes in 24-h ambulatory blood pressure following restoration of sinus rhythm in patients with atrial fibrillation.

Olbers J, Östergren J, Rosenqvist M, Skuladottir H, ... Ljungman P, Witt N
Objective
The interplay between atrial fibrillation and blood pressure (BP) is insufficiently studied. In symptomatic patients with persistent atrial fibrillation, electrical cardioversion (ECV) is often used to restore sinus rhythm. In this prospective study, we investigated how restoration of sinus rhythm affected 24-h ambulatory BP.
Methods
Ninety-eight patients with persistent atrial fibrillation were examined with 24-h ambulatory BP monitoring before and approximately a week after ECV.
Results
Sixty-two patients remained in sinus rhythm at the time of the second ambulatory BP monitoring (AF-SR group), whereas 36 patients had relapsed into atrial fibrillation (AF-AF group). In the AF-SR group, there was a significant increase in mean systolic 24-h BP (5.6 mmHg), a significant decrease in mean diastolic 24-h BP (-4.7 mmHg) and accordingly, a significant 25% (10.4 mmHg) increase in mean 24-h pulse pressure.
Conclusion
These findings may reflect the haemodynamic conditions that are prevalent in atrial fibrillation, ambulatory BP measurement bias in atrial fibrillation or a combination of both factors. From a clinical standpoint, our results suggest that an increased attention to BP is needed when sinus rhythm is restored, as underlying hypertension may be masked by BP changes during atrial fibrillation. From a general standpoint, it may be speculated that BP, as indicated by the relatively large difference in pulse pressure, may be inherently different in atrial fibrillation and may therefore not be interpretable in the equivalent manner as BP in sinus rhythm.



J Hypertens: 20 Aug 2020; epub ahead of print
Olbers J, Östergren J, Rosenqvist M, Skuladottir H, ... Ljungman P, Witt N
J Hypertens: 20 Aug 2020; epub ahead of print | PMID: 32833921
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