Topic: Electrophysiology

Abstract

Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

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

J Am Coll Cardiol: 10 Feb 2020; 75:525-538
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:525-538 | PMID: 32029136
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiometabolic-Based Chronic Disease, Addressing Knowledge and Clinical Practice Gaps: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

In the second part of this JACC State-of-the-Art Review, an early and sustainable preventive care plan is described for cardiometabolic-based chronic disease. This plan can improve cardiometabolic health by targeting early mechanistic events to decrease the risk for certain cardiovascular diseases (e.g., coronary heart disease, heart failure, and atrial fibrillation). Included are various prevention modalities, intensive lifestyle interventions, pharmacotherapy and cardiovascular outcome trial evidence, and bariatric/metabolic procedures. A tactical approach of implementing published clinical practice guidelines/algorithms for early behavioral, adiposity, and dysglycemia targeting is emphasized, as well as relevant educational and research implications.

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

J Am Coll Cardiol: 10 Feb 2020; 75:539-555
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:539-555 | PMID: 32029137
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
Background
Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.
Objectives
This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.
Methods
MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.
Results
This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.
Conclusions
This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

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

J Am Coll Cardiol: 27 Jan 2020; 75:273-285
Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
J Am Coll Cardiol: 27 Jan 2020; 75:273-285 | PMID: 31976865
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort.

Elliott AD, Linz D, Mishima R, Kadhim K, ... La Gerche A, Sanders P
Aims
Physical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort.
Methods and results
We included 402 406 individuals (52.5% female), aged 40-69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74-0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82-1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64-0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias.
Conclusion
The risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.

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: 16 Jan 2020; epub ahead of print
Elliott AD, Linz D, Mishima R, Kadhim K, ... La Gerche A, Sanders P
Eur Heart J: 16 Jan 2020; epub ahead of print | PMID: 31951255
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Aims
To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin.
Methods and results
We conducted a real-world nationwide retrospective cohort study using Taiwan\'s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusion
Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

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: 31 Jan 2020; epub ahead of print
Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006423
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Aims
Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.
Methods and results
One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson\'s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].
Conclusion
Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

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

Eur Heart J: 11 Feb 2020; epub ahead of print
Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049275
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Aims
As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings.
Methods and results
Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set.
Conclusion
Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

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

Eur Heart J: 28 Jan 2020; epub ahead of print
Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Eur Heart J: 28 Jan 2020; epub ahead of print | PMID: 31995195
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study.

Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Aims
Atrial fibrillation (AF) confers higher risk of mortality and morbidity, but the long-term impact of physical activity (PA) and cardiorespiratory fitness (CRF) on outcomes in AF patients is unknown. We, therefore, examined the prospective associations of PA and estimated CRF (eCRF) with all-cause mortality, cardiovascular disease (CVD) mortality, morbidity and stroke in individuals with AF.
Methods and results
We followed 1117 AF patients from the HUNT3 study in 2006-08 until first occurrence of the outcomes or end of follow-up in November 2015. We used Cox proportional hazard regression to examine the prospective associations of self-reported PA and eCRF with the outcomes. Atrial fibrillation patients meeting PA guidelines had lower risk of all-cause [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.75] and CVD mortality (HR 0.54, 95% CI 0.34-0.86) compared with inactive patients. The respective HRs for CVD morbidity and stroke were 0.78 (95% CI 0.58-1.04) and 0.70 (95% CI 0.42-1.15). Each 1-metabolic equivalent task (MET) higher eCRF was associated with a lower risk of all-cause (HR 0.88, 95% CI 0.81-0.95), CVD mortality (HR 0.85, 95% CI 0.76-0.95), and morbidity (HR 0.88, 95% CI 0.82-0.95).
Conclusion
Higher PA and CRF are associated with lower long-term risk of CVD and all-cause mortality in individuals with AF. The findings support a role for regular PA and improved CRF in AF patients, in order to combat the elevated risk for mortality and morbidity.

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: 10 Feb 2020; epub ahead of print
Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Eur Heart J: 10 Feb 2020; epub ahead of print | PMID: 32047884
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of newer generation self-expandable vs. balloon-expandable valves in transcatheter aortic valve implantation: the randomized SOLVE-TAVI trial.

Thiele H, Kurz T, Feistritzer HJ, Stachel G, ... de Waha-Thiele S, Desch S
Aims
Transcatheter aortic valve implantation (TAVI) has emerged as established treatment option in patients with symptomatic aortic stenosis. Technical developments in valve design have addressed previous limitations such as suboptimal deployment, conduction disturbances, and paravalvular leakage. However, there are only limited data available for the comparison of newer generation self-expandable valve (SEV) and balloon-expandable valve (BEV).
Methods and results
SOLVE-TAVI is a multicentre, open-label, 2 × 2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVI comparing SEV (Evolut R, Medtronic Inc., Minneapolis, MN, USA) with BEV (Sapien 3, Edwards Lifesciences, Irvine, CA, USA). The primary efficacy composite endpoint of all-cause mortality, stroke, moderate/severe prosthetic valve regurgitation, and permanent pacemaker implantation at 30 days was powered for equivalence (equivalence margin 10% with significance level 0.05). The primary composite endpoint occurred in 28.4% of SEV patients and 26.1% of BEV patients meeting the prespecified criteria of equivalence [rate difference -2.39 (90% confidence interval, CI -9.45 to 4.66); Pequivalence = 0.04]. Event rates for the individual components were as follows: all-cause mortality 3.2% vs. 2.3% [rate difference -0.93 (90% CI -4.78 to 2.92); Pequivalence < 0.001], stroke 0.5% vs. 4.7% [rate difference 4.20 (90% CI 0.12 to 8.27); Pequivalence = 0.003], moderate/severe paravalvular leak 3.4% vs. 1.5% [rate difference -1.89 (90% CI -5.86 to 2.08); Pequivalence = 0.0001], and permanent pacemaker implantation 23.0% vs. 19.2% [rate difference -3.85 (90% CI -10.41 to 2.72) in SEV vs. BEV patients; Pequivalence = 0.06].
Conclusion
In patients with aortic stenosis undergoing transfemoral TAVI, newer generation SEV and BEV are equivalent for the primary valve-related efficacy endpoint. These findings support the safe application of these newer generation percutaneous valves in the majority of patients with some specific preferences based on individual valve anatomy.

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: 11 Feb 2020; epub ahead of print
Thiele H, Kurz T, Feistritzer HJ, Stachel G, ... de Waha-Thiele S, Desch S
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049283
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Roberts JD, Asaki SY, Mazzanti A, Bos JM, ... Priori SG, Ackerman MJ

Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rarevariants implicated in LQT5 was sought through an international multi-center collaboration.Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries.variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.A total of 32 distinctrare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%).The present study suggests that putative/confirmed loss-of-functionvariants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients.



Circulation: 15 Jan 2020; epub ahead of print
Roberts JD, Asaki SY, Mazzanti A, Bos JM, ... Priori SG, Ackerman MJ
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941373
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial.

Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL.DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms (\"atrial fibrillation\", \"atrial flutter\").Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005).Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients\' prior history of AF, ASCVD, or HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 26 Jan 2020; epub ahead of print
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983236
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.

Daya MR, Leroux BG, Dorian P, Rea TD, ... Kudenchuk PJ,

Antiarrhythmic drugs have not proven to significantly improve overall survival after out-of-hospital cardiac arrest (OHCA) from shock-refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/VT). How this might be influenced by the route of drug administration is not known.In this pre-specified analysis of a randomized, placebo-controlled clinical trial, we compared differences in survival to hospital discharge in adults with shock-refractory VF/VT OHCA who were randomized by emergency medical services (EMS) personnel to an antiarrhythmic drug versus placebo in the Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study (ALPS), when stratified by the intravenous (IV) versus intraosseous (IO) route of administration.Of 3,019 randomized patients with known vascular access site, 2,358 received ALPS drugs IV and 661 patients by IO route. IO and IV groups differed in sex, time-to-EMS arrival, and some CPR characteristics, but were similar in others, including time-to-IV/IO-drug receipt. Overall hospital discharge survival was 23%. Compared to placebo, discharge survival was significantly higher in recipients of IV amiodarone ((adjusted risk ratio (RR) 1.26 (95% confidence interval (CI) 1.06, 1.50); adjusted absolute survival difference 5.5% (95% CI 1.5, 9.5)) and IV lidocaine (RR 1.21 (95% CI 1.02, 1.45)); absolute survival difference 4.7% (95% CI 0.7, 8.8)); but not in recipients of IO amiodarone (RR 0.94 (95% CI 0.66, 1.32)) or IO lidocaine (RR 1.03 (95% CI 0.74, 1.44)). Survival to hospital admission also increased significantly when drugs were given IV but not IO, and favored improved neurological outcome at discharge. There were no outcome differences between IV and IO placebo, indicating the access route itself did not demarcate patients with poor prognosis. The study was underpowered to assess IV/IO-drug interactions, which were not statistically significant.We found no significant effect modification by drug administration route for amiodarone or lidocaine compared to placebo during OHCA. However, point estimates for the effects of both drugs compared to placebo were greater for the IV than IO route across all outcomes and beneficial only for IV. Given that the study was underpowered to statistically assess interactions, these findings signal the potential importance of the drug administration route during resuscitation that merits further investigation.



Circulation: 15 Jan 2020; epub ahead of print
Daya MR, Leroux BG, Dorian P, Rea TD, ... Kudenchuk PJ,
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941354
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells.

Zhang B, Ma S, Rachmin I, He M, ... Fisher DE, Hsu YC

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics, cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.



Nature: 21 Jan 2020; epub ahead of print
Zhang B, Ma S, Rachmin I, He M, ... Fisher DE, Hsu YC
Nature: 21 Jan 2020; epub ahead of print | PMID: 31969699
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Preventive or Deferred Ablation of Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial.

Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,

Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implanted cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation in order to prevent ICD shocks for VT) and deferred ablation after three ICD shocks for VT.The Preventive Ablation of Ventricular Tachycardia in Patients with Myocardial Infarction (BERLIN VT) study was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population.During a mean follow-up of 396{plus minus}284 days, the primary endpoint occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09; 95% CI, 0.62-1.92; P=0.77). Using prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, six versus two patients died (7.9% vs. 2.4%; P=0.18), eight versus two patients were admitted for worsening heart failure (10.4% vs. 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% vs. 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% vs. 48.2%; P=0.050) and appropriate ICD therapy (34.2% vs. 47.0%; P=0.030) were numerically reduced in the preventive ablation group.Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up when compared to the deferred ablation strategy.URL: https://www.clinicaltrials.gov. Unique identifier: NCT02501005.



Circulation: 30 Jan 2020; epub ahead of print
Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,
Circulation: 30 Jan 2020; epub ahead of print | PMID: 32000514
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Women\'s Participation in Cardiovascular Clinical Trials From 2010 to 2017.

Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Background
Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials.
Methods
We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation).
Results
We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (=0.007) and heart failure (=0.01) trials compared with previous periods.
Conclusions
Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials.



Circulation: 17 Feb 2020; 141:540-548
Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Circulation: 17 Feb 2020; 141:540-548 | PMID: 32065763
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Integrated management of atrial fibrillation in primary care: results of the ALL-IN cluster randomized trial.

van den Dries CJ, van Doorn S, Rutten FH, Oudega R, ... Hoes AW, Geersing GJ
Aims
To evaluate whether integrated care for atrial fibrillation (AF) can be safely orchestrated in primary care.
Methods and results
The ALL-IN trial was a cluster randomized, open-label, pragmatic non-inferiority trial performed in primary care practices in the Netherlands. We randomized 26 practices: 15 to the integrated care intervention and 11 to usual care. The integrated care intervention consisted of (i) quarterly AF check-ups by trained nurses in primary care, also focusing on possibly interfering comorbidities, (ii) monitoring of anticoagulation therapy in primary care, and finally (iii) easy-access availability of consultations from cardiologists and anticoagulation clinics. The primary endpoint was all-cause mortality during 2 years of follow-up. In the intervention arm, 527 out of 941 eligible AF patients aged ≥65 years provided informed consent to undergo the intervention. These 527 patients were compared with 713 AF patients in the control arm receiving usual care. Median age was 77 (interquartile range 72-83) years. The all-cause mortality rate was 3.5 per 100 patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm [adjusted hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.37-0.82]. For non-cardiovascular mortality, the adjusted HR was 0.47 (95% CI 0.27-0.82). For other adverse events, no statistically significant differences were observed.
Conclusion
In this cluster randomized trial, integrated care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care.

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

Eur Heart J: 28 Feb 2020; epub ahead of print
van den Dries CJ, van Doorn S, Rutten FH, Oudega R, ... Hoes AW, Geersing GJ
Eur Heart J: 28 Feb 2020; epub ahead of print | PMID: 32112556
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation.

Peretto G, Sala S, Rizzo S, Palmisano A, ... Basso C, Della Bella P
Background
Ventricular arrhythmias (VAs) have never been systematically investigated in patients with myocarditis at different stages.
Objectives
The purpose of this study was to compare baseline and follow-up characteristics of VAs in patients with active myocarditis (AM) versus previous myocarditis (PM).
Methods
A total of 185 consecutive patients (69% males, age 44 ± 15 years, left ventricular ejection fraction 49 ± 14%) with myocarditis and VA at index hospitalization, including ventricular fibrillation, ventricular tachycardia (VT), nonsustained ventricular tachycardia (NSVT), and Lown\'s grade ≥2 premature ventricular complexes, were enrolled. AM and PM groups were defined based on endomyocardial biopsy and cardiac magnetic resonance findings. A subset of patients (n = 46, 25%) also underwent electroanatomic mapping and VA transcatheter ablation.
Results
At presentation, AM patients (n = 123, 66%) more commonly had ventricular fibrillation (8 cases vs. 0 cases; p = 0.053), and both irregular (61% vs. 11%; p < 0.001) and polymorphic VA (NSVT and VT: 19% vs. 2%; p = 0.002; premature ventricular complexes: 63% vs. 16%; p < 0.001). Only in PM patients with NSVT or VT, the dominant morphology (right-bundle branch block with superior axis) was 100% predictive of abnormal LV inferoposterior substrate at both cardiac magnetic resonance and electroanatomic mapping. At 27 ± 7 months prospective follow-up, 55 patients (30%) experienced malignant VA (AM vs. PM, p = 0.385). Although a prevalence of polymorphic and irregular VA was confirmed in AM patients with persistent inflammation in follow-up (58%), a predominance of monomorphic and regular VA was found in AM patients after myocarditis healing (42%), as well as in PM patients (all p < 0.001).
Conclusions
In myocarditis patients, polymorphic and irregular VA are more common during the active inflammatory phase, whereas monomorphic and regular VA are associated with healed myocarditis.

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

J Am Coll Cardiol: 09 Mar 2020; 75:1046-1057
Peretto G, Sala S, Rizzo S, Palmisano A, ... Basso C, Della Bella P
J Am Coll Cardiol: 09 Mar 2020; 75:1046-1057 | PMID: 32138965
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Simultaneous Endocardial and Epicardial Delineation of 3D Reentrant Ventricular Tachycardia.

Tung R, Raiman M, Liao H, Zhan X, ... Xue Y, Wu S
Background
Mechanisms of scar-related ventricular tachycardia (VT) are largely based on computational and animal models that portray a 2-dimensional view.
Objectives
The authors sought to delineate the human VT circuit with a 3-dimensional perspective from recordings obtained by simultaneous endocardial and epicardial mapping.
Methods
High-resolution mapping was performed during 97 procedures in 89 patients with structural heart disease. Circuits were characterized by systematic isochronal analysis to estimate the dimensions of the isthmus and extent of the exit region recorded on both myocardial surfaces.
Results
A total of 151 VT morphologies were mapped, of which 83 underwent simultaneous endocardial and epicardial mapping; 17% of circuits activated in a 2-dimensional plane, restricted to 1 myocardial surface. Three-dimensional activation patterns with nonuniform transmural propagation were observed in 61% of circuits with only 4% showing transmurally uniform activation, and 18% exhibiting focal activation patterns consistent with mid-myocardial reentry. The dimensions of the central isthmus were 17 mm (12 to 28 mm) × 10 mm (9 to 19 mm) with 55% exhibiting a minimal dimension of <1.5 cm. QRS activation was transmural in 63% and located 43 mm (34 to 52 mm) from the central isthmus. On the basis of 6 proposed definitions for epicardial VT, the prevalence of an epicardial circuit ranged from 21% to 80% in ischemic cardiomyopathy and 28% to 77% in nonischemic cardiomyopathy.
Conclusions
A 2D perspective oversimplifies the electrophysiological circuit responsible for reentrant human VT and simultaneous endocardial and epicardial mapping facilitates inferences about mid-myocardial activation. Intricate activation patterns are frequently observed on both myocardial surfaces, and the epicardium is functionally involved in the majority of circuits. Human reentry may exist within isthmus dimensions smaller than 1 cm, whereas QRS activation is often transmural and remote from the critical isthmus target. A 3-dimensional perspective of the VT circuit may enhance the precision of ablative therapy and may support a greater role for adjunctive strategies and technology to address arrhythmogenic tissue harbored in the mid-myocardium and subepicardium.

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

J Am Coll Cardiol: 02 Mar 2020; 75:884-897
Tung R, Raiman M, Liao H, Zhan X, ... Xue Y, Wu S
J Am Coll Cardiol: 02 Mar 2020; 75:884-897 | PMID: 32130924
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial.

Stiell IG, Sivilotti MLA, Taljaard M, Birnie D, ... Wells GA, Perry JJ
Background
Acute atrial fibrillation is the most common arrythmia treated in the emergency department. Our primary aim was to compare conversion to sinus rhythm between pharmacological cardioversion followed by electrical cardioversion (drug-shock), and electrical cardioversion alone (shock-only). Our secondary aim was to compare the effectiveness of two pad positions for electrical cardioversion.
Methods
We did a partial factorial trial of two protocols for patients with acute atrial fibrillation at 11 academic hospital emergency departments in Canada. We enrolled adult patients with acute atrial fibrillation. Protocol 1 was a randomised, blinded, placebo-controlled comparison of attempted pharmacological cardioversion with intravenous procainamide (15 mg/kg over 30 min) followed by electrical cardioversion if necessary (up to three shocks, each of ≥200 J), and placebo infusion followed by electrical cardioversion. For patients having electrical cardioversion, we used Protocol 2, a randomised, open-label, nested comparison of anteroposterior versus anterolateral pad positions. Patients were randomly assigned (1:1, stratified by study site) for Protocol 1 by on-site research personnel using an online electronic data capture system. Randomisation for Protocol 2 occurred 30 min after drug infusion for patients who had not converted and was stratified by site and Protocol 1 allocation. Patients and all research and emergency department staff were masked to treatment allocation for Protocol 1. The primary outcome was conversion to normal sinus rhythm for at least 30 min at any time after randomisation and up to a point immediately after three shocks. Protocol 1 was analysed by intention to treat and Protocol 2 excluded patients who did not receive electrical cardioversion. This study is registered at ClinicalTrials.gov, number NCT01891058.
Findings
Between July 18, 2013, and Oct 17, 2018, we enrolled 396 patients, and none were lost to follow-up. In the drug-shock group (n=204), conversion to sinus rhythm occurred in 196 (96%) patients and in the shock-only group (n=192), conversion occurred in 176 (92%) patients (absolute difference 4%; 95% CI 0-9; p=0·07). The proportion of patients discharged home was 97% (n=198) versus 95% (n=183; p=0·60). 106 (52%) patients in the drug-shock group converted after drug infusion only. No patients had serious adverse events in follow-up. The different pad positions in Protocol 2 (n=244), had similar conversions to sinus rhythm (119 [94%] of 127 in anterolateral group vs 108 [92%] of 117 in anteroposterior group; p=0·68).
Interpretation
Both the drug-shock and shock-only strategies were highly effective, rapid, and safe in restoring sinus rhythm for patients in the emergency department with acute atrial fibrillation, avoiding the need for return to hospital. The drug infusion worked for about half of patients and avoided the resource intensive procedural sedation required for electrical cardioversion. We also found no significant difference between the anterolateral and anteroposterior pad positions for electrical cardioversion. Immediate rhythm control for patients in the emergency department with acute atrial fibrillation leads to excellent outcomes.
Funding
Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 31 Jan 2020; 395:339-349
Stiell IG, Sivilotti MLA, Taljaard M, Birnie D, ... Wells GA, Perry JJ
Lancet: 31 Jan 2020; 395:339-349 | PMID: 32007169
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical and Pharmacological Effects of Apixaban Dose Adjustment in the ARISTOTLE Trial.

Zeitouni M, Giczewska A, Lopes RD, Wojdyla DM, ... Alexander JH,
Background
In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, patients with atrial fibrillation and ≥2 dose-adjustment criteria (age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dl [133 μmol/l]) were randomized to receive apixaban 2.5 mg twice daily or warfarin.
Objectives
The purpose of this study was to describe the effects of apixaban dose adjustment on clinical and pharmacological outcomes.
Methods
Patients receiving the correct dose of study drug were included (n = 18,073). The effect of apixaban 2.5 mg twice daily versus warfarin on population pharmacokinetics, D-dimer, prothrombin fragment 1 + 2 (PF1+2), and clinical outcomes was compared with the standard dose (5 mg twice daily).
Results
Patients receiving apixaban 2.5 mg twice daily exhibited lower apixaban exposure (median area under the concentration time curve at a steady state 2,720 ng/ml vs. 3,599 ng/ml; p < 0.0001) than those receiving the standard dose. In patients with ≥2 dose-adjustment criteria, reductions in D-dimers (p interaction = 0.20) and PF1+2 (p interaction = 0.55) were consistent with those observed in the standard-dose population. Patients with ≥2 dose-adjustment criteria (n = 751) were at higher risk for stroke/systemic embolism, major bleeding, and all-cause death than the standard-dose population (0 or 1 dose-adjustment criterion, n = 17,322). The effect of apixaban 2.5 mg twice daily versus warfarin in the ≥2 dose-adjustment criteria population was consistent with the standard dose in the reductions in stroke or systemic embolism (p interaction = 0.26), major bleeding (p interaction = 0.25), and death (p interaction = 0.72).
Conclusions
Apixaban drug concentrations were lower in patients receiving 2.5 mg twice daily compared with 5 mg twice daily. However, the effects of apixaban dose adjustment to 2.5 mg versus warfarin were consistent for coagulation biomarkers and clinical outcomes, providing reassuring data on efficacy and safety. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE]; NCT00412984).

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

J Am Coll Cardiol: 16 Mar 2020; 75:1145-1155
Zeitouni M, Giczewska A, Lopes RD, Wojdyla DM, ... Alexander JH,
J Am Coll Cardiol: 16 Mar 2020; 75:1145-1155 | PMID: 32164888
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A 63-year-old woman with multiple secondary tumours.

Muresan ID, Agoston-Coldea L, Dumitrascu DL

Clinical introductionA 63-year-old woman recently diagnosed with lung metastasis, after routine chest radiography, was admitted to our hospital for unspecified symptoms, such as dyspnoea on minimal exertion and dry cough. Physical examination showed uncommon signs. The electrocardiogram showed sinus rhythm and incomplete left bundle branch block. Thoracic CT scan revealed bilateral lung and pleural metastases and pelvic CT showed a right femoral bone mass. Transthoracic echocardiography revealed a heterogeneous mass, lateral to the right ventricle, with pericardial effusion. Further, cardiac MRI (cMRI) was performed (figure 1A,B). Diagnosis was completed with an ultrasound-guided biopsy and histopathological examination (figure 1C,D).heartjnl;106/3/202/F1F1F1Figure 1(A,B) Cardiac MRI: asterisk is suggestive of fluid and the white arrow indicates fibrous encapsulation by LGE, (C) H&E stain:white arrow indicating a tumoral cell with atypical mitosis and (D) immunohistochemical staining for smooth muscle actin antibody. QUESTION: Which of the following is the most likely diagnosis?Pericardial lymphoma.Pericardial leiomyosarcoma.Pericardial cyst.Secondary malignant cardiac tumour.Pericardial teratoma.

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

Heart: 30 Jan 2020; 106:202-241
Muresan ID, Agoston-Coldea L, Dumitrascu DL
Heart: 30 Jan 2020; 106:202-241 | PMID: 31915242
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Anticoagulation and Cardiovascular Outcomes in Patients With Atrial Fibrillation and End-Stage Renal Disease.

Pokorney SD, Black-Maier E, Hellkamp AS, Friedman DJ, ... Peterson ED, Piccini JP
Background
Atrial fibrillation (AF) is common in patients with end-stage renal disease (ESRD). The impact of oral anticoagulation (OAC) in ESRD patients is uncertain.
Objectives
The purpose of this study was to describe patterns of OAC use in ESRD patients with AF and their associations with cardiovascular outcomes.
Methods
Using Medicare fee-for-service 5% claims data from 2007 to 2013, we analyzed treatment and outcomes in a cohort of patients with ESRD and AF. Prescription drug benefit information was used to determine the timing of OAC therapy. Cox proportional hazards modeling was used to compare outcomes including death, all-cause stroke, ischemic stroke, hemorrhagic stroke, and bleeding hospitalizations in ESRD patients treated with or without OAC.
Results
The cohort included 8,410 patients with AF and ESRD. A total of 3,043 (36.2%) patients were treated with OAC at some time during the study period. Propensity scores used to match 1,519 patients with AF and ESRD on OAC with 3,018 ESRD patients without OAC. Treatment with OAC was not associated with hospitalization for stroke (hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.23 to 1.35; p = 0.97) or death (HR: 1.02; 95% CI: 0.94 to 1.10; p = 0.62). OAC was associated with an increased risk of hospitalization for bleeding (HR: 1.26; 95% CI: 1.09 to 1.46; p = 0.0017) and intracranial hemorrhage (HR: 1.30; 95% CI: 1.07 to 1.59; p = 0.0094).
Conclusions
OAC utilization was low in patients with AF and ESRD. We found no association between OAC use and reduced risk of stroke or death. OAC use was associated with increased risks of hospitalization for bleeding or intracranial hemorrhage. Alternative stroke prevention strategies are needed in patients with ESRD and AF.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1299-1308
Pokorney SD, Black-Maier E, Hellkamp AS, Friedman DJ, ... Peterson ED, Piccini JP
J Am Coll Cardiol: 23 Mar 2020; 75:1299-1308 | PMID: 32192656
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights from Patients at Risk Long-Term Monitored with Implantable Loop Recorder.

Diederichsen SZ, Haugan KJ, Kronborg C, Graff C, ... Brandes A, Svendsen JH

Stroke is an increasing health problem world-wide. Atrial fibrillation (AF) is a major risk factor for stroke, and the attention towards AF screening is rising, while new monitoring-technologies emerge. We aimed to evaluate the performance of a large panel of screening strategies and to assess population characteristics associated with diagnostic yield.Persons with stroke risk factors but without AF were recruited from the general population to undergo screening with implantable loop recorder (ILR). New-onset AF lasting ≥6 min was adjudicated by senior cardiologists. After continuous monitoring for >3 years complete day-to-day heart rhythm datasets were reconstructed for every participant, including exact time of onset and termination of all AF episodes. Random sampling was applied to assess the sensitivity and negative predictive value (NPV) of screening with various simulated screening strategies compared to ILR. The yield across strategies and population subgroups was compared using non-parametric tests.The rhythm datasets comprised 590 participants enduring a total of 659,758 days of continuous monitoring and 20,110 AF episodes. In this data, a single 10-sec ECG yielded a sensitivity (and NPV) of 1.5% (66%) for AF detection, increasing to 8.3% (67%) for twice-daily 30-sec ECGs during 14 days, and to 11% (68%), 13% (68%), 15% (69%), 21% (70%), and 34% (74%) for a single 24-h, 48-h, 72-h, 7-day, or 30-day continuous monitoring, respectively. AF detection further improved when subsequent screenings were performed, or when the same monitoring-duration was spread over several periods as compared to a single period (e.g. three 24-h monitorings vs. one 72-h monitoring), p<0.0001 for all comparisons. The sensitivity was consistently higher among participants with age ≥75 years, male sex, CHADS2 score >2, or brain natriuretic peptide (NT-proBNP) ≥40 pmol/L, and among participants with underlying ≥24-h AF episodes compared to shorter AF, p<0.0001 for all screening strategies.In screening for AF among participants with stroke risk factors, the diagnostic yield increased with duration, dispersion and number of screenings, although all strategies had low yield compared to ILR. The sensitivity was higher among participants who were older, males, or had higher NT-proBNP.URL: https://clinicaltrials.gov Unique Identifier: NCT02036450.



Circulation: 01 Mar 2020; epub ahead of print
Diederichsen SZ, Haugan KJ, Kronborg C, Graff C, ... Brandes A, Svendsen JH
Circulation: 01 Mar 2020; epub ahead of print | PMID: 32114796
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Exercise-Related Acute Cardiovascular Events and Potential Deleterious Adaptations Following Long-Term Exercise Training: Placing the Risks Into Perspective-An Update: A Scientific Statement From the American Heart Association.

Franklin BA, Thompson PD, Al-Zaiti SS, Albert CM, ... Eijsvogels TMH,

Epidemiological and biological plausibility studies support a cause-and-effect relationship between increased levels of physical activity or cardiorespiratory fitness and reduced coronary heart disease events. These data, plus the well-documented anti-aging effects of exercise, have likely contributed to the escalating numbers of adults who have embraced the notion that \"more exercise is better.\" As a result, worldwide participation in endurance training, competitive long distance endurance events, and high-intensity interval training has increased markedly since the previous American Heart Association statement on exercise risk. On the other hand, vigorous physical activity, particularly when performed by unfit individuals, can acutely increase the risk of sudden cardiac death and acute myocardial infarction in susceptible people. Recent studies have also shown that large exercise volumes and vigorous intensities are both associated with potential cardiac maladaptations, including accelerated coronary artery calcification, exercise-induced cardiac biomarker release, myocardial fibrosis, and atrial fibrillation. The relationship between these maladaptive responses and physical activity often forms a U- or reverse J-shaped dose-response curve. This scientific statement discusses the cardiovascular and health implications for moderate to vigorous physical activity, as well as high-volume, high-intensity exercise regimens, based on current understanding of the associated risks and benefits. The goal is to provide healthcare professionals with updated information to advise patients on appropriate preparticipation screening and the benefits and risks of physical activity or physical exertion in varied environments and during competitive events.



Circulation: 25 Feb 2020:CIR0000000000000749; epub ahead of print
Franklin BA, Thompson PD, Al-Zaiti SS, Albert CM, ... Eijsvogels TMH,
Circulation: 25 Feb 2020:CIR0000000000000749; epub ahead of print | PMID: 32100573
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association.

Chung MK, Eckhardt LL, Chen LY, Ahmed HM, ... Trulock KM,

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with substantial morbidity, mortality, and healthcare use. Great strides have been made in stroke prevention and rhythm control strategies, yet reducing the incidence of AF has been slowed by the increasing incidence and prevalence of AF risk factors, including obesity, physical inactivity, sleep apnea, diabetes mellitus, hypertension, and other modifiable lifestyle-related factors. Fortunately, many of these AF drivers are potentially reversible, and emerging evidence supports that addressing these modifiable risks may be effective for primary and secondary AF prevention. A structured, protocol-driven multidisciplinary approach to integrate lifestyle and risk factor management as an integral part of AF management may help in the prevention and treatment of AF. However, this aspect of AF management is currently underrecognized, underused, and understudied. The purpose of this American Heart Association scientific statement is to review the association of modifiable risk factors with AF and the effects of risk factor intervention. Implementation strategies, care pathways, and educational links for achieving impactful weight reduction, increased physical activity, and risk factor modification are included. Implications for clinical practice, gaps in knowledge, and future directions for the research community are highlighted.



Circulation: 08 Mar 2020:CIR0000000000000748; epub ahead of print
Chung MK, Eckhardt LL, Chen LY, Ahmed HM, ... Trulock KM,
Circulation: 08 Mar 2020:CIR0000000000000748; epub ahead of print | PMID: 32148086
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Apixaban versus Warfarin in Patients with Atrial Fibrillation and Advanced Chronic Kidney Disease.

Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, ... Wallentin L, Granger CB

Compared with the general population, patients with advanced chronic kidney disease (CKD) have a >10-fold higher burden of atrial fibrillation (AF). Limited data are available guiding the use of non-vitamin K antagonist oral anticoagulants in this population.We compared the safety of apixaban with warfarin in 269 patients with AF and advanced CKD (defined as creatinine clearance [CrCl] 25-30 mL/min) enrolled in ARISTOTLE. Cox proportional models were used to estimate hazard ratios (HRs) for major bleeding and major or clinically relevant non-major (CRNM) bleeding. We characterized the pharmacokinetic profile of apixaban by assessing differences in exposure using non-linear mixed effects models.Among patients with CrCl 25-30 mL/min, apixaban caused less major bleeding (HR 0.34, 95% confidence interval [CI] 0.14-0.80) and major or CRNM bleeding (HR 0.35, 95% CI 0.17-0.72) compared with warfarin. Patients with CrCl 25-30 mL/min randomized to apixaban demonstrated a trend towards lower rates of major bleeding when compared with those with CrCl >30 mL/min (p interaction=0.08) and major or CRNM bleeding (p interaction=0.05). Median daily steady state areas under the curve (AUCss) for apixaban 5 mg twice daily were 5512 ng/mL*hr and 3406 ng/mL*hr for patients with CrCl 25-30 mL/min or >30 mL/min, respectively. For apixaban 2.5 mg twice daily, the median exposure was 2780 ng/mL*hr for patients with CrCl 25-30 mL/min. The AUC values for patients with CrCl 25-30 mL/min fell completely within the ranges demonstrated for patients with CrCl >30 mL/min.Among patients with AF and CrCl 25-30 mL/min, apixaban caused less bleeding than warfarin, with even greater reductions in bleeding than in patients with CrCl >30 mL/min. We observed substantial overlap in the range of exposure to apixaban 5 mg twice daily for patients with or without advanced CKD, supporting conventional dosing in patients with CrCl 25-30 mL/min. Randomized controlled studies evaluating the safety and efficacy of apixaban are urgently needed in patients with advanced CKD, including those receiving dialysis.URL: https://ClinicalTrials.gov Unique Identifier: NCT00412984.



Circulation: 11 Mar 2020; epub ahead of print
Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, ... Wallentin L, Granger CB
Circulation: 11 Mar 2020; epub ahead of print | PMID: 32160801
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.

Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; ≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, =0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.



Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914028; epub ahead of print
Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E
Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914028; epub ahead of print | PMID: 32008434
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial.

van der Pluijm RW, Tripura R, Hoglund RM, Pyae Phyo A, ... Dondorp AM,
Background
Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance.
Methods
In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete.
Findings
Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [25%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50).
Interpretation
Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance.
Funding
UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 10 Mar 2020; epub ahead of print
van der Pluijm RW, Tripura R, Hoglund RM, Pyae Phyo A, ... Dondorp AM,
Lancet: 10 Mar 2020; epub ahead of print | PMID: 32171078
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The NCDR Left Atrial Appendage Occlusion Registry.

Freeman JV, Varosy P, Price MJ, Slotwiner D, ... Curtis JP, Masoudi FA
Background
Left atrial appendage occlusion (LAAO) to prevent stroke in patients with atrial fibrillation has been evaluated in 2 randomized trials; post-approval clinical data are limited.
Objectives
The purpose of this study was to describe the National Cardiovascular Data Registry (NCDR) LAAO Registry and present patient, hospital, and physician characteristics and in-hospital adverse event rates for Watchman procedures in the United States during its first 3 years.
Methods
The authors describe the LAAO Registry structure and governance, the outcome adjudication processes, and the data quality and collection processes. They characterize the patient population, performing hospitals, and in-hospital adverse event rates.
Results
A total of 38,158 procedures from 495 hospitals performed by 1,318 physicians in the United States were included between January 2016 and December 2018. The mean patient age was 76.1 ± 8.1 years, the mean CHADS-VASc (congestive heart failure, hypertension, 65 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, female) score was 4.6 ± 1.5, and the mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score was 3.0 ± 1.1. The median annual number of LAAO procedures performed for hospitals was 30 (interquartile range: 4 to 56) and for physicians was 12 (interquartile range: 0 to 14). Procedures were canceled or aborted in 7% of cases; among cases in which a device was deployed, 98.1% were implanted with <5-mm leak. Major in-hospital adverse events occurred in 2.16% of patients; the most common complications were pericardial effusion requiring intervention (1.39%) and major bleeding (1.25%), whereas stroke (0.17%) and death (0.19%) were rare.
Conclusions
The LAAO Registry has enrolled >38,000 patients implanted with the device. Patients were generally older with more comorbidities than those enrolled in the pivotal trials; however, major in-hospital adverse event rates were lower than reported in those trials.

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

J Am Coll Cardiol: 12 Mar 2020; epub ahead of print
Freeman JV, Varosy P, Price MJ, Slotwiner D, ... Curtis JP, Masoudi FA
J Am Coll Cardiol: 12 Mar 2020; epub ahead of print | PMID: 32238316
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Left atrial appendage occlusion with the Amplatzer™ Amulet™ device: full results of the prospective global observational study.

Hildick-Smith D, Landmesser U, Camm AJ, Diener HC, ... Nielsen-Kudsk JE, Tondo C
Aims
To evaluate the safety and efficacy of left atrial appendage occlusion (LAAO) with the Amplatzer™ Amulet™ occluder.
Methods and results
Patients with atrial fibrillation eligible for LAAO were recruited to a prospective global study. Implant procedures were undertaken with echocardiographic guidance. Transoesophageal echocardiography (TOE) was undertaken 1-3 months post-LAAO. Implant and follow-up TOEs were evaluated by a CoreLab. The primary endpoint was a composite of ischaemic stroke and cardiovascular death at 2 years. Serious adverse events were adjudicated by an independent clinical events committee. A total of 1088 patients were enrolled, aged 75.2 ± 8.5 years; 64.5% were male. CHA2DS2-VASc and HAS-BLED scores were 4.2 ± 1.6 and 3.3 ± 1.1, respectively. A total of 71.7% had prior major bleeding, and 82.8% had contraindications to oral anticoagulants. Implant success was 99.1%. Major adverse events (≤7 days post-procedure) occurred in 4.0%, including death (0.3%), stroke (0.4%), major vascular (1.3%), and device embolization (0.2%). A total of 80.2% of patients were discharged on antiplatelet therapy alone. Peridevice flow was <3 mm in 98.4% at follow-up TOE. Device-related thrombus (DRT) was seen in 1.6% of cases. Cardiovascular death or ischaemic stroke occurred in 8.7% of patients at 2 years. The ischaemic stroke rate was 2.2%/year-a 67% reduction compared to the CHA2DS2-VASc predicted rate. Major bleeding (Bleeding Academic Research Consortium type ≥ 3) occurred at rates of 10.1%/year (year 1) and 4.0%/year (year 2).
Conclusion
Following LAAO with the Amplatzer Amulet device, the ischaemic stroke rate was reduced by 67% compared to the predicted risk. Closure was complete in 98.4% of cases and DRT seen in only 1.6%.

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: 02 Apr 2020; epub ahead of print
Hildick-Smith D, Landmesser U, Camm AJ, Diener HC, ... Nielsen-Kudsk JE, Tondo C
Eur Heart J: 02 Apr 2020; epub ahead of print | PMID: 32243499
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation.

Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
Background
Current management of patients with atrial fibrillation (AF) is limited by low detection of AF, non-adherence to guidelines, and lack of consideration of patients\' preferences, thus highlighting the need for a more holistic and integrated approach to AF management.
Objective
The objective of this study was to determine whether a mobile health (mHealth) technology-supported AF integrated management strategy would reduce AF-related adverse events, compared with usual care.
Methods
This is a cluster randomized trial of patients with AF older than 18 years of age who were enrolled in 40 cities in China. Recruitment began on June 1, 2018 and follow-up ended on August 16, 2019. Patients with AF were randomized to receive usual care, or integrated care based on a mobile AF Application (mAFA) incorporating the ABC (Atrial Fibrillation Better Care) Pathway: A, Avoid stroke; B, Better symptom management; and C, Cardiovascular and other comorbidity risk reduction. The primary composite outcome was a composite of stroke/thromboembolism, all-cause death, and rehospitalization. Rehospitalization alone was a secondary outcome. Cardiovascular events were assessed using Cox proportional hazard modeling after adjusting for baseline risk.
Results
There were 1,646 patients allocated to mAFA intervention (mean age, 67.0 years; 38.0% female) with mean follow-up of 262 days, whereas 1,678 patients were allocated to usual care (mean age, 70.0 years; 38.0% female) with mean follow-up of 291 days. Rates of the composite outcome of \'ischemic stroke/systemic thromboembolism, death, and rehospitalization\' were lower with the mAFA intervention compared with usual care (1.9% vs. 6.0%; hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.22 to 0.67; p < 0.001). Rates of rehospitalization were lower with the mAFA intervention (1.2% vs. 4.5%; HR: 0.32; 95% CI: 0.17 to 0.60; p < 0.001). Subgroup analyses by sex, age, AF type, risk score, and comorbidities demonstrated consistently lower HRs for the composite outcome for patients receiving the mAFA intervention compared with usual care (all p < 0.05).
Conclusions
An integrated care approach to holistic AF care, supported by mHealth technology, reduces the risks of rehospitalization and clinical adverse events. (Mobile Health [mHealth] technology integrating atrial fibrillation screening and ABC management approach trial; ChiCTR-OOC-17014138).

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

J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534
Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534 | PMID: 32241367
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.

Chamberlain JM, Kapur J, Shinnar S, Elm J, ... ,
Background
Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.
Methods
In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.
Findings
Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.
Interpretation
Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.
Funding
National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 19 Mar 2020; epub ahead of print
Chamberlain JM, Kapur J, Shinnar S, Elm J, ... ,
Lancet: 19 Mar 2020; epub ahead of print | PMID: 32203691
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiomyopathy associated with the Ala143Thr variant of the gene.

Valtola K, Nino-Quintero J, Hedman M, Lottonen-Raikaslehto L, ... Laakso M, Kuusisto J
Objective
To investigate whether the Ala143Thr variant of thegene (A143T/), with conflicting interpretations of pathogenicity, is associated with Fabry cardiomyopathy.
Methods
The index patient, a woman in her 60s with cardiomyopathy, was screened for variants in 59 cardiomyopathy-related genes. A143T/, the only rare variant found, was screened in 10 relatives. GLA activity and lyso-Gb3 levels were measured and echocardiography was performed in 8 of 9 subjects carrying A143T/. Cardiac magnetic resonance (CMR) imaging and F-fluorodeoxyglucose (FDG) positron emission tomography/CT (PET/CT) were performed in four adult A143T/ carriers. Endomyocardial biopsy was obtained from two adult A143T/ carrying sons of the index patient.
Results
The index patient and her elder son had a pacemaker implantation because of sick sinus syndrome and atrioventricular block. GLA activities were decreased to 25%-40% of normal in both sons and one granddaughter. Lyso-Gb3 levels were elevated in both sons. In CMR, the index patient and her two sons had left ventricular (LV) hypertrophy and/or dilatation. The elder son had late gadolinium enhancement, high CMR-derived T1 time and positive FDG signal in PET/CT in the basal inferolateral LV wall. The younger son had low T1 time and the mother had positive FDG signal in PET/CT in the basal inferolateral LV wall. Endomyocardial biopsy of both sons showed myocardial accumulation compatible with glycolipids in light and electron microscopy, staining with anti-Gb3 antibody available for the younger son. Five female relatives with A143T/ had no cardiomyopathy in cardiac imaging.
Conclusions
A143T/ is likely a late-onset Fabry cardiomyopathy causing variant with incomplete penetrance.

© 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: 15 Jan 2020; epub ahead of print
Valtola K, Nino-Quintero J, Hedman M, Lottonen-Raikaslehto L, ... Laakso M, Kuusisto J
Heart: 15 Jan 2020; epub ahead of print | PMID: 31949022
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Characteristics and Outcomes of Retinal Artery Occlusion: Nationally Representative Data.

Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS

Background and Purpose- There are few large studies examining comorbidities, outcomes, and acute interventions for patients with retinal artery occlusion (RAO). RAO shares pathophysiology with acute ischemic stroke (AIS); direct comparison may inform emergent treatment, evaluation, and secondary prevention. Methods- The National Readmissions Database contains data on ≈50% of US hospitalizations from 2013 to 2015. We used , , codes to identify and compare index RAO and AIS admissions, comorbidities, and interventions and Clinical Comorbidity Software codes to identify readmissions causes, using survey-weighted methods when possible. Cumulative risk of all-cause readmission after RAO ≤1 year was estimated by Kaplan-Meier analysis. Results- Among 4871 RAO and 1 239 963 AIS admissions, patients with RAO were less likely (<0.0001) than patients with AIS to have diabetes mellitus (RAO, 24.3% versus AIS, 36.8%), congestive heart failure (9.1% versus 14.8%), atrial fibrillation (15.5% versus 25.2%), or hypertension (62.2% versus 67.6%) but more likely to have valvular disease (13.3% versus 10.5%) and tobacco usage (38.6% versus 32.9%). In RAO admissions, thrombolysis was administered in 2.9% (5.8% in central RAO subgroup, versus 8.0% of AIS), therapeutic anterior chamber paracentesis in 1.0%, thrombectomy in none; 1.4% received carotid endarterectomy during index admission, 1.6% within 30 days. Nearly 1 in 10 patients with RAO were readmitted within 30 days and were more than twice as likely as patients with AIS to be readmitted for dysrhythmia or endocarditis. Readmission for stroke after RAO was the highest within the first 150 days after index admission, and risk was higher in central RAO than in branch RAO. Conclusions- Patients with RAO had high prevalence of many stroke risk factors, particularly valvular disease and smoking, which can be addressed to minimize subsequent risk. Despite less baseline atrial fibrillation, RAO patients were more likely to be readmitted for atrial fibrillation/dysrhythmias. A variety of interventions was administered. AIS risk is the highest shortly after RAO, emphasizing the importance of urgent, thorough neurovascular evaluation.



Stroke: 16 Jan 2020:STROKEAHA119027034; epub ahead of print
Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS
Stroke: 16 Jan 2020:STROKEAHA119027034; epub ahead of print | PMID: 31951154
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy beyond ejection fraction.

Cannatà A, De Angelis G, Boscutti A, Normand C, ... Merlo M, Sinagra G

Sudden cardiac death and arrhythmia-related events in patients with non-ischaemic dilated cardiomyopathy (NICM) have been significantly reduced over the last couple of decades as a result of evidence-based pharmacological and non-pharmacological therapeutic strategies. Nevertheless, the arrhythmic stratification in patients with NICM remains extremely challenging, and the simple indication based on left ventricular ejection fraction appears to be insufficient. Therefore, clinicians need to go beyond the current criteria for implantable cardioverter-defibrillator implantation in the direction of a multiparametric evaluation of arrhythmic risk. Several parameters for arrhythmic risk stratification, ranging from electrocardiographic, echocardiographic, imaging-derived and genetic markers, are crucial for proper arrhythmic risk stratification and a multiparametric evaluation of risk in patients with NICM. In particular, integration of cardiac magnetic resonance parameters (mostly late gadolinium enhancement) and specific genetic information (ie, presence ofmutations) appears fundamental for proper implementation of the current arrhythmic risk stratification. Finally, a novel approach focused on both arrhythmic risk and prediction of left ventricular reverse remodelling during follow-up might be useful for effective multiparametric and dynamic arrhythmic risk stratification in NICM. In the future, a complete and integrated evaluation might be mandatory to implement arrhythmic risk prediction in patients with NICM and to discriminate the competing risk between heart failure-related events and life-threatening arrhythmias.

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

Heart: 20 Jan 2020; epub ahead of print
Cannatà A, De Angelis G, Boscutti A, Normand C, ... Merlo M, Sinagra G
Heart: 20 Jan 2020; epub ahead of print | PMID: 31964657
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The Risk / Benefit Tradeoff of Antithrombotic Therapy in Patients with Atrial Fibrillation Early and Late After an Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights from AUGUSTUS.

Alexander JH, Wojdyla D, Vora AN, Thomas L, ... Mehran R, Lopes RD

In AUGUSTUS, patients with atrial fibrillation (AF) and a recent acute coronary syndrome (ACS) and/or those undergoing percutaneous coronary intervention (PCI) had less bleeding with apixaban than vitamin K antagonist (VKA) and with placebo than aspirin, however, the number of ischemic events was numerically higher with placebo. The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events) over time with apixaban versus VKA and aspirin versus placebo.In AUGUSTUS, 4614 patients with AF and recent ACS and/or PCI on a P2Y inhibitor were randomized to blinded aspirin or placebo and to open-label apixaban or VKA for 6 months. In a post-hoc analysis, we compared the risk of 3 composite bleeding outcomes and 3 composite ischemic outcomes from randomization through 30 days and from 30 days to 6 months with apixaban and VKA and with aspirin and placebo.Compared with VKA, apixaban had either lower or similar risk of bleeding and ischemic outcomes from randomization to 30 days and from 30 days to 6 months. From randomization to 30 days, aspirin caused more severe bleeding (absolute risk difference 0.97%, 95% CI 0.23 to 1.70) and fewer severe ischemic events (absolute risk difference -0.91%, 95% CI -1.74 to -0.08) than placebo. From 30 days to 6 months, the risk of severe bleeding was higher with aspirin than placebo (absolute risk difference 1.25%, 95% CI 0.23 to 2.27) while the risk of severe ischemic events was similar (absolute risk difference -0.17%, 95% CI -1.33 to 0.98).In patients with AF and recent ACS and/or PCI receiving a P2Y inhibitor, apixaban is preferred over VKA. Use of aspirin acutely and for up to 30 days results in an equal tradeoff between an increase in severe bleeding and reduction in severe ischemic events. After 30 days, aspirin continued to increase bleeding without significantly reducing ischemic events. These results inform shared, patient-centric, decision making regarding the ideal duration of use of aspirin after an ACS and/or PCI in patients with AF receiving oral anticoagulation.URL: https://clinicaltrials.gov Unique Identifier: NCT02415400.



Circulation: 28 Mar 2020; epub ahead of print
Alexander JH, Wojdyla D, Vora AN, Thomas L, ... Mehran R, Lopes RD
Circulation: 28 Mar 2020; epub ahead of print | PMID: 32223444
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: Insights from the SHaRe Registry.

Marstrand P, Han L, Day SM, Olivotto I, ... Ho CY,

The terminology \"end-stage\" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (herein referred to as HCM-LVSD), defined when left ventricular ejection fraction (LVEF) <50% is present. The prognosis of HCM-LVSD has reportedly been poor, but due to its relative rarity, natural history remains incompletely characterized.Data from eleven high-volume HCM specialty centers comprising the international Sarcomeric Human Cardiomyopathy Registry (SHaRe) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development.From a cohort of 6,793 HCM patients, 553 (8%) met criteria for HCM-LVSD. Overall, 75% of HCM-LVSD patients experienced clinically relevant events and 35% met the composite outcome (all-cause death (n=128), cardiac transplantation (n=55) or left ventricular assist device implantation (n=9). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (Hazard Ratio (HR) 5.6 [95% Confidence Interval 2.3-13.5]), atrial fibrillation (HR 2.6 [1.7, 3.5]), LVEF <35% (HR 2.0 [1.3, 2.8]). The incidence of new HCM-LVSD was ~7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater LV cavity size (HR 1.1 [1.0-1.3] and wall thickness (HR 1.3 [1.1, 1.4]), LVEF 50-60% (HR 1.8 [1.2, 2.8]-2.8 [1.8, 4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR 2.3 [1.0, 4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR 1.5 [1.0, 2.1] and 2.5 [1.2, 5.1], respectively).HCM-LVSD affects approximately 8% of HCM patients. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death-equivalent with an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and in the risk for incident development of HCM-LVSD (thin filament variants).



Circulation: 30 Mar 2020; epub ahead of print
Marstrand P, Han L, Day SM, Olivotto I, ... Ho CY,
Circulation: 30 Mar 2020; epub ahead of print | PMID: 32228044
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.

Wang D, Hu B, Hu C, Zhu F, ... Wang X, Peng Z
Importance
In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.
Objective
To describe the epidemiological and clinical characteristics of NCIP.
Design, setting, and participants
Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020.
Exposures
Documented NCIP.
Main outcomes and measures
Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked.
Results
Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0).
Conclusions and relevance
In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.



JAMA: 06 Feb 2020; epub ahead of print
Wang D, Hu B, Hu C, Zhu F, ... Wang X, Peng Z
JAMA: 06 Feb 2020; epub ahead of print | PMID: 32031570
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Dual Versus Triple Therapy for Atrial Fibrillation After Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis.

Khan SU, Osman M, Khan MU, Khan MS, ... Hasan RK, Michos ED
Background
The safety and effectiveness of dual therapy (direct oral anticoagulant [DOAC] plus P2Y12 inhibitor) versus triple therapy (vitamin K antagonist plus aspirin and P2Y12 inhibitor) in patients with nonvalvular atrial fibrillation (AF) after percutaneous coronary intervention (PCI) is unclear.
Purpose
To examine the effects of dual versus triple therapy on bleeding and ischemic outcomes in adults with AF after PCI.
Data sources
Searches of PubMed, EMBASE, and the Cochrane Library (inception to 31 December 2019) and ClinicalTrials.gov (7 January 2020) without language restrictions; journal Web sites; and reference lists.
Study selection
Randomized controlled trials that compared the effects of dual versus triple therapy on bleeding, mortality, and ischemic events in adults with AF after PCI.
Data extraction
Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence.
Data synthesis
Four trials encompassing 7953 patients were selected. At the median follow-up of 1 year, high-certainty evidence showed that dual therapy was associated with reduced risk for major bleeding compared with triple therapy (risk difference [RD], -0.013 [95% CI, -0.025 to -0.002]). Low-certainty evidence showed inconclusive effects of dual versus triple therapy on risks for all-cause mortality (RD, 0.004 [CI, -0.010 to 0.017]), cardiovascular mortality (RD, 0.001 [CI, -0.011 to 0.013]), myocardial infarction (RD, 0.003 [CI, -0.010 to 0.017]), stent thrombosis (RD, 0.003 [CI, -0.005 to 0.010]), and stroke (RD, -0.003 [CI, -0.010 to 0.005]). The upper bounds of the CIs for these effects were compatible with possible increased risks with dual therapy.
Limitation
Heterogeneity of study designs, dosages of DOACs, and types of P2Y12 inhibitors.
Conclusion
In adults with AF after PCI, dual therapy reduces risk for bleeding compared with triple therapy, whereas its effects on risks for death and ischemic end points are still unclear.
Primary funding source
None.



Ann Intern Med: 16 Mar 2020; epub ahead of print
Khan SU, Osman M, Khan MU, Khan MS, ... Hasan RK, Michos ED
Ann Intern Med: 16 Mar 2020; epub ahead of print | PMID: 32176890
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Value of a Machine Learning Approach for Predicting Clinical Outcomes in Young Patients With Hypertension.

Wu X, Yuan X, Wang W, Liu K, ... Zhou S, Song L

Risk stratification of young patients with hypertension remains challenging. Generally, machine learning (ML) is considered a promising alternative to traditional methods for clinical predictions because it is capable of processing large amounts of complex data. We, therefore, explored the feasibility of an ML approach for predicting outcomes in young patients with hypertension and compared its performance with that of approaches now commonly used in clinical practice. Baseline clinical data and a composite end point-comprising all-cause death, acute myocardial infarction, coronary artery revascularization, new-onset heart failure, new-onset atrial fibrillation/atrial flutter, sustained ventricular tachycardia/ventricular fibrillation, peripheral artery revascularization, new-onset stroke, end-stage renal disease-were evaluated in 508 young patients with hypertension (30.83±6.17 years) who had been treated at a tertiary hospital. Construction of the ML model, which consisted of recursive feature elimination, extreme gradient boosting, and 10-fold cross-validation, was performed at the 33-month follow-up evaluation, and the model\'s performance was compared with that of the Cox regression and recalibrated Framingham Risk Score models. An 11-variable combination was considered most valuable for predicting outcomes using the ML approach. The C statistic for identifying patients with composite end points was 0.757 (95% CI, 0.660-0.854) for the ML model, whereas for Cox regression model and the recalibrated Framingham Risk Score model it was 0.723 (95% CI, 0.636-0.810) and 0.529 (95% CI, 0.403-0.655). The ML approach was comparable with Cox regression for determining the clinical prognosis of young patients with hypertension and was better than that of the recalibrated Framingham Risk Score model.



Hypertension: 15 Mar 2020:HYPERTENSIONAHA11913404; epub ahead of print
Wu X, Yuan X, Wang W, Liu K, ... Zhou S, Song L
Hypertension: 15 Mar 2020:HYPERTENSIONAHA11913404; epub ahead of print | PMID: 32172622
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Blood Pressure Control and Dementia Risk in Midlife Patients With Atrial Fibrillation.

Kim D, Yang PS, Jang E, Tae Yu H, ... Lip GYH, Joung B

Atrial fibrillation (AF) is associated with increased risk of cognitive impairment and dementia, even with no overt stroke. Hypertension has been a potentially modifiable risk factor for dementia, especially in midlife (<70 years) individuals. We aimed to investigate the associations of blood pressure (BP) and hypertension burden with dementia risk among midlife AF patients. From the Korean National Health Insurance Service database, we enrolled 171 228 incident AF patients aged 50 to 69 years with no prior dementia from 2005 to 2016. During a mean of 6.6 years of follow-up, 9909 patients received a first-time diagnosis of dementia. U-shaped relationships were noted between systolic or diastolic BP and dementia risk: A 10 mm Hg increase or decrease in systolic BP starting from 120 mm Hg was associated with 4.4% (95% CI, 2.7%-6.0%) and 4.6% (95% CI, 0.1%-8.2%) higher dementia risk, respectively. An increase or decrease in diastolic BP starting from 80 mm Hg also increased dementia risk. In subtype analyses, Alzheimer disease increases with BP decrease whereas vascular dementia increases according to BP increase. When BP changes over time were accounted for in time-updated models, BP of 120 to 129/80 to 84 mm Hg was associated with the lowest dementia risk. Increasing hypertension burden (the proportion of days with increased BP during follow-up) was associated with higher dementia risk (hazard ratio, 1.10 per 10% increase [95% CI, 1.08-1.12]). Among midlife AF patients, there were a U-shaped association of BP and a log-linear association of hypertension burden with dementia risk. Minimizing the burden of hypertension in AF patients might help to prevent dementia.



Hypertension: 15 Mar 2020:HYPERTENSIONAHA11914388; epub ahead of print
Kim D, Yang PS, Jang E, Tae Yu H, ... Lip GYH, Joung B
Hypertension: 15 Mar 2020:HYPERTENSIONAHA11914388; epub ahead of print | PMID: 32172620
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiovascular Regulation by the Neuronal BBSome.

Guo DF, Reho JJ, Morgan DA, Rahmouni K

The BBSome, a complex of 8 BBS (Bardet-Biedl syndrome) proteins known for its role in the control of cilia function and other cellular processes, has been implicated in blood pressure control, but the underlying mechanisms are not fully understood. Here, we show that neuronal BBSome plays an important role in blood pressure regulation. Targeted inactivation of the BBSome in the nervous system throughgene deletion causes sympathetically mediated increase in blood pressure in mice. This phenotype is reproduced by selective ablation of thegene from the LRb (leptin receptor)-expressing neurons. Strikingly, the well-known role of the BBSome in the regulation of cilia formation and function is unlikely to account for the prohypertensive effect of BBSome inactivation as disruption of the IFT (intraflagellar transport) machinery required for ciliogenesis by deleting thegene in LRb neurons had no effect on arterial pressure and sympathetic nerve activity. Furthermore, we found thatgene deletion from AgRP (agouti-related protein) neurons or POMC (proopiomelanocortin) neurons increased renal and splanchnic sympathetic nerve activity without altering blood pressure. This lack of blood pressure increase despite the sympathetic overdrive may be explained by vascular adrenergic desensitization as indicated by the reduced vascular contractile response evoked by phenylephrine and the decreased expression of adrenergic receptors. Our results identify the neuronal BBSome as a new player in hemodynamic, sympathetic, and vascular regulation, in a manner independent of cilia.



Hypertension: 08 Mar 2020:HYPERTENSIONAHA11914373; epub ahead of print
Guo DF, Reho JJ, Morgan DA, Rahmouni K
Hypertension: 08 Mar 2020:HYPERTENSIONAHA11914373; epub ahead of print | PMID: 32148123
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension: The ERADICATE-AF Randomized Clinical Trial.

Steinberg JS, Shabanov V, Ponomarev D, Losik D, ... Pokushalov EA, Romanov AB
Importance
Renal denervation can reduce cardiac sympathetic activity that may result in an antiarrhythmic effect on atrial fibrillation.
Objective
To determine whether renal denervation when added to pulmonary vein isolation enhances long-term antiarrhythmic efficacy.
Design, setting, and participants
The Evaluate Renal Denervation in Addition to Catheter Ablation to Eliminate Atrial Fibrillation (ERADICATE-AF) trial was an investigator-initiated, multicenter, single-blind, randomized clinical trial conducted at 5 referral centers for catheter ablation of atrial fibrillation in the Russian Federation, Poland, and Germany. A total of 302 patients with hypertension despite taking at least 1 antihypertensive medication, paroxysmal atrial fibrillation, and plans for ablation were enrolled from April 2013 to March 2018. Follow-up concluded in March 2019.
Interventions
Patients were randomized to either pulmonary vein isolation alone (n = 148) or pulmonary vein isolation plus renal denervation (n = 154). Complete pulmonary vein isolation to v an end point of elimination of all pulmonary vein potentials; renal denervation using an irrigated-tip ablation catheter delivering radiofrequency energy to discrete sites in a spiral pattern from distal to proximal in both renal arteries.
Main outcomes and measures
The primary end point was freedom from atrial fibrillation, atrial flutter, or atrial tachycardia at 12 months. Secondary end points included procedural complications within 30 days and blood pressure control at 6 and 12 months.
Results
Of the 302 randomized patients (median age, 60 years [interquartile range, 55-65 years]; 182 men [60.3%]), 283 (93.7%) completed the trial. All successfully underwent their assigned procedures. Freedom from atrial fibrillation, flutter, or tachycardia at 12 months was observed in 84 of 148 (56.5%) of those undergoing pulmonary vein isolation alone and in 111 of 154 (72.1%) of those undergoing pulmonary vein isolation plus renal denervation (hazard ratio, 0.57; 95% CI, 0.38 to 0.85; P = .006). Of 5 prespecified secondary end points, 4 are reported and 3 differed between groups. Mean systolic blood pressure from baseline to 12 months decreased from 151 mm Hg to 147 mm Hg in the isolation-only group and from 150 mm Hg to 135 mm Hg in the renal denervation group (between-group difference, -13 mm Hg; 95% CI, -15 to -11 mm Hg; P < .001). Procedural complications occurred in 7 patients (4.7%) in the isolation-only group and 7 (4.5%) of the renal denervation group.
Conclusions and relevance
Among patients with paroxysmal atrial fibrillation and hypertension, renal denervation added to catheter ablation, compared with catheter ablation alone, significantly increased the likelihood of freedom from atrial fibrillation at 12 months. The lack of a formal sham-control renal denervation procedure should be considered in interpreting the results of this trial.
Trial registration
ClinicalTrials.gov Identifier: NCT01873352.



JAMA: 20 Jan 2020; 323:248-255
Steinberg JS, Shabanov V, Ponomarev D, Losik D, ... Pokushalov EA, Romanov AB
JAMA: 20 Jan 2020; 323:248-255 | PMID: 31961420
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial.

Lamontagne F, Richards-Belle A, Thomas K, Harrison DA, ... Mouncey PR,
Importance
Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.
Objective
To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.
Design, setting, and participants
A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.
Interventions
Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).
Main outcome and measures
The primary clinical outcome was all-cause mortality at 90 days.
Results
Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).
Conclusions and relevance
Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.
Trial registration
isrctn.org Identifier: ISRCTN10580502.



JAMA: 11 Feb 2020; epub ahead of print
Lamontagne F, Richards-Belle A, Thomas K, Harrison DA, ... Mouncey PR,
JAMA: 11 Feb 2020; epub ahead of print | PMID: 32049269
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study.

Fralick M, Colacci M, Schneeweiss S, Huybrechts KF, Lin KJ, Gagne JJ
Background
Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking.
Objective
To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation.
Design
New-user, active-comparator, retrospective cohort study.
Setting
A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019.
Patients
Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706).
Measurements
The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding.
Results
39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1).
Limitation
Unmeasured confounding, incomplete laboratory data.
Conclusion
In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban.
Primary funding source
Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women\'s Hospital.



Ann Intern Med: 09 Mar 2020; epub ahead of print
Fralick M, Colacci M, Schneeweiss S, Huybrechts KF, Lin KJ, Gagne JJ
Ann Intern Med: 09 Mar 2020; epub ahead of print | PMID: 32150751
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Financial and resource costs of transvenous lead extraction in a high-volume lead extraction centre.

Gould J, Sidhu BS, Porter B, Sieniewicz BJ, ... Razavi R, Rinaldi CA
Objectives
Transvenous lead extraction (TLE) poses a significant economic and resource burden on healthcare systems; however, limited data exist on its true cost. We therefore estimate real-world healthcare reimbursement costs of TLE to the UK healthcare system at a single extraction centre.
Methods
Consecutive admissions entailing TLE at a high-volume UK centre between April 2013 and March 2018 were prospectively recorded in a computer registry. In the hospital\'s National Health Service (NHS) clinical coding/reimbursement database, 447 cases were identified. Mean reimbursement cost (n=445) and length of stay (n=447) were calculated. Ordinary least squares regressions estimated the relationship between cost (bed days) and clinical factors.
Results
Mean reimbursement cost per admission was £17 399.09±£13 966.49. Total reimbursement for all TLE admissions was £7 777 393.51. Mean length of stay was 16.3±15.16 days with a total of 7199 bed days. Implantable cardioverter-defibrillator and cardiac resynchronisation therapy defibrillator devices incurred higher reimbursement costs (70.5% and 68.7% higher, respectively, both p<0.001). Heart failure and prior valve surgery also incurred significantly higher reimbursement costs. Prior valve surgery and heart failure were associated with 8.3 (p=0.017) and 5.5 (p=0.021) additional days in hospital, respectively.
Conclusions
Financial costs to the NHS from TLE are substantial. Consideration should therefore be given to cost/resource-sparing potential of leadless/extravascular cardiac devices that negate the need for TLE particularly in patients with prior valve surgery and/or heart failure. Additionally, use of antibiotic envelopes and other interventions that reduce infection risk in patients receiving transvenous leads should be considered.

© 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: 12 Jan 2020; epub ahead of print
Gould J, Sidhu BS, Porter B, Sieniewicz BJ, ... Razavi R, Rinaldi CA
Heart: 12 Jan 2020; epub ahead of print | PMID: 31932286
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

P2Y inhibitors with oral anticoagulation for percutaneous coronary intervention with atrial fibrillation: a systematic review and meta-analysis.

Lupercio F, Giancaterino S, Villablanca PA, Han F, ... Mahmud E, Hsu JC
Objective
This study aimed to compare the safety and efficacy of third-generation P2Y inhibitors versus clopidogrel in combination with oral anticoagulation (OAC) with or without aspirin in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI).
Methods
We performed a systematic review including both prospective and retrospective studies that compared dual and triple antithrombotic regimens for bleeding and major adverse cardiac events (MACE) in patients with AF undergoing PCI. We analysed rates of bleeding and MACE by P2Y inhibitor choice. Risk ratio (RR) 95% CIs were measured using the Mantel-Haenszel method. Where study heterogeneity was low (I <25%), we used the fixed effects model, otherwise the random effects model was used.
Results
A total of 22 014 patients were analysed from the seven studies included. Among patients treated with both OAC and P2Y inhibitor with or without aspirin, 90% (n=9708) were treated with clopidogrel, 8% (n=830) with ticagrelor, and 2% (n=191) with prasugrel. When compared with clopidogrel, use of ticagrelor (RR 1.36; 95% CI 1.18 to 1.57) and prasugrel (RR 2.11; 95% CI 1.34 to 3.30) were associated with increased rates of bleeding. Compared with clopidogrel, there were no significant differences in rates of MACE with ticagrelor (RR 1.03; 95% CI 0.65 to 1.62) or prasugrel (RR 1.49; 95% CI 0.69 to 3.24).
Conclusion
Based on this meta-analysis, the use of clopidogrel is associated with a lower rate of bleeding compared with ticagrelor or prasugrel in patients with AF on OAC undergoing PCI.

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

Heart: 06 Feb 2020; epub ahead of print
Lupercio F, Giancaterino S, Villablanca PA, Han F, ... Mahmud E, Hsu JC
Heart: 06 Feb 2020; epub ahead of print | PMID: 32034008
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

Chan XHS, Win YN, Haeusler IL, Tan JY, ... Price RN, White NJ
Background
Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.
Methods and findings
We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.
Conclusions
Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.



PLoS Med: 28 Feb 2020; 17:e1003040
Chan XHS, Win YN, Haeusler IL, Tan JY, ... Price RN, White NJ
PLoS Med: 28 Feb 2020; 17:e1003040 | PMID: 32134952
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Safety and Outcomes of Intravenous Thrombolysis in Posterior Versus Anterior Circulation Stroke: Results From the Safe Implementation of Treatments in Stroke Registry and Meta-Analysis.

Keselman B, Gdovinová Z, Jatuzis D, Melo TPE, ... Lees KR, Mazya MV

Background and Purpose- Posterior circulation stroke (PCS) accounts for 5% to 19% of patients with acute stroke receiving intravenous thrombolysis. We aimed to compare safety and outcomes following intravenous thrombolysis between patients with PCS and anterior circulation stroke (ACS) and incorporate the results in a meta-analysis. Methods- We included patients in the Safe Implementation of Treatments in Stroke Thrombolysis Registry 2013 to 2017 with computed tomography/magnetic resonance angiographic occlusion data. Outcomes were parenchymal hematoma, symptomatic intracerebral hemorrhage (SICH) per SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study), ECASS II (Second European Co-operative Stroke Study) and NINDS (Neurological Disorders and Stroke definition), 3-month modified Rankin Scale score, and death. Adjustment for SICH risk factors (age, sex, National Institutes of Health Stroke Scale, blood pressure, glucose, and atrial fibrillation) and center was done using inverse probability treatment weighting, after which an average treatment effect (ATE) was calculated. Meta-analysis of 13 studies comparing outcomes in PCS versus ACS after intravenous thrombolysis was conducted. Results- Of 5146 patients, 753 had PCS (14.6%). Patients with PCS had lower median National Institutes of Health Stroke Scale: 7 (interquartile range, 4-13) versus 13 (7-18), <0.001 and fewer cerebrovascular risk factors. In patients with PCS versus ACS, parenchymal hematoma occurred in 3.2% versus 7.9%, ATE (95% CI): -4.7% (-6.3% to 3.0%); SICH SITS-MOST in 0.6% versus 1.9%, ATE: -1.4% (-2.2% to -0.7%); SICH NINDS in 3.1% versus 7.8%, ATE: -3.0% (-6.3% to 0.3%); SICH ECASS II in 1.8% versus 5.4%, ATE: -2.3% (-5.3% to 0.7%). In PCS versus ACS, 3-month outcomes (70% data availability) were death 18.5% versus 20.5%, ATE: 6.0% (0.7%-11.4%); modified Rankin Scale score 0-1, 45.2% versus 37.5%, ATE: 1.7% (-6.6% to 3.2%); modified Rankin Scale score 0-2, 61.3% versus 49.4%, ATE: 2.4% (3.1%-7.9%). Meta-analysis showed relative risk for SICH in PCS versus ACS being 0.49 (95% CI, 0.32-0.75). Conclusions- The risk of bleeding complications after intravenous thrombolysis in PCS was half that of ACS, with similar functional outcomes and higher risk of death, acknowledging limitations of the National Institutes of Health Stroke Scale for stroke severity or infarct size adjustment.



Stroke: 08 Jan 2020:STROKEAHA119027071; epub ahead of print
Keselman B, Gdovinová Z, Jatuzis D, Melo TPE, ... Lees KR, Mazya MV
Stroke: 08 Jan 2020:STROKEAHA119027071; epub ahead of print | PMID: 31914885
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Characteristics and outcomes of patients with normal left atrial pressure undergoing transcatheter mitral valve repair.

Sims JR, Reeder GS, Guerrero M, Alkhouli M, ... Rihal CS, Eleid MF
Objective
A subset of patients at the time of transcatheter mitral valve repair (TMVR) will have normal left atrial pressure (LAP) (<13 mm Hg) despite having severe mitral regurgitation (MR). The goal of this study was to determine clinical characteristics and outcomes in patients with normal LAP undergoing TMVR.
Methods
A single-centre retrospective cohort of consecutive patients who underwent transcatheter edge-to-edge mitral valve clip and continuous LAP monitoring between 5/1/2014 and 5/1/2018 was analysed. One-year mortality was compared by Kaplan-Meier survival curves. Multivariable analysis was performed to identify predictors of normal LAP and 1 year mortality.
Results
Of the 204 patients undergoing TMVR, 65% were men and the mean age was 81. Of these patients, 31 (15%) had normal LAP (mean LAP 10.5 mm Hg, mean V wave 16.5 mm Hg) and 173 had elevated LAP (mean LAP 19 mm Hg, mean V wave 32.5 mm Hg). The prevalence of severe MR was not different between groups, although the normal LAP group had significantly lower effective regurgitant orifice area and regurgitant volume. Other notable baseline characteristics including prior cardiac surgery, atrial fibrillation, hypertension, diabetes, congestive heart failure, body mass index, mechanism of MR and ejection fraction were similar between groups. However, there was an increased prevalence of chronic lung disease (CLD) (45.2% vs 17.3%, p<0.001) in the normal LAP group. On multivariate analysis, the only significant predictor of normal LAP was the presence of CLD (OR 4.79 (1.83-12.36), p=0.001) and 1-year mortality was significantly higher in the normal LAP group (32.3% vs 12.7%, p=0.006). After adjustment for comorbidities, normal LAP was no longer a predictor of 1-year mortality (RR 1.62 (0.64-4.06), p=0.32); however, CLD (RR 3.44 (1.37-8.67), p=0.01) remained a statistically significant predictor.
Conclusion
Normal LAP at the time of TMVR is associated with a higher incidence of CLD which independently predicts increased 1-year mortality. In patients with CLD and apparently severe MR, measurement of LAP may help identify those with lower likelihood of benefit from TMVR.

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

Heart: 23 Jan 2020; epub ahead of print
Sims JR, Reeder GS, Guerrero M, Alkhouli M, ... Rihal CS, Eleid MF
Heart: 23 Jan 2020; epub ahead of print | PMID: 31980440
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Role of atrial arrhythmia and ventricular response in atrial fibrillation induced atrial remodeling.

Guichard JB, Xiong F, Qi XY, L\'Heureux N, ... Costa AD, Nattel S
Aims
No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial versus associated ventricular arrhythmia to remodeling. This study assessed the roles of atrial arrhythmia versus high ventricular rate in AF-associated remodeling.
Methods and results
Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-bpm atrial-tachypacing maintaining AF (AF w/o-AVB); atrial-tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80-bpm); 160-bpm ventricular-tachypacing (V160) reproducing the response-rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-bpm (CTL). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF-groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF-groups (w/o-AVB and AF+AVB) and modestly in V160. AF-duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene upregulation only in AF w/o-AVB. Connexin43 gene-expression was reduced only in AF w/o-AVB. An additional group of 240-bpm ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: versus other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF-duration, strongly decreased left-ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation.
Conclusions
The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodeling and novel considerations for ventricular rate-control.
Translational perspective
AF often produces a rapid and irregular arrhythmia in both the atria and ventricles. This study evaluates the contributions of AF-induced atrial versus ventricular arrhythmia to atrial remodeling. Each component produced discrete features: AF-induced atrial arrhythmia caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF-induction by premature ectopic beats, conduction slowing and moderate atrial fibrosis; whereas ventricular arrhythmia slightly increased vulnerability, slowed conduction and induced moderate fibrosis without affecting repolarization/refractoriness,. Combined atrial and ventricular arrhythmia abbreviated refractoriness, strongly increased vulnerability and fibrosis and greatly increased AF stability/duration. This work suggests that in the absence of ventricular rate control, the rapid ventricular response can cause AF-promoting atrial remodeling without overt heart failure; further research is needed to clarify the clinical relevance of these findings.

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

Cardiovasc Res: 23 Jan 2020; epub ahead of print
Guichard JB, Xiong F, Qi XY, L'Heureux N, ... Costa AD, Nattel S
Cardiovasc Res: 23 Jan 2020; epub ahead of print | PMID: 31977017
Go to: DOI | PubMed | PDF | Google Scholar |
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: 03 Feb 2020; epub ahead of print
Diamantino AC, Nascimento BR, Beaton AZ, Nunes MCP, ... Sable C, Brant LCC
Heart: 03 Feb 2020; epub ahead of print | PMID: 32019822
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Disparity in implantable cardioverter defibrillator therapy among minority South Asians in the United Kingdom.

Mistry A, Vali Z, Sidhu B, Budgeon C, ... Samani NJ, Ng GA
Objective
There are large geographical differences in implantable cardioverter defibrillator (ICD) implantation rates for reasons not completely understood. In an increasingly multiethnic population, we sought out to investigate whether ethnicity influenced ICD implantation rates.
Methods
This was a retrospective, cohort study of new ICD implantation or upgrade to ICD from January 2006 to February 2019 in recipients of Caucasian or South Asian ethnicity at a single tertiary centre in the UK. Data were obtained from a routinely collected local registry. Crude rates of ICD implantation were calculated for the population of Leicestershire county and were age-standardised to the UK population using the UK National Census of 2011.
Results
The Leicestershire population was 980 328 at the time of the Census, of which 761 403 (77.7%) were Caucasian and 155 500 (15.9%) were South Asian. Overall, 2650 ICD implantations were performed in Caucasian (91.9%) and South Asian (8.1%) patients. South Asians were less likely than Caucasians to receive an ICD (risk ratio (RR) 0.43, 95% CI 0.37 to 0.49, p<0.001) even when standardised for age (RR 0.75, 95% CI 0.74 to 0.75, p<0.001). This remained the case for primary prevention indication (age-standardised RR 0.91, 95% CI 0.90 to 0.91, p<0.001), while differences in secondary prevention ICD implants were even greater (age-standardised RR 0.49, 95% CI 0.48 to 0.50, p<0.001).
Conclusion
Despite a universal and free healthcare system, ICD implantation rates were significantly lower in the South Asian than the Caucasian population residing in the UK. Whether this is due to cultural acceptance or an unbalanced consideration is unclear.

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

Heart: 09 Jan 2020; epub ahead of print
Mistry A, Vali Z, Sidhu B, Budgeon C, ... Samani NJ, Ng GA
Heart: 09 Jan 2020; epub ahead of print | PMID: 31924714
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ten-year trends in the incidence, treatment and outcomes of patients with mitral stenosis in Korea.

Kim JY, Kim SH, Myong JP, Choi Y, ... Oh YS, Lee MY
Objective
Mitral stenosis increases the risk of atrial fibrillation (AF) and stroke. Large data underlying the trend in incidence, treatment and outcomes of mitral stenosis are lacking.
Methods
Based on the Health Insurance Review and Assessment Service database in Republic of Korea, patients who were diagnosed with mitral stenosis between 2007 and 2016 were enrolled. Trends in the incidence rate and changing patterns of treatment and outcome for stroke and systemic embolism and intracranial haemorrhage (ICH) were analysed.
Results
A total of 42 075 patients (mean age 60.7±13.5 years, 13 303 (31.6%) male) were included in the present study. The number included 27 824 (66.1%) patients with mitral stenosis and comorbid AF. The age-standardised annual incidence rate per 100 000 of mitral stenosis in Korea decreased remarkably from 10.3 to 3.6 over 10 years. The use of anticoagulation therapy increased consistently. The annual incidence of stroke and systemic embolism showed signs of plateau, while the incidence of ICH increased.
Conclusions
The overall incidence rate of mitral stenosis in Korean population has decreased remarkably. As increasing the use of vitamin K antagonist, the annual incidence rate of ICH was increased but the rate of stroke incidence reached a plateau. Alternative effective anticoagulation strategy should be investigated.

© 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: 05 Feb 2020; epub ahead of print
Kim JY, Kim SH, Myong JP, Choi Y, ... Oh YS, Lee MY
Heart: 05 Feb 2020; epub ahead of print | PMID: 32029525
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Left atrial cross-sectional area is a novel measure of atrial shape associated with cardioembolic strokes.

Tan TC, Nunes MCP, Handschumacher M, Pontes-Neto O, ... Ay H, Hung J
Objective
Cardioembolic (CE) stroke carries significant morbidity and mortality. Left atrial (LA) size has been associated with CE risk. We hypothesised that differential LA remodelling impacts on pathophysiological mechanism of major CE strokes.
Methods
A cohort of consecutive patients hospitalised with ischaemic stroke, classified into CE versus non-CE strokes using the Causative Classification System for Ischaemic Stroke were enrolled. LA shape and remodelling was characterised by assessing differences in maximal LA cross-sectional area (LA-CSA) in a cohort of 40 prospectively recruited patients with ischaemic stroke using three-dimensional (3D) echocardiography. Flow velocity profiles were measured in spherical versus ellipsoidal in vitro models to determine if LA shape influences flow dynamics. Two-dimensional (2D) LA-CSA was subsequently derived from standard echocardiographic views and compared with 3D LA-CSA.
Results
A total of 1023 patients with ischaemic stroke were included, 230 (22.5%) of them were classified as major CE. The mean age was 68±16 years, and 464 (45%) were women. The 2D calculated LA-CSA correlated strongly with the LA-CSA measured by 3D in both end-systole and end-diastole. In vitro flow models showed shape-related differences in mid-level flow velocity profiles. Increased LA-CSA was associated with major CE stroke (adjusted relative risk 1.10, 95% CI 1.04 to 1.16; p<0.001), independent of age, gender, atrial fibrillation, left ventricular ejection fraction and CHADS-VASc score. Specifically, the inclusion of LA-CSA in a model with traditional risk factors for CE stroke resulted in significant improvement in model performance with the net reclassification improvement of 0.346 (95% CI 0.189 to 0.501; p=0.00001) and the integrated discrimination improvement of 0.013 (95% CI 0.003 to 0.024; p=0.0119).
Conclusions
LA-CSA is a marker of adverse LA shape associated with CE stroke, reflecting importance of differential LA remodelling, not simply LA size, in the mechanism of CE risk.

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

Heart: 23 Jan 2020; epub ahead of print
Tan TC, Nunes MCP, Handschumacher M, Pontes-Neto O, ... Ay H, Hung J
Heart: 23 Jan 2020; epub ahead of print | PMID: 31980438
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.

Zhang D, Tu H, Wang C, Cao L, ... Wadman MC, Li YL
Aims
Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic postganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF.
Methods and results
Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time PCR and Western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry ECG recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/fibrillation (VT/VF), but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats.
Conclusions
Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.
Translational perspectives
Our present study demonstrates that inhibition of N-type Ca2+ channels in CSP neurons attenuates CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias. The clinical significance of this study is to open a new avenue in therapeutics working against lethal ventricular arrhythmias in patients with CHF. N-type Ca2+ channels in CSP neurons could be a new therapeutic target for cardiac sympathetic overactivation and ventricular arrhythmias in CHF. Exploring specific, small-molecule N-type Ca2+ channel blockers with local targeting drug delivery system could translate to clinical trials and applications that improve outcomes for patients with CHF.

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

Cardiovasc Res: 28 Jan 2020; epub ahead of print
Zhang D, Tu H, Wang C, Cao L, ... Wadman MC, Li YL
Cardiovasc Res: 28 Jan 2020; epub ahead of print | PMID: 31995173
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Late onset of new conduction disturbances requiring permanent pacemaker implantation following TAVI.

Kooistra NHM, van Mourik MS, Rodríguez-Olivares R, Maass AH, ... Vis MM, Stella PR
Background
The timing of onset and associated predictors of late new conduction disturbances (CDs) leading to permanent pacemaker implantation (PPI) following transcatheter aortic valve implantation (TAVI) are still unknown, however, essential for an early and safe discharge. This study aimed to investigate the timing of onset and associated predictors of late onset CDs in patients requiring PPI (LCP) following TAVI.
Methods and results
We performed retrospective analysis of prospectively collected data from five large volume centres in Europe. Post-TAVI electrocardiograms and telemetry data were evaluated in patients with a PPI post-TAVI to identify the onset of new advanced CDs. Early onset CDs were defined as within 48 hours after procedure, and late onset CDs as after 48 hours. A total of 2804 patients were included for analysis. The PPI rate was 12%, of which 18% was due to late onset CDs (>48 hours). Independent predictors for LCP were pre-existing non-specific intraventricular conduction delay, pre-existing right bundle branch block, self-expandable valves and predilation. At least one of these risk factors was present in 98% of patients with LCP. Patients with a balloon-expandable valve without predilation did not develop CDs requiring PPI after 48 hours.
Conclusions
Safe early discharge might be feasible in patients without CDs in the first 48 hours after TAVI if no risk factors for LCP are present.

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

Heart: 30 Jan 2020; epub ahead of print
Kooistra NHM, van Mourik MS, Rodríguez-Olivares R, Maass AH, ... Vis MM, Stella PR
Heart: 30 Jan 2020; epub ahead of print | PMID: 32005676
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis.

Ronchi C, Bernardi J, Mura M, Stefanello M, ... Gnecchi M, Zaza A

NOS1AP SNPs correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action potential duration (APD) to facilitate arrhythmias.
Aims
To test 1) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; 2) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency.
Methods and results
In GP-CMs NOS1 was inhibited by SMTC (or L-VNIO); LQT1 was mimicked by IKs blockade (JNJ203) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harboring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139) respectively. In GP-CMs: NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed \"transient inward current\" events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs AS) hiPSC-CMs: APD was longer and ICaL larger; NOS1AP and NOS1 expression and colocalization were decreased.
Conclusions
the minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.

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

Cardiovasc Res: 14 Feb 2020; epub ahead of print
Ronchi C, Bernardi J, Mura M, Stefanello M, ... Gnecchi M, Zaza A
Cardiovasc Res: 14 Feb 2020; epub ahead of print | PMID: 32061134
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Early Initiation of Direct Oral Anticoagulants After Onset of Stroke and Short- and Long-Term Outcomes of Patients With Nonvalvular Atrial Fibrillation.

Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, ... Koga M,

Background and Purpose- We aimed to compare outcomes of ischemic stroke patients with nonvalvular atrial fibrillation between earlier and later initiation of direct oral anticoagulants (DOACs) after stroke onset. Methods- From data for 1192 nonvalvular atrial fibrillation patients with acute ischemic stroke or transient ischemic attack in a prospective, multicenter, observational study, patients who started DOACs during acute hospitalization were included and divided into 2 groups according to a median day of DOAC initiation after onset. Outcomes included stroke or systemic embolism, major bleeding, and death at 3 months, as well as those at 2 years. Results- DOACs were initiated during acute hospitalization in 499 patients in median 4 (interquartile range, 2-7) days after onset. Thus, 223 patients (median age, 74 [interquartile range, 68-81] years; 78 women) were assigned to the early group (≤3 days) and 276 patients (median age, 75 [interquartile range, 69-82] years; 101 women) to the late (≥4 days) group. The early group had lower baseline National Institutes of Health Stroke Scale score and smaller infarcts than the late group. The rate at which DOAC administration persisted at 2 years was 85.2% overall, excluding patients who died or were lost to follow-up. Multivariable Cox shared frailty models showed comparable hazards between the groups at 2 years for stroke or systemic embolism (hazard ratio, 0.86 [95% CI, 0.47-1.57]), major bleeding (hazard ratio, 1.39 [95% CI, 0.42-4.60]), and death (hazard ratio, 0.61 [95% CI, 0.28-1.33]). Outcome risks at 3 months also did not significantly differ between the groups. Conclusions- Risks for events including stroke or systemic embolism, major bleeding, and death were comparable whether DOACs were started within 3 days or from 4 days or more after the onset of nonvalvular atrial fibrillation-associated ischemic stroke or transient ischemic attack. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01581502.



Stroke: 21 Jan 2020:STROKEAHA119028118; epub ahead of print
Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, ... Koga M,
Stroke: 21 Jan 2020:STROKEAHA119028118; epub ahead of print | PMID: 31964290
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ischemic Stroke and Bleeding: Clinical Benefit of Anticoagulation in Atrial Fibrillation After Intracerebral Hemorrhage.

Stanton RJ, Eckman MH, Woo D, Moomaw CJ, ... Flaherty ML, Kleindorfer DO

Background and Purpose- Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHADS-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult. Methods- We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)-a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHADS-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs. Results- Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs. Conclusions- Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH. Clinical trial registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00930280.



Stroke: 30 Jan 2020:STROKEAHA119027370; epub ahead of print
Stanton RJ, Eckman MH, Woo D, Moomaw CJ, ... Flaherty ML, Kleindorfer DO
Stroke: 30 Jan 2020:STROKEAHA119027370; epub ahead of print | PMID: 32000590
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

An adaptable implementation package targeting evidence-based indicators in primary care: A pragmatic cluster-randomised evaluation.

Willis TA, Collinson M, Glidewell L, Farrin AJ, ... Foy R,
Background
In primary care, multiple priorities and system pressures make closing the gap between evidence and practice challenging. Most implementation studies focus on single conditions, limiting generalisability. We compared an adaptable implementation package against an implementation control and assessed effects on adherence to four different evidence-based quality indicators.
Methods and findings
We undertook two parallel, pragmatic cluster-randomised trials using balanced incomplete block designs in general practices in West Yorkshire, England. We used \'opt-out\' recruitment, and we randomly assigned practices that did not opt out to an implementation package targeting either diabetes control or risky prescribing (Trial 1); or blood pressure (BP) control or anticoagulation in atrial fibrillation (AF) (Trial 2). Within trials, each arm acted as the implementation control comparison for the other targeted indicator. For example, practices assigned to the diabetes control package acted as the comparison for practices assigned to the risky prescribing package. The implementation package embedded behaviour change techniques within audit and feedback, educational outreach, and computerised support, with content tailored to each indicator. Respective patient-level primary endpoints at 11 months comprised the following: achievement of all recommended levels of haemoglobin A1c (HbA1c), BP, and cholesterol; risky prescribing levels; achievement of recommended BP; and anticoagulation prescribing. Between February and March 2015, we recruited 144 general practices collectively serving over 1 million patients. We stratified computer-generated randomisation by area, list size, and pre-intervention outcome achievement. In April 2015, we randomised 80 practices to Trial 1 (40 per arm) and 64 to Trial 2 (32 per arm). Practices and trial personnel were not blind to allocation. Two practices were lost to follow-up but provided some outcome data. We analysed the intention-to-treat (ITT) population, adjusted for potential confounders at patient level (sex, age) and practice level (list size, locality, pre-intervention achievement against primary outcomes, total quality scores, and levels of patient co-morbidity), and analysed cost-effectiveness. The implementation package reduced risky prescribing (odds ratio [OR] 0.82; 97.5% confidence interval [CI] 0.67-0.99, p = 0.017) with an incremental cost-effectiveness ratio of £1,359 per quality-adjusted life year (QALY), but there was insufficient evidence of effect on other primary endpoints (diabetes control OR 1.03, 97.5% CI 0.89-1.18, p = 0.693; BP control OR 1.05, 97.5% CI 0.96-1.16, p = 0.215; anticoagulation prescribing OR 0.90, 97.5% CI 0.75-1.09, p = 0.214). No statistically significant effects were observed in any secondary outcome except for reduced co-prescription of aspirin and clopidogrel without gastro-protection in patients aged 65 and over (adjusted OR 0.62; 97.5% CI 0.39-0.99; p = 0.021). Main study limitations concern our inability to make any inferences about the relative effects of individual intervention components, given the multifaceted nature of the implementation package, and that the composite endpoint for diabetes control may have been too challenging to achieve.
Conclusions
In this study, we observed that a multifaceted implementation package was clinically and cost-effective for targeting prescribing behaviours within the control of clinicians but not for more complex behaviours that also required patient engagement.
Trial registration
The study is registered with the ISRCTN registry (ISRCTN91989345).



PLoS Med: 30 Jan 2020; 17:e1003045
Willis TA, Collinson M, Glidewell L, Farrin AJ, ... Foy R,
PLoS Med: 30 Jan 2020; 17:e1003045 | PMID: 32109257
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A human embryonic stem cell reporter line for monitoring chemical-induced cardiotoxicity.

Tsai SY, Ghazizadeh Z, Wang HJ, Amin S, ... Evans T, Chen S
Aims 
Human embryonic stem cells (hESCs) can be used to generate scalable numbers of cardiomyocytes (CMs) for studying cardiac biology, disease modelling, drug screens, and potentially for regenerative therapies. A fluorescence-based reporter line will significantly enhance our capacities to visualize the derivation, survival, and function of hESC-derived CMs. Our goal was to develop a reporter cell line for real-time monitoring of live hESC-derived CMs.
Methods and results 
We used CRISPR/Cas9 to knock a mCherry reporter gene into the MYH6 locus of hESC lines, H1 and H9, enabling real-time monitoring of the generation of CMs. MYH6:mCherry+ cells express atrial or ventricular markers and display a range of cardiomyocyte action potential morphologies. At 20 days of differentiation, MYH6:mCherry+ cells show features characteristic of human CMs and can be used successfully to monitor drug-induced cardiotoxicity and oleic acid-induced cardiac arrhythmia.
Conclusion 
We created two MYH6:mCherry hESC reporter lines and documented the application of these lines for disease modelling relevant to cardiomyocyte biology.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 29 Feb 2020; 116:658-670
Tsai SY, Ghazizadeh Z, Wang HJ, Amin S, ... Evans T, Chen S
Cardiovasc Res: 29 Feb 2020; 116:658-670 | PMID: 31173076
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology.

Dietrichs ES, McGlynn K, Allan A, Connolly A, ... Tveita T, Smith GL
Aims
Treatment of arrhythmias evoked by hypothermia/rewarming remains challenging, and the underlying mechanisms are unclear. This in vitro experimental study assessed cardiac electrophysiology in isolated rabbit hearts at temperatures occurring in therapeutic and accidental hypothermia.
Methods and results
Detailed ECG, surface electrogram, and panoramic optical mapping were performed in isolated rabbit hearts cooled to moderate (31°C) and severe (17°C) hypothermia. Ventricular activation was unchanged at 31°C while action potential duration (APD) was significantly prolonged (176.9 ± 4.2 ms vs. 241.0 ± 2.9 ms, P < 0.05), as was ventricular repolarization. At 17°C, there were proportionally similar delays in both activation and repolarization. These changes were reflected in the QRS and QT intervals of ECG recordings. Ventricular fibrillation threshold was significantly reduced at 31°C (16.3 ± 3.1 vs. 35 ± 3.5 mA, P < 0.05) but increased at 17°C (64.2 ± 9.9, P < 0.05). At 31°C, transverse conduction was relatively unchanged by cooling compared to longitudinal conduction, but at 17°C both transverse and longitudinal conduction were proportionately reduced to a similar extent. The gap junction uncoupler heptanol had a larger relative effect on transverse than longitudinal conduction and was able to restore the transverse/longitudinal conduction ratio, returning ventricular fibrillation threshold to baseline values (16.3 ± 3.1 vs. 36.3 ± 4.3 mA, P < 0.05) at 31°C. Rewarming to 37°C restored the majority of the electrophysiological parameters.
Conclusions
Moderate hypothermia does not significantly change ventricular conduction time but prolongs repolarization and is pro-arrhythmic. Further cooling to severe hypothermia causes parallel changes in ventricular activation and repolarization, changes which are anti-arrhythmic. Therefore, relative changes in QRS and QT intervals (QR/QTc) emerge as an ECG-biomarker of pro-arrhythmic activity. Risk for ventricular fibrillation appears to be linked to the relatively low temperature sensitivity of ventricular transmural conduction, a conclusion supported by the anti-arrhythmic effect of heptanol at 31°C.

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

Cardiovasc Res: 06 Feb 2020; epub ahead of print
Dietrichs ES, McGlynn K, Allan A, Connolly A, ... Tveita T, Smith GL
Cardiovasc Res: 06 Feb 2020; epub ahead of print | PMID: 32031595
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Modes of late mortality in patients with a Fontan circulation.

Poh C, Hornung T, Celermajer DS, Radford DJ, ... Winlaw D, d\'Udekem Y
Objectives
The mechanisms of attrition of the Fontan population have been poorly characterised and it is unclear whether some of the deaths are potentially preventable. We analysed the circumstances of late death in patients with a Fontan circulation, with a special focus on identifying lesions amenable to intervention that may have contributed to the decline of their circulation.
Methods
Between 1975 and 2018, a total of 105 patients from a Bi-National Registry died beyond 1 year after Fontan completion, at a median age of 18.6 (IQR 13.8-26.0) years old, 12.7 (IQR 6.0-19.3) years after Fontan completion.
Results
A total of 105 patients died-63 patients (60%) with an atriopulmonary (AP) Fontan, 21 patients (20%) with a lateral tunnel (LT) and 21 patients (20%) with an extracardiac conduit (ECC). 72 patients (69%) were reviewed within 2 years preceding death, with 32% (23/72) deemed to be clinically well. Fontan circulatory failure was the most common cause of death in 42 patients (45%). Other causes of death included sudden death/arrhythmia (19%), perioperative death (12%), neurological complication (7%) and thromboembolism (7%). All patients with an LT or ECC who died from Fontan failure had at least one surgical defect that was amenable to intervention at time of death.
Conclusions
Conventional clinical surveillance has been insensitive in detecting a significant proportion of patients at risk of late death. Fontan circulatory failure contributes to half of the late deaths. Patients with an LT or ECC Fontan who died with a clinical picture of circulation failure may have potentially correctable lesions.

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

Heart: 24 Feb 2020; epub ahead of print
Poh C, Hornung T, Celermajer DS, Radford DJ, ... Winlaw D, d'Udekem Y
Heart: 24 Feb 2020; epub ahead of print | PMID: 32098807
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes.

Tazmini K, Frisk M, Lewalle A, Laasmaa M, ... Oie E, Louch WE

Hypokalemia occurs in up to 20% of hospitalized patients, and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes.To investigate pro-arrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes.Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K] from 5.0 to 2.7 mM) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca overload, and increased generation of both spontaneous Ca waves and delayed afterdepolarizations (DADs). However, similar Ca-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na-K ATPase and Na-Ca exchanger proteins within these structures, as reduction in Na pump activity locally inhibited Ca extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations (EADs) during hypokalemia, associated with Ca overload. However, EADs also occurred in untubulated atrial cells, despite Ca quiescence. These phase-3 EADs were rather linked to reactivation of non-equilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na current-driven EADs in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K current (I); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes.Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium, but also vary between atrial myocytes depending on subcellular structure and electrophysiology.



Circ Res: 18 Feb 2020; epub ahead of print
Tazmini K, Frisk M, Lewalle A, Laasmaa M, ... Oie E, Louch WE
Circ Res: 18 Feb 2020; epub ahead of print | PMID: 32070187
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Outcomes of transcatheter aortic valve implantations in high-volume or low-volume centres in Germany.

Oettinger V, Kaier K, Heidt T, Hortmann M, ... von Zur Mühlen C, Stachon P
Objective
Transcatheter aortic valve implantation (TAVI) is the most common aortic valve replacement in Germany. Since 2015, to ensure high-quality procedures, hospitals in Germany and other countries that meet the minimum requirement of 50 interventions per centre are being certified to perform TAVI. This study analyses the impact of these requirements on case number and in-hospital outcomes.
Methods
All isolated TAVI procedures and in-hospital outcomes between 2008 and 2016 were identified by International Classification of Diseases (ICD) and the German Operation and Procedure Classification codes.
Results
73 467 isolated transfemoral and transapical TAVI procedures were performed in Germany between 2008 and 2016. During this period, the number of TAVI procedures per year rose steeply, whereas the overall rates of hospital mortality and complications declined. In 2008, the majority of procedures were performed in hospitals with fewer than 50 cases per year (54.63%). Until 2014, the share of patients treated in low-volume centres constantly decreased to 5.35%. After the revision of recommendations, it further declined to 1.99%. In the 2 years after the introduction of the minimum requirements on case numbers, patients were at decreased risk for in-hospital mortality when treated in a high-volume centre (risk-adjusted OR 0.62, p=0.012). The risk for other in-hospital outcomes (stroke, permanent pacemaker implantation and bleeding events) did not differ after risk adjustment (p=0.346, p=0.142 and p=0.633).
Conclusion
A minimum volume of 50 procedures per centre and year appears suitable to allow for sufficient routine and thus better in-hospital outcomes, while ensuring nationwide coverage of TAVI procedures.

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

Heart: 17 Feb 2020; epub ahead of print
Oettinger V, Kaier K, Heidt T, Hortmann M, ... von Zur Mühlen C, Stachon P
Heart: 17 Feb 2020; epub ahead of print | PMID: 32071092
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Validity of daily self-pulse palpation for atrial fibrillation screening in patients 65 years and older: A cross-sectional study.

Ghazal F, Theobald H, Rosenqvist M, Al-Khalili F
Background
The European Society of Cardiology guidelines recommend (Class IA) single-time-point screening for atrial fibrillation (AF) using pulse palpation. The role of pulse palpation for AF detection has not been validated against electrocardiogram (ECG) recordings. We aimed to study the validity of AF screening using self-pulse palpation compared with an ECG recording conducted at the same time using a handheld ECG 3 times a day for 2 weeks.
Methods and findings
In this cross-sectional screening study, patients 65 years of age and older attending 4 primary care centers (PCCs) outside Stockholm County were invited to take part in AF screening from July 2017 to December 2018. Patients were included irrespective of their reason for visiting the PCC. Handheld intermittent ECGs 3 times per day were offered to patients without AF for a period of 2 weeks, and patients were instructed in how to take their own pulse at the same time. A total of 1,010 patients (mean age 73 years, 61% female, with an average CHA2DS2-VASc score 2.9) participated in the study, and 27 (2.7%, 95% CI 1.8%-3.9%) new cases of AF were detected. Anticoagulants (ACs) could be initiated in 26 (96%, 95% CI 81%-100%) of these cases. A total of 53,782 simultaneous ECG recordings and pulse measurements were registered. AF was verified in 311 ECG recordings, of which the pulse was palpated as irregular in 77 recordings (25%, 95% CI 20%-30% sensitivity per measurement occasion). Of the 27 AF cases, 15 cases felt an irregular pulse on at least one occasion (56%, 95% CI 35%-75% sensitivity per individual). 187 individuals without AF felt an irregular pulse on at least one occasion. The specificity per measurement occasion and per individual was (98%, 95% CI 98%-98%) and (81%, 95% CI 78%-83%), respectively.
Conclusions
AF screening using self-pulse palpation 3 times daily for 2 weeks has lower sensitivity compared with simultaneous intermittent ECG. Thus, it may be better to screen for AF using intermittent ECG without stepwise screening using pulse palpation. A limitation of this model could be the reduced availability of handheld ECG recorders in primary care centers.



PLoS Med: 28 Feb 2020; 17:e1003063
Ghazal F, Theobald H, Rosenqvist M, Al-Khalili F
PLoS Med: 28 Feb 2020; 17:e1003063 | PMID: 32231369
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Computational Pipeline to Predict Cardiotoxicity:From the Atom to the Rhythm.

Yang PC, DeMarco KR, Aghasafari P, Jeng MT, ... Vorobyov I, Clancy CE

Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery.To predict the impact of a drug from the drug chemistry on the cardiac rhythm.In a new linkage, we connected atomistic scale information to protein, cell and tissue scales by predicting drug binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction.We present a multiscale model framework to predict electro-toxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.



Circ Res: 23 Feb 2020; epub ahead of print
Yang PC, DeMarco KR, Aghasafari P, Jeng MT, ... Vorobyov I, Clancy CE
Circ Res: 23 Feb 2020; epub ahead of print | PMID: 32091972
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function.

Seidel M, de Meritens CR, Johnson L, Parthimos D, ... Lai FA, Zissimopoulos S
Aims
The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer.
Methods and results
We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively-charged side chains of two aspartate residues (D179 and D180) within the β8-β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The β8-β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8-β9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8-β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the β8-β9 domain in channel closing.
Conclusions
These results suggest that efficient N-terminus inter-subunit communication mediated by the β8-β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.
Translational potential
Our findings that the RyR2 β8-β9 loop is involved in both Ca2+ release channel opening and closing have important clinical implications. This RyR2 domain is a known \"hot-spot\" for mutations associated with arrhythmogenic cardiac disease, which could produce hypersensitive as well as hyposensitive channels. Therapeutic strategies currently focus on gain-of-function RyR2 channels to suppress sarcoplasmic reticulum Ca2+ release either indirectly with class I/II anti-arrhythmic drugs, or by directly targeting RyR2 to inhibit channel activity. These strategies may not only be ineffective, but they may exacerbate the malignant phenotype in the case of loss-of-function RyR2 mutations.

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

Cardiovasc Res: 19 Feb 2020; epub ahead of print
Seidel M, de Meritens CR, Johnson L, Parthimos D, ... Lai FA, Zissimopoulos S
Cardiovasc Res: 19 Feb 2020; epub ahead of print | PMID: 32077934
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Atrial Fibrillation-Associated Ischemic Stroke Patients With Prior Anticoagulation Have Higher Risk for Recurrent Stroke.

Tanaka K, Koga M, Lee KJ, Kim BJ, ... Toyoda K,

Background and Purpose- Ischemic stroke associated with nonvalvular atrial fibrillation (NVAF) despite prior anticoagulation may indicate underlying problems that nullify the stroke-preventing effects of oral anticoagulants. We aimed to evaluate the risk for recurrent stroke in patients with NVAF with prior anticoagulation, compared with that in patients without prior anticoagulation. Methods- This study comprised pooled individual patient data on NVAF-associated acute ischemic stroke or transient ischemic attack from 2011 to 2014 arising from the Clinical Research Collaboration for Stroke in Korea (15 South Korean stroke centers) and the Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-NVAF registry (18 Japanese stroke centers). Data on 4841 eligible patients from the Clinical Research Collaboration for Stroke in Korea registry were pooled with data on all patients (n=1192) in the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry. The primary outcome was recurrent ischemic stroke. The secondary outcomes were hemorrhagic stroke and all-cause death. Outcome events were captured up to 1 year after the index event. Results- Among the 6033 patients in the full cohort, 5645 patients were analyzed, of whom 1129 patients (20.0%) had received prior anticoagulation. Median age was 75 years (interquartile range, 69-81 years), and 2649 patients (46.9%) were women. Follow-up data of 4617 patient-years (median follow-up 365 days, interquartile range 335-365 days) were available. The cumulative incidence of recurrent ischemic stroke in patients with prior anticoagulation was 5.3% (60/1129), compared with the 2.9% (130/4516) incidence in patients without prior anticoagulation. The risk for recurrent ischemic stroke was higher in patients with prior anticoagulation than in those without (multivariable Cox shared-frailty model, hazard ratio 1.50 [95% CI, 1.02-2.21]). No significant differences in the risks for hemorrhagic stroke and mortality were seen between the 2 groups. Conclusions- The risk for recurrent ischemic stroke may be higher in NVAF-associated stroke patients with prior anticoagulation than in those without prior anticoagulation. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01581502.



Stroke: 25 Feb 2020:STROKEAHA119027275; epub ahead of print
Tanaka K, Koga M, Lee KJ, Kim BJ, ... Toyoda K,
Stroke: 25 Feb 2020:STROKEAHA119027275; epub ahead of print | PMID: 32098607
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of incidence rates and risk factors of heart failure between two male cohorts born 30 years apart.

Ergatoudes C, Hansson PO, Svärdsudd K, Rosengren A, ... Pivodic A, Fu M
Objective
To compare two cohorts of middle-aged men from the general population born 30 years apart for incidence and predictors of heart failure (HF).
Methods
Two population samples of men, born in 1913 (n=855) and in 1943 (n=797), were examined at 50 years of age and followed up for 21 years (1963-1994 and 1993-2014). Cox regression analysis was used to examine the impact of different factors on the risk of developing HF.
Results
Eighty men born in 1913 (9.4%) and 42 men born in 1943 (5.3%) developed HF during follow-up; adjusted HRs comparing the two cohorts (born 1943 vs 1913) were: 0.46 (95% CI 0.28 to 0.74, p=0.002). In both cohorts, higher body mass index, higher diastolic blood pressure, treatment for hypertension, onset of either atrial fibrillation (AF), ischaemic heart disease and diabetes mellitus were associated with higher risk of HF. Higher heart rate was associated with an increased risk only in men born in 1913, whereas higher systolic blood pressure (SBP), smoking, higher glucose, higher cholesterol and physical inactivity were associated with an increased risk in men born in 1943. AF contributed higher risk of incident HF, whereas SBP and physical inactivity contributed lower risk in men born in 1943 compared with men born in 1913.
Conclusions
Men born in 1943 had half the risk of HF after their 50s than those born 30 years earlier. AF, obesity, ischaemic heart disease, diabetes and hypertension remain important precursors of HF.

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

Heart: 28 Feb 2020; epub ahead of print
Ergatoudes C, Hansson PO, Svärdsudd K, Rosengren A, ... Pivodic A, Fu M
Heart: 28 Feb 2020; epub ahead of print | PMID: 32114518
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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: 05 Mar 2020; epub ahead of print
LaRosa AR, Claxton J, O'Neal WT, Lutsey PL, ... Alonso A, Magnani JW
Heart: 05 Mar 2020; epub ahead of print | PMID: 32144188
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Trends of r-tPA (Recombinant Tissue-Type Plasminogen Activator) Treatment and Treatment-Influencing Factors in Acute Ischemic Stroke.

Marko M, Posekany A, Szabo S, Scharer S, ... Greisenegger S,

Background and Purpose- Frequencies of treatment with r-tPA (recombinant tissue-type plasminogen activator) are increasing over the past 15 years. However, published data on the influence of various demographic and clinical factors on r-tPA treatment as well as estimates of future trajectories are limited. We evaluated time trends and future trajectories of r-tPA treatment in patients with acute stroke and the influence of various factors on r-tPA treatment by analyzing data of 103 970 patients enrolled in the Austrian Stroke Unit Registry from 2006 to 2018, of which 18 953 were treated with r-tPA. Methods- Time trends of r-tPA-treatment were investigated in predefined subgroups (minor/major stroke, age, anterior/posterior circulation stroke); limited exponential time series models were calculated to estimate future trends of r-tPA-treatment. Logistic regression models were calculated to estimate the influence of clinical variables on r-tPA-treatment. Results- Overall, r-tPA treatment frequencies increased from 9.9% in 2006 to 21.8% in 2018. We observed a particular increase in patients >80 years, patients presenting with a National Institutes of Health Stroke Scale Score of 2 to 3, patients with posterior circulation stroke, patients with wake-up stroke, and patients without atrial fibrillation. Forecast of overall r-tPA frequencies predicted a further but flattened increase up to 24% by 2025. Logistic regression of time-dependent associations of clinical variables with r-tPA-treatment revealed increasing odds of r-tPA-treatment in patients with a posterior circulation stroke and decreasing odds of r-tPA-treatment in patients with atrial fibrillation. Conclusions- We observed a positive development of r-tPA-treatment frequencies mirroring increasing confidence with intravenous thrombolysis in clinical practice; however, decreasing odds of r-tPA-treatment over time in patients with atrial fibrillation deserve particular attention.



Stroke: 01 Mar 2020:STROKEAHA119027921; epub ahead of print
Marko M, Posekany A, Szabo S, Scharer S, ... Greisenegger S,
Stroke: 01 Mar 2020:STROKEAHA119027921; epub ahead of print | PMID: 32114931
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Multimodality imaging in patients with post-cardiac injury syndrome.

Verma BR, Chetrit M, Gentry Iii JL, Noll A, ... Jellis C, Klein AL

This review article is focused on the role of echocardiography, cardiac CT and cardiac magnetic resonance (CMR) imaging in diagnosing and managing patients with post-cardiac injury syndrome (PCIS). Clinically, the spectrum of pericardial diseases under PCIS varies not only in form and severity of presentation but also in the timing varying from weeks to months, thus making it difficult to diagnose. Pericarditis developing after recent or remote myocardial infarction, cardiac surgery or ablation if left untreated or under-treated could worsen into complicated pericarditis which can lead to decreased quality of life and increased morbidity. Colchicine in combination with other anti-inflammatory agents (non-steroidal anti-inflammatory drugs) is proven to prevent and treat acute pericarditis as well as its relapses under various scenarios. Imaging modalities such as echocardiography, CT and CMR play a pivotal role in diagnosing PCIS especially in difficult cases or when clinical suspicion is low. Echocardiography is the tool of choice for emergent bedside evaluation for cardiac tamponade and to electively study the haemodynamics impact of constrictive pericarditis. CT can provide information on pericardial thickening, calcification, effusions and lead perforations. CMR can provide pericardial tissue characterisation, haemodynamics changes and guide long-term treatment course with anti-inflammatory agents. It is important to be familiar with the indications as well as findings from these multimodality imaging tools for clinical decision-making.

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

Heart: 10 Mar 2020; epub ahead of print
Verma BR, Chetrit M, Gentry Iii JL, Noll A, ... Jellis C, Klein AL
Heart: 10 Mar 2020; epub ahead of print | PMID: 32161040
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prediction of prognosis in patients with tetralogy of Fallot based on deep learning imaging analysis.

Diller GP, Orwat S, Vahle J, Bauer UMM, ... Baumgartner H,
Objective
To assess the utility of machine learning algorithms for automatically estimating prognosis in patients with repaired tetralogy of Fallot (ToF) using cardiac magnetic resonance (CMR).
Methods
We included 372 patients with ToF who had undergone CMR imaging as part of a nationwide prospective study. Cine loops were retrieved and subjected to automatic deep learning (DL)-based image analysis, trained on independent, local CMR data, to derive measures of cardiac dimensions and function. This information was combined with established clinical parameters and ECG markers of prognosis.
Results
Over a median follow-up period of 10 years, 23 patients experienced an endpoint of death/aborted cardiac arrest or documented ventricular tachycardia (defined as >3 documented consecutive ventricular beats). On univariate Cox analysis, various DL parameters, including right atrial median area (HR 1.11/cm², p=0.003) and right ventricular long-axis strain (HR 0.80/%, p=0.009) emerged as significant predictors of outcome. DL parameters were related to adverse outcome independently of left and right ventricular ejection fraction and peak oxygen uptake (p<0.05 for all). A composite score of enlarged right atrial area and depressed right ventricular longitudinal function identified a ToF subgroup at significantly increased risk of adverse outcome (HR 2.1/unit, p=0.007).
Conclusions
We present data on the utility of machine learning algorithms trained on external imaging datasets to automatically estimate prognosis in patients with ToF. Due to the automated analysis process these two-dimensional-based algorithms may serve as surrogates for labour-intensive manually attained imaging parameters in patients with ToF.

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

Heart: 10 Mar 2020; epub ahead of print
Diller GP, Orwat S, Vahle J, Bauer UMM, ... Baumgartner H,
Heart: 10 Mar 2020; epub ahead of print | PMID: 32161041
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Non-Traumatic Subdural Hemorrhage and Risk of Arterial Ischemic Events.

Murthy SB, Wu X, Diaz I, Parasram M, ... Sheth KN, Kamel H

Background and Purpose- The risk of arterial ischemic events after subdural hemorrhage (SDH) is poorly understood. This study aimed to evaluate the risk of acute ischemic stroke and myocardial infarction among patients with and without nontraumatic SDH. Methods- We performed a retrospective cohort study using claims data from 2008 through 2014 from a nationally representative sample of Medicare beneficiaries. The exposure was nontraumatic SDH. Our primary outcome was an arterial ischemic event, a composite of acute ischemic stroke and acute myocardial infarction. Secondary outcomes were ischemic stroke alone and myocardial infarction alone. We used validated , ,diagnosis codes to identify our predictor and outcomes. Using Cox regression and corresponding survival probabilities, adjusted for demographics and vascular comorbidities, we computed the hazard ratio in 4-week intervals after SDH discharge. We performed secondary analyses stratified by strong indications for antithrombotic therapy (composite of atrial fibrillation, peripheral vascular disease, valvular heart disease, and venous thromboembolism). Results- Among 1.7 million Medicare beneficiaries, 2939 were diagnosed with SDH. In the 4 weeks after SDH, patients\' risk of an arterial ischemic event was substantially increased (hazard ratio, 3.6 [95% CI, 1.9-5.5]). There was no association between SDH diagnosis and arterial ischemic events beyond 4 weeks. In secondary analysis, during the 4 weeks after SDH, patients\' risk of ischemic stroke was increased (hazard ratio, 4.2 [95% CI, 2.1-7.3]) but their risk of myocardial infarction was not (hazard ratio, 0.8 [95% CI, 0.2-1.7]). Patients with strong indications for antithrombotic therapy had increased risks for arterial ischemic events similar to patients in the primary analysis, but those without such indications did not demonstrate an increased risk for arterial ischemic events. Conclusions- Among Medicare beneficiaries, we found a heightened risk of arterial ischemic events driven by an increased risk of ischemic stroke, in the 4 weeks after nontraumatic SDH. This increased risk may be due to interruption of antithrombotic therapy after SDH diagnosis.



Stroke: 16 Mar 2020:STROKEAHA119028510; epub ahead of print
Murthy SB, Wu X, Diaz I, Parasram M, ... Sheth KN, Kamel H
Stroke: 16 Mar 2020:STROKEAHA119028510; epub ahead of print | PMID: 32178587
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association Between High-Sensitivity Cardiac Troponin and Risk of Stroke in 96 702 Individuals: A Meta-Analysis.

Broersen LHA, Stengl H, Nolte CH, Westermann D, ... Siegerink B, Scheitz JF

Background and Purpose- Our study aim was to estimate risk of incident stroke based on levels of hs-cTn (high-sensitivity cardiac troponin), a specific biomarker indicating myocardial injury, in the general population, patients with atrial fibrillation, and patients with previous stroke. Methods- Embase, PubMed, and Web of Science were searched until March 14, 2019 to identify relevant articles. Randomized controlled trials and cohort studies assessing the risk of incident stroke based on hs-cTn were eligible. Pooled adjusted hazard ratios including 95% CI were calculated using a random-effects model due to study heterogeneity per population, coding of hs-cTn (categorical/continuous data), per hs-cTn subunit (T or I), for low risk of bias, and for all-cause and ischemic stroke separately. Results- We included 17 articles with 96 702 participants. In studies conducted in the general population (n=12; 77 780 participants), the pooled adjusted hazard ratio for incident stroke was 1.25 (CI, 1.10-1.40) for high versus low hs-cTn (as defined by included studies) during an average follow-up of 1 to 20 years (median 10). When categorical data were used, this was increased to 1.58 (CI, 1.26-1.90). The results were robust when accounting for stroke classification (all-cause stroke/ischemic stroke), hs-cTn subunit, risk of bias, and coding of hs-cTn. In patients with atrial fibrillation (4 studies; 18 725 participants), the pooled adjusted hazard ratio for incident stroke was 1.95 (CI, 1.29-2.62) for high versus low hs-cTn. Due to lack of data (one study, 197 participants), no meta-analysis could be performed in patients with previous stroke. Conclusions- This meta-analysis suggests that hs-cTn can be regarded as a risk marker for incident stroke, with different effect size in different subgroups. More research about the association between hs-cTn and incident stroke in high-risk populations is needed, especially in patients with history of ischemic stroke.



Stroke: 09 Feb 2020:STROKEAHA119028323; epub ahead of print
Broersen LHA, Stengl H, Nolte CH, Westermann D, ... Siegerink B, Scheitz JF
Stroke: 09 Feb 2020:STROKEAHA119028323; epub ahead of print | PMID: 32078461
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy.

Suffee N, Moore-Morris T, Jagla B, Mougenot N, ... Puceat M, Hatem SN

Fibro-fatty infiltration of sub-epicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation (AF).Here, we examined if the epicardium that contains multipotent cells is involved in this remodeling process.109 human surgical right atrial specimens were evaluated. There was a relatively greater extent of epicardial thickening and dense fibrofatty infiltrates in atrial tissue sections from patients aged over 70 years who had mitral valve disease or AF when compared to patients aged less than 70 years with ischemic cardiomyopathy as indicated using logistic regression adjusted for age and gender. Cells co-expressing markers of epicardial progenitors and fibroblasts were detected in fibro-fatty infiltrates. Such epicardial remodeling was reproduced in an experimental model of atrial cardiomyopathy in rat and in Wilm\'s Tumor-1 (WT1);ROSA-tdT mice. In the latter, genetic lineage tracing demonstrated the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of human adult epicardial-derived cells (aEPDCs) expressing Platelet-derived growth factor receptor-alpha (PDGFRalpha were isolated and differentiated into myofibroblasts in the presence of angiotensin-II. Furthermore, single cell RNA-seqencing analysis identified several clusters of aEPDCs and revealed their specification from adipogenic to fibrogenic cells in the rat model of atrial cardiomyopathy. Epicardium is reactivated during the formation of the atrial cardiomyopathy. Subsets of aEPDCs, pre-programmed towards a specific cell fate, contribute to fibro-fatty infiltration of sub-epicardium of diseased atria. Our study reveals the biological basis for chronic atrial myocardial remodeling that paves the way of AF.



Circ Res: 15 Mar 2020; epub ahead of print
Suffee N, Moore-Morris T, Jagla B, Mougenot N, ... Puceat M, Hatem SN
Circ Res: 15 Mar 2020; epub ahead of print | PMID: 32175811
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes.

Lee YK, Sala L, Mura M, Rocchetti M, ... Tse HF, Gnecchi M
Aims
In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action.
Methods and results
We generated human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from two patients carrying the same KCNQ1-Y111C mutation, but presenting opposite clinical phenotypes. We showed that the phenotype of the iPSC-CMs derived from the symptomatic patient is due to impaired trafficking and increased degradation of the mutant KCNQ1 and wild-type human ether-a-go-go-related gene. In the iPSC-CMs of the asymptomatic (AS) patient, the activity of an E3 ubiquitin-protein ligase (Nedd4L) involved in channel protein degradation was reduced and resulted in a decreased arrhythmogenic substrate. Two single-nucleotide variants (SNVs) on the Myotubularin-related protein 4 (MTMR4) gene, an interactor of Nedd4L, were identified by whole-exome sequencing as potential contributors to decreased Nedd4L activity. Correction of these SNVs by CRISPR/Cas9 unmasked the LQTS phenotype in AS cells. Importantly, the same MTMR4 variants were present in 77% of AS Y111C mutation carriers of a separate cohort. Thus, genetically mediated interference with Nedd4L activation seems associated with protective effects.
Conclusion
Our finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS. It provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway.

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

Cardiovasc Res: 15 Mar 2020; epub ahead of print
Lee YK, Sala L, Mura M, Rocchetti M, ... Tse HF, Gnecchi M
Cardiovasc Res: 15 Mar 2020; epub ahead of print | PMID: 32173736
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Atrial fibrillation and the risk of cardiovascular disease and mortality in the Hypertension in the Very Elderly Trial.

Antikainen RL, Peters R, Beckett NS, Rajkumar C, Bulpitt CJ
Objective
To assess the prognostic value of electrocardiographic atrial fibrillation in older hypertensive people in the randomized, placebo-controlled Hypertension in the Very Elderly Trial.
Methods
Hypertension in the Very Elderly Trial randomized 3845 hypertensive people aged 80 years and over, 3273 with electrographic data on the presence or absence of atrial fibrillation at baseline and without established cardiovascular disease. Multivariate Cox proportional hazard models were used to estimate hazard ratios with 95% confidence intervals (CIs) for all-cause mortality, incident fatal and nonfatal major cardiovascular events, all-stroke and all-heart failure. The mean follow-up time was 2.1 years.
Results
Baseline prevalence of atrial fibrillation was 5.8%. Compared with people without atrial fibrillation at baseline, after adjustments the presence of atrial fibrillation was associated with increased risk of mortality (hazard ratio = 2.49, 95% CI = 1.80-3.44, P < 0.001), of nonfatal and fatal cardiovascular events (hazard ratio = 2.47, 95% CI = 1.71-3.55, P < 0.001), all-stroke (hazard ratio = 2.47, 95% CI = 1.34-4.56, P = 0.004) and all-heart failure (hazard ratio 2.33, 95% CI = 1.10-4.93, P = 0.027).
Conclusion
Atrial fibrillation is an important risk factor to consider when assessing older hypertensive adults as it is associated with increased risk of mortality, nonfatal and fatal cardiovascular events, stroke and heart failure.



J Hypertens: 07 Jan 2020; epub ahead of print
Antikainen RL, Peters R, Beckett NS, Rajkumar C, Bulpitt CJ
J Hypertens: 07 Jan 2020; epub ahead of print | PMID: 31917714
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Dabigatran Reversal Before Intravenous Tenecteplase in Acute Ischemic Stroke.

Beharry J, Waters MJ, Drew R, Fink JN, ... Kleinig TJ, Wu TY

Background and Purpose- Reversal of dabigatran before intravenous thrombolysis in patients with acute ischemic stroke has been well described using alteplase but experience with intravenous tenecteplase is limited. Tenecteplase seems at least noninferior to alteplase in patients with intracranial large vessel occlusion. We report on the experience of dabigatran reversal before tenecteplase thrombolysis for acute ischemic stroke. Methods- We included consecutive patients with ischemic stroke receiving dabigatran prestroke treated with intravenous tenecteplase after receiving idarucizumab. Patients were from 2 centers in New Zealand and Australia. We reported the clinical, laboratory, and radiological characteristics and their functional outcome. Results- We identified 13 patients receiving intravenous tenecteplase after dabigatran reversal. Nine (69%) were male, median age was 79 (interquartile range, 69-85) and median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 4-21). Atrial fibrillation was the indication for dabigatran therapy in all patients. All patients had a prolonged thrombin clotting time (median, 80 seconds [interquartile range, 57-113]). Seven patients with large vessel occlusion were referred for endovascular thrombectomy, 2 of these patients (29%) had early recanalization with tenecteplase abrogating thrombectomy. No patients had parenchymal hemorrhage or symptomatic hemorrhagic transformation. Favorable functional outcome (modified Rankin Scale score, 0-2) occurred in 8 (62%) patients. Two deaths occurred from large territory infarction. Conclusions- Our experience suggests intravenous thrombolysis with tenecteplase following dabigatran reversal using idarucizumab may be safe in selected patients with acute ischemic stroke. Further studies are required to more precisely estimate the efficacy and risk of clinically significant hemorrhage.



Stroke: 24 Mar 2020:STROKEAHA119028327; epub ahead of print
Beharry J, Waters MJ, Drew R, Fink JN, ... Kleinig TJ, Wu TY
Stroke: 24 Mar 2020:STROKEAHA119028327; epub ahead of print | PMID: 32208845
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cold-Inducible RNA-Binding Protein Prevents an Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase.

Xie D, Geng L, Xiong K, Zhao T, ... Liang D, Chen YH

The stress response of heart rate (HR), which is determined by the plasticity of the sinus node (SAN), is essential for cardiac function and survival in mammals. As an RNA binding protein, cold-inducible RNA-binding protein (CIRP) can act as a stress regulator. Previously, we\'ve documented that CIRP regulates cardiac electrophysiology at post-transcriptional level, suggesting its role in SAN plasticity, especially upon stress conditions.Our aim was to clarify the role of CIRP in SAN plasticity and HR regulation under stress conditions.Telemetric ECG monitoring demonstrated an excessive acceleration of HR under isoprenaline (ISO) stimulation in conscious CIRP knockout (CIRP-KO) rats. Patch clamp analysis and confocal microscopic Ca2+ imaging of isolated SAN cells (SANCs) demonstrated that ISO stimulation induced a faster spontaneous firing rate in CIRP-KO SANCs than that in wild type (WT) SANCs. A higher concentration of cyclic adenosine monophosphate (cAMP), the key mediator of pacemaker activity, was detected in CIRP-KO SAN tissues than in WT SAN tissues. RNA-sequencing and quantitative real-time polymerase chain reaction (qPCR) analyses of single cells revealed that the 4B and 4D subtypes of phosphodiesterase (PDE), which controls cAMP degradation, were significantly decreased in CIRP-KO SANCs. A PDE4 inhibitor (Rolipram) abolished the difference in beating rate resulting from CIRP deficiency. The mechanistic study showed that CIRP stabilized the mRNA of PDE4B and PDE4D by direct mRNA binding, thereby regulating the protein expression of PDE4B and PDE4D at post-transcriptional level.CIRP acts as an mRNA stabilizer of specific PDEs to control the cAMP concentration in SAN, maintaining the appropriate HR stress response.



Circ Res: 25 Mar 2020; epub ahead of print
Xie D, Geng L, Xiong K, Zhao T, ... Liang D, Chen YH
Circ Res: 25 Mar 2020; epub ahead of print | PMID: 32212953
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Impact of Bariatric Surgery on Atrial Fibrillation Type.

Donnellan E, Wazni O, Elshazly M, Kanj M, ... Jaber W, Saliba W

- Obesity is an independent risk factor for atrial fibrillation (AF) and is associated with a higher AF burden. Recently, weight loss has been found to be associated with a significant reversal in AF type. Bariatric surgery (BS) is associated with reductions in inflammation, left atrial and ventricular remodeling, sleep apnea, blood pressure and improved glycemic control, all of which may reduce AF burden. In this study we sought to determine the impact of BS on AF type.- We studied AF type prior to and following BS in 220 morbidly obese patients (BMI Ȧ5; 40 kg/m). All patients underwent extended outpatient cardiac rhythm monitoring within 12 months of BS and at least 1 year after BS.- There was a significant reduction in BMI following BS from 49.7±9 to 37.2±9 kg/m. Weight loss was greatest in the gastric bypass group with a mean % weight loss of 25% compared to 19% in patients who underwent sleeve gastrectomy and 16% following gastric banding (p<0.0001). Significant reductions in CRP, NT-proBNP, HbA1C and systolic blood pressure were observed in all 3 groups. Reversal of AF type occurred in 71% of patients following gastric bypass, 56% of patients who underwent sleeve gastrectomy and 50% of patients following gastric banding (p=0.004). On Cox proportional hazards analyses, % weight loss was significantly associated with AF reversal (p=0.0002).- Bariatric surgery is associated with significant reductions in weight, inflammatory markers, blood pressure and AF type and the beneficial effects appear to be greatest in those undergoing gastric bypass surgery. This study further exemplifies the importance of weight loss and risk factor modification in AF management.



Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print
Donnellan E, Wazni O, Elshazly M, Kanj M, ... Jaber W, Saliba W
Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print | PMID: 31940441
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Physiological Left Bundle Branch Pacing Validated by Ultra-high Density Ventricular Mapping in a Swine Model.

Qian Z, Hou X, Wang Y, Jiang H, ... Wang B, Zou J

Left bundle branch (LBB) pacing was first reported by Huang et al in 2017 and following studies demonstrated that LBB pacing could provide favorable left ventricular (LV) electrical and mechanical synchrony. However, the mechanism of LV activation during LBB pacing is not fully understood. This study aimed to elucidate the detailed LV endocardial activation during LBB pacing in a swine model using an ultra-high density electroanatomic mapping system.



Circ Arrhythm Electrophysiol: 13 Jan 2020; epub ahead of print
Qian Z, Hou X, Wang Y, Jiang H, ... Wang B, Zou J
Circ Arrhythm Electrophysiol: 13 Jan 2020; epub ahead of print | PMID: 31935122
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Incidence of Ischemic Stroke in Individuals With and Without Aortic Valve Stenosis: A Danish Retrospective Cohort Study.

Andreasen C, Gislason GH, Køber L, Abdulla J, ... Torp-Pedersen C, Andersson C

Background and Purpose- Aortic valve stenosis may lead to atrial and ventricular remodeling, predisposes to atrial fibrillation, and may also be an independent risk factor of ischemic stroke. However, information on stroke rates among persons with aortic valve stenosis are sparse. We aimed to determine the incidence rates and relative risks of ischemic stroke in individuals with diagnosed aortic valve stenosis compared with age- and sex-matched controls. Methods- All patients with incident aortic valve stenosis aged >18 years (n=79 310) and age- and sex-matched controls were identified using the Danish nationwide registries (1997-2017). Incidence rates per 1000 person-years (PY) and multivariable adjusted hazard ratios with 95% CIs were reported. Results- In total, 873 373 individuals (median age 77 years, 51.5% men, 9.1% with aortic valve stenosis) were included. Ischemic stroke occurred in 70 205 (8.0%) individuals during 4 880 862 PY of follow-up. Incidence rates of ischemic stroke were 13.3/1000 PY among the controls compared with 30.4/1000 PY in patients with aortic valve stenosis, corresponding to a hazard ratio of 1.31 (95% CI, 1.28-1.34). In all age-groups, the incidence rates and relative risks were significantly increased in patients with aortic valve stenosis compared with controls, but the relative risk was greater for younger individuals (eg, age group, 18-45 years: hazard ratio, 5.94 [95% CI, 4.10-8.36]). In patients with aortic valve stenosis above 65 years of age, the risk of ischemic stroke was markedly lower after aortic valve replacement (30.3 versus 19.6/1000 PY before and after valve replacement). Among people with atrial fibrillation the incidence rate of ischemic stroke was 1.5 times higher when aortic valve stenosis was present (33.0/1000 PY versus 49.9/1000 PY). Conclusions- People with aortic valve stenosis have a significantly increased risk of ischemic stroke compared with age- and sex-matched controls. Future studies are warranted to explore whether antithrombotic therapy may be beneficial in some individuals.



Stroke: 26 Mar 2020:STROKEAHA119028389; epub ahead of print
Andreasen C, Gislason GH, Køber L, Abdulla J, ... Torp-Pedersen C, Andersson C
Stroke: 26 Mar 2020:STROKEAHA119028389; epub ahead of print | PMID: 32216533
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Protein Biomarkers and Risk of Atrial Fibrillation: The Framingham Heart Study.

Staerk L, Preis SR, Lin H, Lubitz SA, ... Benjamin EJ, Trinquart L

- Identification of protein biomarkers associated with incident atrial fibrillation (AF) may improve the understanding of the pathophysiology, risk prediction, and development of new therapeutics for AF. We examined the associations between 85 protein biomarkers and incident AF.- We included participants Ȧ5;50 years of age from the Framingham Heart Study Offspring and Third Generation cohorts, who had 85 fasting plasma proteins measured using Luminex xMAP platform. Hazard ratios (per 1 standard deviation increment of rank normalized biomarker [HR]) and 95% confidence intervals (CI) for incident AF were calculated using Cox regression models adjusted for age, sex, height, weight, current smoking, systolic blood pressure, diastolic blood pressure, hypertension treatment, diabetes, valvular heart disease, prevalent myocardial infarction, and prevalent heart failure. We used the False Discovery Rate to account for multiple testing.- The study sample comprised 3378 participants (54% women), with mean (SD) age of 61.5 (8.4) years. In total, 401 developed AF over a mean follow-up of 12.3±3.8 years. We observed lower hazard of incident AF associated with higher mean levels of insulin-like growth factor 1 (IGF1) (HR per 1 standard deviation increment in protein level = 0.84; 95% CI, 0.76-0.93), and higher hazard of incident AF associated with higher mean levels of both insulin-like growth factor-binding protein 1 (IGFBP1) (HR = 1.24; 95% CI, 1.1-1.39) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (HR = 1.73; 95% CI, 1.52-1.96).- Decreased levels of IGF1 and increased levels of IGFBP1 and NT-proBNP were associated with higher risk of incident AF.



Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print
Staerk L, Preis SR, Lin H, Lubitz SA, ... Benjamin EJ, Trinquart L
Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print | PMID: 31941368
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Evaluation of ECG Imaging to Map Haemodynamically Stable and Unstable Ventricular Arrhythmias.

Graham AJ, Orini M, Zacur E, Dhillon G, ... Schilling RJ, Lambiase PD

- ECG Imaging (ECGI) has been used to guide treatment of ventricular ectopy and arrhythmias. However, the accuracy of ECGI in localizing the origin of arrhythmias during catheter ablation of ventricular tachycardia (VT) in structurally abnormal hearts remains to be fully validated.- During catheter ablation of VT, simultaneous mapping was performed using electro-anatomical mapping (EAM) (CARTO, Biosense-Webster) and ECGI (CardioInsight™, Medtronic) in 18 patients. Sites of entrainment, pace-mapping and termination during ablation were used to define the VT site of origin (SoO). Distance between SoO and the site of earliest activation on ECGI were measured using co-registered geometries from both systems. The accuracy of ECGI vs a 12-lead surface ECG algorithm was compared.- A total of 29 VTs were available for comparison. Distance between SoO and sites of earliest activation in ECGI was 22.6, 13.9-36.2 mm (median, first-third quartile). ECGI mapped VT sites of origin onto the correct AHA segment with higher accuracy than a validated 12-lead ECG algorithm (83.3% vs 38.9%, P=0.015).- This simultaneous assessment demonstrates that CardioInsight™ localizes VT circuits with sufficient accuracy to provide a region of interest for targeting mapping for ablation. Resolution is not sufficient to guide discrete radiofrequency lesion delivery via catheter ablation without concomitant use of an electro-anatomical mapping system, but may be sufficient for segmental ablation with radiotherapy.



Circ Arrhythm Electrophysiol: 13 Jan 2020; epub ahead of print
Graham AJ, Orini M, Zacur E, Dhillon G, ... Schilling RJ, Lambiase PD
Circ Arrhythm Electrophysiol: 13 Jan 2020; epub ahead of print | PMID: 31934784
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association of Left Atrial High-Resolution Late Gadolinium Enhancement on Cardiac Magnetic Resonance with Electrogram Abnormalities Beyond Voltage in Patients with Atrial Fibrillation.

Kuo L, Zado E, Frankel D, Santangeli P, ... Nazarian S, Desjardins B

- Conflicting data have been reported on the association of left atrial (LA) late gadolinium enhancement (LGE) with atrial voltage in patients with atrial fibrillation. The association of LGE with electrogram (EGM) fractionation and delay remains to be examined. We sought to examine the association between LA LGE on cardiac magnetic resonance (CMR) and EGM abnormalities in patients with atrial fibrillation (AF).- High-resolution LGE CMR was performed prior to EGM mapping and ablation in AF patients. CMR features were quantified using LA myocardial signal intensity z-score (SI-Z), a continuous normalized variable, as well as a dichotomous LGE variable based upon previously validated methodology. EGM mapping was performed pre-ablation during sinus rhythm or LA pacing, and EGM locations were co-registered with CMR images. Analyses were performed using multi-level patient-clustered mixed effects regression models.- In the 40 AF patients (age 63.2 ± 9.2 years, 1312.3 ± 767.3 EGM points per patient), lower bipolar voltage was associated with higher SI-Z in patients who had undergone previous ablation (coefficient=-0.049, p<0.001), but not in ablation-naïve patients (coefficient=-0.004, p=0.7). LA EGM activation delay was associated with SI-Z in patients with previous ablation (SI-Z: coefficient=0.004, p<0.001; LGE: coefficient=0.04, p<0.001) but not in ablation-naïve patients. In contrast, increased LA EGM fractionation was associated with SI-Z (coefficient=0.012, p=0.03) and LGE (coefficient=0.035, P<0.001) only in ablation-naïve patients.- The association of LA LGE with voltage is modified by ablation. Importantly, in ablation naïve patients, atrial LGE is associated with EGM fractionation even in the absence of voltage abnormalities.



Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print
Kuo L, Zado E, Frankel D, Santangeli P, ... Nazarian S, Desjardins B
Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print | PMID: 31940244
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Epicardial Connections Involving Pulmonary Veins: The Prevalence, Predic-tors and Implications for Ablation Outcome.

Barrio-López MT, Sanchez-Quintana D, Garcia Martinez J, Betancur A, ... Garcia F, Almendral J

- The presence of epicardial connections (ECs) between pulmonary veins (PVs) and other anatomical structures may hinder PV isolation. In this study we analyzed their prevalence, location, associated factors and clinical implications.- Five hundred and thirty-four consecutive patients with atrial fibrillation (AF) undergoing radiofrequency ablation were included. We considered that an EC was present if: 1) the first pass around the PV antrum did not produce PV isolation and 2) subsequent atrial activation during PV pacing showed that the earliest site was located away from the ablation line and later activation sites were observed near the ablation line. Clinical, and electrophysological variables were collected from all patients. Patients were followed during 12.9±9.4 months and any documented atrial tachyarrhythmia after the 3-month blanking period was classified as a recurrence.- Out of the 534 patients included, 72 (13.5%) were found to have 81 ECs. There was a significant association between the presence ECs and structural heart disease (SHD) (15.3% in patients without ECs vs. 36.5% in patient with ECs; p<0.001) and patent foramen ovale (PFO) (4.6% vs. 13.5%; p=0.002). The presence of a left common trunk was significantly associated with the absence of ECs (29.6% in patients without ECs vs 16.2% in patients with ECs; p=0.014). Patients with ECs had lower acute success in PV isolation compared with patients without ECs (99.1% vs. 86.1%; p<0.001). After adjusting for age, sex, type of AF, LA area, hypertension, SHD, presence of left common trunk, patent foramen ovale and time for AF diagnosis to the ablation we found a significantly higher risk of atrial tachyarrhythmia recurrences in patients with ECs compared with patients without ECs (hazard ratio: 1.7; 95% confidence inter-val: 1.1-2.9; p=0.04).- ECs between PVs and other adjacent structures are frequent in patient with AF (prevalence: 13.5%). SHD and a PFO are strongly associated with the presence of ECs. ECs reduce the acute and chronic success of PV isolation.



Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print
Barrio-López MT, Sanchez-Quintana D, Garcia Martinez J, Betancur A, ... Garcia F, Almendral J
Circ Arrhythm Electrophysiol: 14 Jan 2020; epub ahead of print | PMID: 31940223
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Differences by Race/Ethnicity in the Prevalence of Clinically-detected and Monitor-detected Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis.

Heckbert SR, Austin TR, Jensen PN, Chen LY, ... Kronmal RA, Psaty BM

- African Americans are consistently found to have a lower prevalence of clinically-detected atrial fibrillation (AF) than whites, despite a higher prevalence of major AF risk factors and higher risk of ischemic stroke. Long-term ambulatory electrocardiographic (ECG) monitors provide the opportunity for unbiased AF detection. We determined differences by race/ethnicity in the prevalence of clinically-detected AF and in the proportion with monitor-detected AF.- We conducted a cross-sectional analysis in the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based cohort study that enrolled 6814 Americans free of clinically-recognized cardiovascular disease in 2000-2002. At the 2016-2018 examination, 1556 individuals participated in an ancillary study involving ambulatory ECG monitoring and had follow-up for clinically-detected AF since cohort entry.- Among 1556 participants, 41% were white, 25% African American, 21% Hispanic, and 14% Chinese; 51% were women; and the mean age was 74 years. The prevalence of clinically-detected AF after 14.4 years\' follow-up was 11.3% in whites, 6.6% in African Americans, 7.8% in Hispanics, and 9.9% in Chinese, and was significantly lower in African Americans than in whites, in both unadjusted and risk factor-adjusted analyses (adjusted rate difference, -6.6%, 95% CI -10.1, -3.1%, P < 0.001). By contrast, in the same individuals, the proportion with monitor-detected AF using a 14-day ambulatory ECG monitor was similar in the four race/ethnic groups: 7.1%, 6.4%, 6.9%, and 5.2%, respectively (compared with whites, all P > 0.5).- The prevalence of clinically-detected AF was substantially lower in African American than in white participants, without or with adjustment for AF risk factors. However, unbiased AF detection by ambulatory monitoring in the same individuals revealed little difference in the proportion with AF by race/ethnicity. These findings provide support for the hypothesis of differential detection by race/ethnicity in the clinical recognition of AF, which may have important implications for stroke prevention.



Circ Arrhythm Electrophysiol: 13 Jan 2020; epub ahead of print
Heckbert SR, Austin TR, Jensen PN, Chen LY, ... Kronmal RA, Psaty BM
Circ Arrhythm Electrophysiol: 13 Jan 2020; epub ahead of print | PMID: 31934795
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Older ...

This program is still in alpha version.