Topic: Electrophysiology

Abstract

Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis.

Kang DH, Park SJ, Lee SA, Lee S, ... Lee JW, Park SW
Background
The timing and indications for surgical intervention in asymptomatic patients with severe aortic stenosis remain controversial.
Methods
In a multicenter trial, we randomly assigned 145 asymptomatic patients with very severe aortic stenosis (defined as an aortic-valve area of ≤0.75 cm with either an aortic jet velocity of ≥4.5 m per second or a mean transaortic gradient of ≥50 mm Hg) to early surgery or to conservative care according to the recommendations of current guidelines. The primary end point was a composite of death during or within 30 days after surgery (often called operative mortality) or death from cardiovascular causes during the entire follow-up period. The major secondary end point was death from any cause during follow-up.
Results
In the early-surgery group, 69 of 73 patients (95%) underwent surgery within 2 months after randomization, and there was no operative mortality. In an intention-to-treat analysis, a primary end-point event occurred in 1 patient in the early-surgery group (1%) and in 11 of 72 patients in the conservative-care group (15%) (hazard ratio, 0.09; 95% confidence interval [CI], 0.01 to 0.67; P = 0.003). Death from any cause occurred in 5 patients in the early-surgery group (7%) and in 15 patients in the conservative-care group (21%) (hazard ratio, 0.33; 95% CI, 0.12 to 0.90). In the conservative-care group, the cumulative incidence of sudden death was 4% at 4 years and 14% at 8 years.
Conclusions
Among asymptomatic patients with very severe aortic stenosis, the incidence of the composite of operative mortality or death from cardiovascular causes during the follow-up period was significantly lower among those who underwent early aortic-valve replacement surgery than among those who received conservative care. (Funded by the Korean Institute of Medicine; RECOVERY ClinicalTrials.gov number, NCT01161732.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 08 Jan 2020; 382
Kang DH, Park SJ, Lee SA, Lee S, ... Lee JW, Park SW
N Engl J Med: 08 Jan 2020; 382 | PMID: 31733181
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Abstract

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
Background
Excessive alcohol consumption is associated with incident atrial fibrillation and adverse atrial remodeling; however, the effect of abstinence from alcohol on secondary prevention of atrial fibrillation is unclear.
Methods
We conducted a multicenter, prospective, open-label, randomized, controlled trial at six hospitals in Australia. Adults who consumed 10 or more standard drinks (with 1 standard drink containing approximately 12 g of pure alcohol) per week and who had paroxysmal or persistent atrial fibrillation in sinus rhythm at baseline were randomly assigned in a 1:1 ratio to either abstain from alcohol or continue their usual alcohol consumption. The two primary end points were freedom from recurrence of atrial fibrillation (after a 2-week \"blanking period\") and total atrial fibrillation burden (proportion of time in atrial fibrillation) during 6 months of follow-up.
Results
Of 140 patients who underwent randomization (85% men; mean [±SD] age, 62±9 years), 70 were assigned to the abstinence group and 70 to the control group. Patients in the abstinence group reduced their alcohol intake from 16.8±7.7 to 2.1±3.7 standard drinks per week (a reduction of 87.5%), and patients in the control group reduced their alcohol intake from 16.4±6.9 to 13.2±6.5 drinks per week (a reduction of 19.5%). After a 2-week blanking period, atrial fibrillation recurred in 37 of 70 patients (53%) in the abstinence group and in 51 of 70 patients (73%) in the control group. The abstinence group had a longer period before recurrence of atrial fibrillation than the control group (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; P = 0.005). The atrial fibrillation burden over 6 months of follow-up was significantly lower in the abstinence group than in the control group (median percentage of time in atrial fibrillation, 0.5% [interquartile range, 0.0 to 3.0] vs. 1.2% [interquartile range, 0.0 to 10.3]; P = 0.01).
Conclusions
Abstinence from alcohol reduced arrhythmia recurrences in regular drinkers with atrial fibrillation. (Funded by the Government of Victoria Operational Infrastructure Support Program and others; Australian New Zealand Clinical Trials Registry number, ACTRN12616000256471.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:20-28
Voskoboinik A, Kalman JM, De Silva A, Nicholls T, ... Taylor AJ, Kistler PM
N Engl J Med: 01 Jan 2020; 382:20-28 | PMID: 31893513
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Abstract

Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A.

Pasi KJ, Rangarajan S, Mitchell N, Lester W, ... Pierce GF, Wong WY
Background
Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ.
Methods
We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.
Results
Three years after infusion, two participants (one who had received 6×10 vector genomes [vg] per kilogram of body weight and one who had received 2×10 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.
Conclusions
Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 vg per kilogram or 6×10 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:29-40
Pasi KJ, Rangarajan S, Mitchell N, Lester W, ... Pierce GF, Wong WY
N Engl J Med: 01 Jan 2020; 382:29-40 | PMID: 31893514
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Abstract

Circulating stem cells and cardiovascular outcomes: from basic science to the clinic.

Fadini GP, Mehta A, Dhindsa DS, Bonora BM, ... Nagareddy P, Quyyumi AA

The cardiovascular and haematopoietic systems have fundamental inter-relationships during development, as well as in health and disease of the adult organism. Although haematopoietic stem cells (HSCs) emerge from a specialized haemogenic endothelium in the embryo, persistence of haemangioblasts in adulthood is debated. Rather, the vast majority of circulating stem cells (CSCs) is composed of bone marrow-derived HSCs and the downstream haematopoietic stem/progenitors (HSPCs). A fraction of these cells, known as endothelial progenitor cells (EPCs), has endothelial specification and vascular tropism. In general, the levels of HSCs, HSPCs, and EPCs are considered indicative of the endogenous regenerative capacity of the organism as a whole and, particularly, of the cardiovascular system. In the last two decades, the research on CSCs has focused on their physiologic role in tissue/organ homoeostasis, their potential application in cell therapies, and their use as clinical biomarkers. In this review, we provide background information on the biology of CSCs and discuss in detail the clinical implications of changing CSC levels in patients with cardiovascular risk factors or established cardiovascular disease. Of particular interest is the mounting evidence available in the literature on the close relationships between reduced levels of CSCs and adverse cardiovascular outcomes in different cohorts of patients. We also discuss potential mechanisms that explain this association. Beyond CSCs\' ability to participate in cardiovascular repair, levels of CSCs need to be interpreted in the context of the broader connections between haematopoiesis and cardiovascular function, including the role of clonal haematopoiesis and inflammatory myelopoiesis.

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

Eur Heart J: 30 Dec 2019; epub ahead of print
Fadini GP, Mehta A, Dhindsa DS, Bonora BM, ... Nagareddy P, Quyyumi AA
Eur Heart J: 30 Dec 2019; epub ahead of print | PMID: 31891403
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Abstract

Changes in Quality of Care after Hospital Mergers and Acquisitions.

Beaulieu ND, Dafny LS, Landon BE, Dalton JB, Kuye I, McWilliams JM
Background
The hospital industry has consolidated substantially during the past two decades and at an accelerated pace since 2010. Multiple studies have shown that hospital mergers have led to higher prices for commercially insured patients, but research about effects on quality of care is limited.
Methods
Using Medicare claims and Hospital Compare data from 2007 through 2016 on performance on four measures of quality of care (a composite of clinical-process measures, a composite of patient-experience measures, mortality, and the rate of readmission after discharge) and data on hospital mergers and acquisitions occurring from 2009 through 2013, we conducted difference-in-differences analyses comparing changes in the performance of acquired hospitals from the time before acquisition to the time after acquisition with concurrent changes for control hospitals that did not have a change in ownership.
Results
The study sample included 246 acquired hospitals and 1986 control hospitals. Being acquired was associated with a modest differential decline in performance on the patient-experience measure (adjusted differential change, -0.17 SD; 95% confidence interval [CI], -0.26 to -0.07; P = 0.002; the change was analogous to a fall from the 50th to the 41st percentile) and no significant differential change in 30-day readmission rates (-0.10 percentage points; 95% CI, -0.53 to 0.34; P = 0.72) or in 30-day mortality (-0.03 percentage points; 95% CI, -0.20 to 0.14; P = 0.72). Acquired hospitals had a significant differential improvement in performance on the clinical-process measure (0.22 SD; 95% CI, 0.05 to 0.38; P = 0.03), but this could not be attributed conclusively to a change in ownership because differential improvement occurred before acquisition.
Conclusions
Hospital acquisition by another hospital or hospital system was associated with modestly worse patient experiences and no significant changes in readmission or mortality rates. Effects on process measures of quality were inconclusive. (Funded by the Agency for Healthcare Research and Quality.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 01 Jan 2020; 382:51-59
Beaulieu ND, Dafny LS, Landon BE, Dalton JB, Kuye I, McWilliams JM
N Engl J Med: 01 Jan 2020; 382:51-59 | PMID: 31893515
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Abstract

Complete revascularization reduces cardiovascular death in patients with ST-segment elevation myocardial infarction and multivessel disease: systematic review and meta-analysis of randomized clinical trials.

Pavasini R, Biscaglia S, Barbato E, Tebaldi M, ... D\'Ascenzo F, Campo G
Aims
The aim of this work was to investigate the prognostic impact of revascularization of non-culprit lesions in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease by performing a meta-analysis of available randomized clinical trials (RCTs).
Methods and results
Data from six RCTs comparing complete vs. culprit-only revascularization in STEMI patients with multivessel disease were analysed with random effect generic inverse variance method meta-analysis. The endpoints were expressed as hazard ratio (HR) with 95% confidence interval (CI). The primary outcome was cardiovascular death. Main secondary outcomes of interest were all-cause death, myocardial infarction (MI), and repeated coronary revascularization. Overall, 6528 patients were included (3139 complete group, 3389 culprit-only group). After a follow-up ranging between 1 and 3 years (median 2 years), cardiovascular death was significantly reduced in the group receiving complete revascularization (HR 0.62, 95% CI 0.39-0.97, I2 = 29%). The number needed to treat to prevent one cardiovascular death was 70 (95% CI 36-150). The secondary endpoints MI and revascularization were also significantly reduced (HR 0.68, 95% CI 0.55-0.84, I2 = 0% and HR 0.29, 95% CI 0.22-0.38, I2 = 36%, respectively). Needed to treats were 45 (95% CI 37-55) for MI and 8 (95% CI 5-13) for revascularization. All-cause death (HR 0.81, 95% CI 0.56-1.16, I2 = 27%) was not affected by the revascularization strategy.
Conclusion
In a selected study population of STEMI patients with multivessel disease, a complete revascularization strategy is associated with a reduction in cardiovascular death. This reduction is concomitant with that of MI and the need of repeated revascularization.

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

Eur Heart J: 30 Dec 2019; epub ahead of print
Pavasini R, Biscaglia S, Barbato E, Tebaldi M, ... D'Ascenzo F, Campo G
Eur Heart J: 30 Dec 2019; epub ahead of print | PMID: 31891653
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Abstract

Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.

Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, ... Witztum JL,
Background
Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.
Methods
We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L, referred to here as APO(a)-L (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).
Results
The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-L resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-L dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.
Conclusions
APO(a)-L reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 31 Dec 2019; epub ahead of print
Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, ... Witztum JL,
N Engl J Med: 31 Dec 2019; epub ahead of print | PMID: 31893580
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Abstract

Fractional flow reserve in clinical practice: from wire-based invasive measurement to image-based computation.

Tu S, Westra J, Adjedj J, Ding D, ... Reiber JHC, Wijns W

Fractional flow reserve (FFR) and instantaneous wave-free ratio are the present standard diagnostic methods for invasive assessment of the functional significance of epicardial coronary stenosis. Despite the overall trend towards more physiology-guided revascularization, there remains a gap between guideline recommendations and the clinical adoption of functional evaluation of stenosis severity. A number of image-based approaches have been proposed to compute FFR without the use of pressure wire and induced hyperaemia. In order to better understand these emerging technologies, we sought to highlight the principles, diagnostic performance, clinical applications, practical aspects, and current challenges of computational physiology in the catheterization laboratory. Computational FFR has the potential to expand and facilitate the use of physiology for diagnosis, procedural guidance, and evaluation of therapies, with anticipated impact on resource utilization and patient outcomes.

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

Eur Heart J: 29 Dec 2019; epub ahead of print
Tu S, Westra J, Adjedj J, Ding D, ... Reiber JHC, Wijns W
Eur Heart J: 29 Dec 2019; epub ahead of print | PMID: 31886479
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Abstract

Health Care Hotspotting - A Randomized, Controlled Trial.

Finkelstein A, Zhou A, Taubman S, Doyle J
Background
There is widespread interest in programs aiming to reduce spending and improve health care quality among \"superutilizers,\" patients with very high use of health care services. The \"hotspotting\" program created by the Camden Coalition of Healthcare Providers (hereafter, the Coalition) has received national attention as a promising superutilizer intervention and has been expanded to cities around the country. In the months after hospital discharge, a team of nurses, social workers, and community health workers visits enrolled patients to coordinate outpatient care and link them with social services.
Methods
We randomly assigned 800 hospitalized patients with medically and socially complex conditions, all with at least one additional hospitalization in the preceding 6 months, to the Coalition\'s care-transition program or to usual care. The primary outcome was hospital readmission within 180 days after discharge.
Results
The 180-day readmission rate was 62.3% in the intervention group and 61.7% in the control group. The adjusted between-group difference was not significant (0.82 percentage points; 95% confidence interval, -5.97 to 7.61). In contrast, a comparison of the intervention-group admissions during the 6 months before and after enrollment misleadingly suggested a 38-percentage-point decline in admissions related to the intervention because the comparison did not account for the similar decline in the control group.
Conclusions
In this randomized, controlled trial involving patients with very high use of health care services, readmission rates were not lower among patients randomly assigned to the Coalition\'s program than among those who received usual care. (Funded by the National Institute on Aging and others; ClinicalTrials.gov number, NCT02090426; American Economic Association registry number, AEARCTR-0000329.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 08 Jan 2020; 382:152-162
Finkelstein A, Zhou A, Taubman S, Doyle J
N Engl J Med: 08 Jan 2020; 382:152-162 | PMID: 31914242
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Abstract

Chronic infarct size after spontaneous coronary artery dissection: implications for pathophysiology and clinical management.

Al-Hussaini A, Abdelaty AMSEK, Gulsin GS, Arnold JR, ... McCann GP, Adlam D
Aims
To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury.
Methods and results
One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case-control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P <0.01) compared to healthy controls. Infarcts were small with few large infarcts (median 4.06%; range 0-30.9%) and 39% having no detectable late gadolinium enhancement (LGE). Female SCAD patients presenting with STEMI had similar sized infarcts to female Type-1 STEMI patients age <75 years. Multivariate modelling demonstrated STEMI at presentation, initial TIMI 0/1 flow, multivessel SCAD, and a Beighton score >4 were associated with larger infarcts [>10% left ventricular (LV) mass].
Conclusion
The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

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

Eur Heart J: 02 Jan 2020; epub ahead of print
Al-Hussaini A, Abdelaty AMSEK, Gulsin GS, Arnold JR, ... McCann GP, Adlam D
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898721
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Abstract

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes.

Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, ... Komrokji RS, List AF
Background
Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study.
Methods
In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48.
Results
Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.
Conclusions
Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 08 Jan 2020; 382:140-151
Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, ... Komrokji RS, List AF
N Engl J Med: 08 Jan 2020; 382:140-151 | PMID: 31914241
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Abstract

Clinical impact of conduction disturbances in transcatheter aortic valve replacement recipients: a systematic review and meta-analysis.

Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Aims
The clinical impact of new-onset persistent left bundle branch block (NOP-LBBB) and permanent pacemaker implantation (PPI) on transcatheter aortic valve replacement (TAVR) recipients remains controversial. We aimed to evaluate the impact of (i) periprocedural NOP-LBBB and PPI post-TAVR on 1-year all-cause death, cardiac death, and heart failure hospitalization and (ii) NOP-LBBB on the need for PPI at 1-year follow-up.
Methods and results
We performed a systematic search from PubMed and EMBASE databases for studies reporting raw data on 1-year clinical impact of NOP-LBBB or periprocedural PPI post-TAVR. Data from 30 studies, including 7792 patients (12 studies) and 42 927 patients (21 studies) for the evaluation of the impact of NOP-LBBB and PPI after TAVR were sourced, respectively. NOP-LBBB was associated with an increased risk of all-cause death [risk ratio (RR) 1.32, 95% confidence interval (CI) 1.17-1.49; P < 0.001], cardiac death (RR 1.46, 95% CI 1.20-1.78; P < 0.001), heart failure hospitalization (RR 1.35, 95% CI 1.05-1.72; P = 0.02), and PPI (RR 1.89, 95% CI 1.58-2.27; P < 0.001) at 1-year follow-up. Periprocedural PPI after TAVR was associated with a higher risk of all-cause death (RR 1.17, 95% CI 1.11-1.25; P < 0.001) and heart failure hospitalization (RR 1.18, 95% CI 1.03-1.36; P = 0.02). Permanent pacemaker implantation was not associated with an increased risk of cardiac death (RR 0.84, 95% CI 0.67-1.05; P = 0.13).
Conclusion
NOP-LBBB and PPI after TAVR are associated with an increased risk of all-cause death and heart failure hospitalization at 1-year follow-up. Periprocedural NOP-LBBB also increased the risk of cardiac death and PPI within the year following the procedure. Further studies are urgently warranted to enhance preventive measures and optimize the management of conduction disturbances post-TAVR.

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 Jan 2020; epub ahead of print
Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31899484
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Abstract

Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis.

Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG

Inflammation is a hallmark and potent driver of pathological vascular remodelling in atherosclerosis. However, current anti-inflammatory therapeutic strategies have shown mixed results. As an alternative perspective on the conundrum of chronic inflammation emerging evidence points towards a small subset of senescent cells as a critical player and central node driving atherosclerosis. Senescent cells belonging to various cell types are a dominant and chronic source of a large array of pro-inflammatory cytokines and various additional plaque destabilizing factors, being involved with various aspects of atherosclerosis pathogenesis. Antagonizing these key agitators of local chronic inflammation and plaque instability may provide a causative and multi-purpose therapeutic strategy to treat atherosclerosis. Anti-senescence treatment options with translational potential are currently in development. However, several questions and challenges remain to be addressed before these novel treatment approaches may enter the clinical setting.

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

Eur Heart J: 02 Jan 2020; epub ahead of print
Stojanović SD, Fiedler J, Bauersachs J, Thum T, Sedding DG
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898722
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Abstract

Long-term clinical outcome and performance of transcatheter aortic valve replacement with a self-expandable bioprosthesis.

Testa L, Latib A, Brambilla N, De Marco F, ... Petronio AS, Bedogni F
Aims 
In the last decade, transcatheter aortic valve (TAV) replacement determined a paradigm shift in the treatment of patients with severe symptomatic aortic stenosis. Data on long-term TAV performance are still limited. We sought to evaluate the clinical and haemodynamic outcomes of the CoreValve self-expandable valve up to 8-year follow-up (FU).
Methods and results 
Nine hundred and ninety inoperable or high-risk patients were treated with the CoreValve TAV in eight Italian Centres from June 2007 to December 2011. The median FU was 4.4 years (interquartile range 1.4-6.7 years). Longest FU reached 11 years. A total of 728 died within 8-year FU (78.3% mortality from Kaplan-Meier curve analysis). A significant functional improvement was observed in the majority of patients and maintained over time, with 79.3% of surviving patients still classified New York Heart Association class ≤ II at 8 years. Echocardiographic data showed that the mean transprosthetic aortic gradient remained substantially unchanged (9 ± 4 mmHg at discharge, 9 ± 5 mmHg at 8 years, P = 0.495). The rate of Grade 0/1 paravalvular leak was consistent during FU with no significant change from post-procedure to FU ≥5 years in paired analysis (P = 0.164). Structural valve deterioration (SVD) and late bioprosthetic valve failure (BVF) were defined according to a modification of the 2017 EAPCI/ESC/EACTS criteria. In cumulative incidence functions at 8 years, moderate and severe SVD were 3.0% [95% confidence interval (CI) 2.1-4.3%] and 1.6% (95% CI 0.6-3.9%), respectively, while late BVF was 2.5% (95% CI 1.2-5%).
Conclusion 
While TAVs are questioned about long-term performance and durability, the results of the present research provide reassuring 8-year evidence on the CoreValve first-generation self-expandable bioprosthesis.

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

Eur Heart J: 05 Jan 2020; epub ahead of print
Testa L, Latib A, Brambilla N, De Marco F, ... Petronio AS, Bedogni F
Eur Heart J: 05 Jan 2020; epub ahead of print | PMID: 31904800
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Abstract

Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: implication for myocardial infarction.

Carnevale R, Sciarretta S, Valenti V, di Nonno F, ... Tanzilli G, Violi F
Aims
Low-grade endotoxaemia is detectable in human circulation but its role in thrombosis is still unclear.
Methods and results
We measured serum lipopolysaccharide (LPS) concentration, soluble P-selectin (sP-selectin), a marker of platelet activation, and zonulin, a marker of gut permeability, in peripheral circulation, coronary thrombi, and intracoronary blood of patients with ST-elevation myocardial infarction (STEMI, n = 50) and stable angina (SA) (n = 50), respectively, and in controls (n = 50). Experimental study was carried out in mice to assess if Escherichia coli-LPS (E. coli-LPS) possess thrombotic property. Coronary thrombi from STEMI showed higher concentrations of LPS, sP-selectin vs. intracoronary blood of SA and peripheral blood of controls (P < 0.001). Zonulin was higher in STEMI compared to the other two groups [4.57 (3.34-5.22); 2.56 (0.41-4.36); 1.95 (1.22-2.65) ng/mL; P < 0.001] and correlated with LPS (Rs = 0.585; P < 0.001). Escherichia coli DNA was positive in 34% of STEMI vs. 12% of SA and 4% of controls (P < 0.001). In a subgroup of 12 STEMI, immunohistochemical analysis of coronary thrombi showed positivity for leucocyte Toll-like receptor 4 (TLR4), cathepsin G, and LPS from E. coli in 100%, 80%, and 25% of samples, respectively. E. coli-LPS injected in mice to reach LPS concentrations like those detected in coronary thrombi was associated with enhanced artery thrombosis and platelet activation, an effect blunted by TLR4 inhibitor co-administration. In vitro study demonstrated that LPS from E. coli enhanced platelet aggregation via TLR4-mediated leucocyte cathepsin G activation.
Conclusion
ST-elevation myocardial infarction patients disclose an enhanced gut permeability that results in LPS translocation in human circulation and eventually thrombus growth at site of artery lesion via leucocyte-platelet interaction.

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 Jan 2020; epub ahead of print
Carnevale R, Sciarretta S, Valenti V, di Nonno F, ... Tanzilli G, Violi F
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31898723
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Abstract

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study.

Schnorbus B, Daiber A, Jurk K, Warnke S, ... Münzel T, Gori T
Aims
In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome.
Methods and results
The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the clopidogrel and ticagrelor group (both P < 0.01), but not in the prasugrel group. During follow-up, prasugrel was superior to clopidogrel [mean difference 2.13, 95% confidence interval (CI) 0.68-3.58; P = 0.0047] and ticagrelor (mean difference 1.57, 95% CI 0.31-2.83; P = 0.0155), but this difference was limited to patients who received the study therapy 2 h before stenting. Ticagrelor was not significantly superior to clopidogrel (mean difference 0.55, 95% CI -0.73 to 1.82; P = 0.39). No significant differences were seen among groups for low-flow-mediated dilation. Plasma interleukin (IL)-6 (P = 0.02 and P = 0.01, respectively) and platelet aggregation reactivity in response to adenosine diphosphate (P = 0.002 and P = 0.035) were lower in the prasugrel compared to clopidogrel and ticagrelor group.
Conclusion
As compared to ticagrelor and clopidogrel, therapy with prasugrel in patients undergoing stenting for an acute coronary syndrome is associated with improved endothelial function, stronger platelet inhibition, and reduced IL-6 levels, all of which may have prognostic implications. This effect was lost in patients who received the study medication immediately after stenting.
Eudract-no
2011-005305-73.

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 Jan 2020; epub ahead of print
Schnorbus B, Daiber A, Jurk K, Warnke S, ... Münzel T, Gori T
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31899473
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Abstract

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Background
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
Methods
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m), doxorubicin (50 mg/m), and vincristine (1·4 mg/m, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Findings
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
Interpretation
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
Funding
Deutsche Krebshilfe.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 20 Dec 2020; 394:2271-2281
Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Lancet: 20 Dec 2020; 394:2271-2281 | PMID: 31868632
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Abstract

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

Juul SE, Comstock BA, Wadhawan R, Mayock DE, ... Heagerty PJ,
Background
High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.
Methods
In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.
Results
A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.
Conclusions
High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jan 2020; 382:233-243
Juul SE, Comstock BA, Wadhawan R, Mayock DE, ... Heagerty PJ,
N Engl J Med: 15 Jan 2020; 382:233-243 | PMID: 31940698
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Abstract

JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency.

Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, ... Bogunovic D, Alangari AA

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on . The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Jan 2020; 382:256-265
Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, ... Bogunovic D, Alangari AA
N Engl J Med: 15 Jan 2020; 382:256-265 | PMID: 31940699
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Abstract

Variation in Bystander Cardiopulmonary Resuscitation Delivery and Subsequent Survival From Out-of-Hospital Cardiac Arrest Based on Neighborhood-Level Ethnic Characteristics.

Blewer AL, Schmicker RH, Morrison LJ, Aufderheide TP, ... Abella BS,
Background
Bystander cardiopulmonary resuscitation (B-CPR) delivery and survival after out-of-hospital cardiac arrest vary at the neighborhood level, with lower survival seen in predominantly black neighborhoods. Although the Hispanic population is the fastest-growing minority population in the United States, few studies have assessed whether the proportion of Hispanic residents in a neighborhood is associated with B-CPR delivery and survival from out-of-hospital cardiac arrest. We assessed whether B-CPR rates and survival vary by neighborhood-level ethnicity. We hypothesized that neighborhoods with a higher proportion of Hispanic residents have lower B-CPR rates and lower survival.
Methods
We conducted a retrospective cohort study using data from the Resuscitation Outcomes Consortium Epistry at US sites. Neighborhoods were classified by census tract based on percentage of Hispanic residents: <25%, 25% to 50%, 51% to 75%, or >75%. We independently modeled the likelihood of receipt of B-CPR and survival by neighborhood-level ethnicity controlling for site and patient-level confounding characteristics.
Results
From 2011 to 2015, the Resuscitation Outcomes Consortium collected 27 481 US arrest events; after excluding pediatric arrests, emergency medical services-witnessed arrests, or arrests occurring in a healthcare or institutional facility, 18 927 were included. B-CPR was administered in 37% of events. In neighborhoods with <25% Hispanic residents, B-CPR was administered in 39% of events, whereas it was administered in 27% of events in neighborhoods with >75% Hispanic residents. Compared with <25% Hispanic neighborhoods in a multivariable analysis, out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods had lower B-CPR rates (51% to 75% Hispanic: odds ratio, 0.79 [CI, 0.65-0.95], =0.014; >75% Hispanic: odds ratio, 0.72 [CI, 0.55-0.96], =0.025) and lower survival rates (globalvalue 0.029; >75% Hispanic: odds ratio, 0.56 [CI, 0.34-0.93], =0.023).
Conclusions
Individuals with out-of-hospital cardiac arrest in predominantly Hispanic neighborhoods were less likely to receive B-CPR and had lower likelihood of survival. These findings suggest a need to understand the underlying disparities in cardiopulmonary resuscitationdelivery and an unmet cardiopulmonary resuscitationtraining need in Hispanic communities.



Circulation: 06 Jan 2020; 141:34-41
Blewer AL, Schmicker RH, Morrison LJ, Aufderheide TP, ... Abella BS,
Circulation: 06 Jan 2020; 141:34-41 | PMID: 31887076
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Abstract

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

Luo W, Wang Y, Zhang L, Ren P, ... LeMaire SA, Shen YH
Background
Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.
Methods
The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in -deficient () mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.
Results
In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model,mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challengedmice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.
Conclusions
Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.



Circulation: 06 Jan 2020; 141:42-66
Luo W, Wang Y, Zhang L, Ren P, ... LeMaire SA, Shen YH
Circulation: 06 Jan 2020; 141:42-66 | PMID: 31887080
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Abstract

Trends in U.S. Ambulatory Cardiovascular Care 2013 to 2017: JACC Review Topic of the Week.

Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA

The National Cardiovascular Data Registry PINNACLE (Practice Innovation and Clinical Excellence) Registry is the largest outpatient cardiovascular practice registry in the world. It tracks real-world management and quality of 4 common cardiovascular conditions: heart failure, coronary artery disease, atrial fibrillation, and hypertension. In 2013, the PINNACLE Registry contained information on 2,898,505 patients, cared for by 4,859 providers in 431 practices. By 2017, the registry contained information on 6,040,996 patients, cared for by 8,853 providers in 724 practices. During this time period, care processes for PINNACLE patients generally improved. Among patients with heart failure, combined beta-blocker and renin-angiotensin antagonist medication rates increased from 60.7% to 72.8%. Among patients with coronary artery disease, statin medication rates increased from 66% to 80.1%. Among patients with atrial fibrillation, oral anticoagulation rates increased from 52.7% to 65.2%. In contrast, blood pressure control rates among patients with hypertension were largely stable. PINNACLE data also fueled a variety of quality measurement programs and 51 peer-reviewed publications.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 06 Jan 2020; 75:93-112
Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA
J Am Coll Cardiol: 06 Jan 2020; 75:93-112 | PMID: 31918838
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Abstract

Incident Heart Failure and Long-Term Risk for Venous Thromboembolism.

Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
Background
Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown.
Objectives
In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed.
Methods
During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE.
Results
Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE.
Conclusions
In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

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

J Am Coll Cardiol: 20 Jan 2020; 75:148-158
Fanola CL, Norby FL, Shah AM, Chang PP, ... Cushman M, Folsom AR
J Am Coll Cardiol: 20 Jan 2020; 75:148-158 | PMID: 31948643
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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
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Impact:
Abstract

Atrial Failure as a Clinical Entity: JACC Review Topic of the Week.

Bisbal F, Baranchuk A, Braunwald E, Bayés de Luna A, Bayés-Genís A

Atrial dysfunction has been widely considered a marker or consequence of other cardiac conditions rather than the cause itself. Here, we propose the term atrial failure as a clinically relevant entity, defined as any atrial dysfunction causing impaired heart performance, symptoms, and worsening quality of life or life expectancy. Aspects of the etiology, mechanisms, and consequences of atrial failure are discussed. Recent advances in cardiac electrophysiology and imaging have improved our understanding of the highly complex atrial anatomy and function, underlying the paramount importance of the atria in optimal heart performance. It is time to reappraise the concept of the failing atrium as a primary cause or aggravating factor of the symptoms in many of our patients. The concept of atrial failure may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction.

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

J Am Coll Cardiol: 20 Jan 2020; 75:222-232
Bisbal F, Baranchuk A, Braunwald E, Bayés de Luna A, Bayés-Genís A
J Am Coll Cardiol: 20 Jan 2020; 75:222-232 | PMID: 31948652
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Impact:
Abstract

Peripartum Cardiomyopathy: JACC State-of-the-Art Review.

Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U

Peripartum cardiomyopathy is a form of systolic heart failure affecting young women toward the end of pregnancy or in the months following delivery. Incidence is higher in African-American women and in women with older maternal age, hypertensive disorders of pregnancy, and multiple gestation pregnancies. Symptoms of heart failure mimic those of normal pregnancy, often resulting in a delay in diagnosis and preventable complications. Echocardiography showing decreased myocardial function is essential for the diagnosis. Medical management is similar to heart failure with reduced ejection fraction of other etiologies, but adjustments during pregnancy are necessary to ensure fetal safety. Variable outcomes include complete recovery, persistent heart failure, arrhythmias, thromboembolic events, and death. Subsequent pregnancy confers substantial risk of relapse and even death if there is incomplete myocardial recovery. Additional research about the etiology, optimal therapy including the use of bromocriptine, long-term outcomes, and duration of treatment after recovery are needed.

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

J Am Coll Cardiol: 20 Jan 2020; 75:207-221
Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U
J Am Coll Cardiol: 20 Jan 2020; 75:207-221 | PMID: 31948651
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Impact:
Abstract

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis.

Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Aims
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis.
Methods and results
We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e\' were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001).
Conclusion
The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

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
Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Eur Heart J: 16 Jan 2020; epub ahead of print | PMID: 31950987
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Abstract

Obesity as a Causal Risk Factor for Aortic Valve Stenosis.

Kaltoft M, Langsted A, Nordestgaard BG
Background
Causal risk factors for aortic valve stenosis are poorly understood, limiting the possibility of preventing the most common heart valve disease.
Objectives
The hypothesis was tested that genetically based obesity measured by body mass index is causally associated with risk of aortic valve stenosis and replacement.
Methods
The authors included 108,211 individuals from the Copenhagen General Population Study. Participants had measurements of body mass index, waist-hip ratio, and waist circumference, and information on 5 genetic variants associated with obesity. A Mendelian randomization design was used to investigate genetic and observational associations of obesity with incident aortic valve stenosis (n = 1,215) and replacement (n = 467) for a median follow-up time of 8.7 years.
Results
Genetically increased body mass index was causally associated with increased risk of aortic valve stenosis. Compared with an unweighted allele score of 0 to 3, individuals with an allele score 7 to 10 had a mean increase in body mass index of 0.87 kg/m, and the age and sex-adjusted hazard ratio for aortic valve stenosis was 1.3 (95% confidence interval [CI]: 1.0 to 1.7) for allele score 4, 1.4 (95% CI: 1.1 to 1.8) for allele score 5 to 6, and 1.6 (95% CI: 1.3 to 2.1) for allele score 7 to 10 (p for trend: 9 × 10). A 1-kg/m increase in body mass index was associated with causal risk ratios for aortic valve stenosis and replacement, respectively, of 1.52 (95% CI: 1.23 to 1.87) and 1.49 (95% CI: 1.07 to 2.08) genetically, and with corresponding hazard ratios of 1.06 (95% CI: 1.05 to 1.08) and 1.06 (95% CI: 1.03 to 1.08) observationally.
Conclusions
Obesity from human genetics was causally associated with higher risk of aortic valve stenosis and replacement.

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

J Am Coll Cardiol: 20 Jan 2020; 75:163-176
Kaltoft M, Langsted A, Nordestgaard BG
J Am Coll Cardiol: 20 Jan 2020; 75:163-176 | PMID: 31948645
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Impact:
Abstract

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome.

Bittner VA, Szarek M, Aylward PE, Bhatt DL, ... Schwartz GG,
Background
Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).
Objectives
A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).
Methods
One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.
Results
Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).
Conclusions
Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

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

J Am Coll Cardiol: 20 Jan 2020; 75:133-144
Bittner VA, Szarek M, Aylward PE, Bhatt DL, ... Schwartz GG,
J Am Coll Cardiol: 20 Jan 2020; 75:133-144 | PMID: 31948641
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Impact:
Abstract

Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest.

Matsuyama T, Komukai S, Izawa J, Gibo K, ... Ohta B, Kitamura T
Background
There is little evidence about pre-hospital advanced life support including epinephrine administration for pediatric out-of-hospital cardiac arrests (OHCAs).
Objectives
This study aimed to assess the effect of pre-hospital epinephrine administration by emergency-medical-service (EMS) personnel for pediatric OHCA.
Methods
This nationwide population-based observational study in Japan enrolled pediatric patients age 8 to 17 years with OHCA between January 2007 and December 2016. Patients were sequentially matched with or without epinephrine during cardiac arrest using a risk-set matching based on time-dependent propensity score (probability of receiving epinephrine) calculated at each minute after initiation of cardiopulmonary resuscitation by EMS personnel. The primary endpoint was 1-month survival. Secondary endpoints were 1-month survival with favorable neurological outcome, defined as the cerebral performance category scale of 1 or 2, and pre-hospital return of spontaneous circulation (ROSC).
Results
During the study period, a total of 1,214,658 OHCA patients were registered, and 3,961 pediatric OHCAs were eligible for analyses. Of these, 306 (7.7%) patients received epinephrine and 3,655 (92.3%) did not receive epinephrine. After time-dependent propensity score-sequential matching, 608 patients were included in the matched cohort. In the matched cohort, there were no significant differences between the epinephrine and no epinephrine groups in 1-month survival (epinephrine: 10.2% [31 of 304] vs. no epinephrine: 7.9% [24 of 304]; risk ratio [RR]: 1.13 [95% confidence interval (CI): 0.67 to 1.93]) and favorable neurological outcome (epinephrine: 3.6% [11 of 304] vs. no epinephrine: 2.6% [8 of 304]; RR: 1.56 [95% CI: 0.61 to 3.96]), whereas the epinephrine group had a higher likelihood of achieving pre-hospital ROSC (epinephrine: 11.2% [34 of 304] vs. no epinephrine: 3.3% [10 of 304]; RR: 3.17 [95% CI: 1.54 to 6.54]).
Conclusions
In this study, pre-hospital epinephrine administration was associated with ROSC, whereas there were no significant differences in 1-month survival and favorable neurological outcome between those with and without epinephrine.

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

J Am Coll Cardiol: 20 Jan 2020; 75:194-204
Matsuyama T, Komukai S, Izawa J, Gibo K, ... Ohta B, Kitamura T
J Am Coll Cardiol: 20 Jan 2020; 75:194-204 | PMID: 31948649
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Abstract

Acute Stroke During Pregnancy and Puerperium.

Elgendy IY, Gad MM, Mahmoud AN, Keeley EC, Pepine CJ
Background
Acute stroke during pregnancy or within 6 weeks of childbirth is devastating for the mother and her family, yet data regarding incidence and contemporary trends are very limited.
Objectives
This study sought to investigate the incidence and outcomes of acute stroke and transient ischemic attack during pregnancy or within 6 weeks of childbirth in a large database.
Methods
The National Inpatient Sample was queried to identify women age ≥18 years in the United States with pregnancy-related hospitalizations from January 1, 2007, to September 30, 2015. Temporal trends in acute stroke (ischemic and hemorrhagic)/transient ischemic attack incidence and in-hospital mortality were extracted.
Results
Among 37,360,772 pregnancy-related hospitalizations, 16,694 (0.045%) women had an acute stroke. The rates of acute stroke did not change (42.8 per 100,000 hospitalizations in 2007 vs. 42.2 per 100,000 hospitalizations in 2015; p = 0.10). Among those with acute stroke, there were increases in prevalence of obesity, smoking, hyperlipidemia, migraine, and gestational hypertension. Importantly, in-hospital mortality rates were almost 385-fold higher among those who had a stroke (42.1 per 1,000 pregnancy-related hospitalizations vs. 0.11 per 1,000 pregnancy-related hospitalizations; p < 0.0001). The rates of in-hospital mortality among pregnant women with acute stroke decreased (5.5% in 2007 vs. 2.7% in 2015; p < 0.001).
Conclusions
In this contemporary analysis of pregnancy-related hospitalizations, acute stroke occurred in 1 of every 2,222 hospitalizations, and these rates did not decrease over approximately 9 years. The prevalence of most stroke risk factors has increased. Acute stroke during pregnancy and puerperium was associated with high maternal mortality, although it appears to be trending downward. Future studies to better identify mechanisms and approaches to prevention and management of acute stroke during pregnancy and puerperium are warranted.

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

J Am Coll Cardiol: 20 Jan 2020; 75:180-190
Elgendy IY, Gad MM, Mahmoud AN, Keeley EC, Pepine CJ
J Am Coll Cardiol: 20 Jan 2020; 75:180-190 | PMID: 31948647
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Abstract

Machine learning-based mortality prediction of patients undergoing cardiac resynchronization therapy: the SEMMELWEIS-CRT score.

Tokodi M, Schwertner WR, Kovács A, Tősér Z, ... Merkely B, Kosztin A
Aims
Our aim was to develop a machine learning (ML)-based risk stratification system to predict 1-, 2-, 3-, 4-, and 5-year all-cause mortality from pre-implant parameters of patients undergoing cardiac resynchronization therapy (CRT).
Methods and results
Multiple ML models were trained on a retrospective database of 1510 patients undergoing CRT implantation to predict 1- to 5-year all-cause mortality. Thirty-three pre-implant clinical features were selected to train the models. The best performing model [SEMMELWEIS-CRT score (perSonalizEd assessMent of estiMatEd risk of mortaLity With machinE learnIng in patientS undergoing CRT implantation)], along with pre-existing scores (Seattle Heart Failure Model, VALID-CRT, EAARN, ScREEN, and CRT-score), was tested on an independent cohort of 158 patients. There were 805 (53%) deaths in the training cohort and 80 (51%) deaths in the test cohort during the 5-year follow-up period. Among the trained classifiers, random forest demonstrated the best performance. For the prediction of 1-, 2-, 3-, 4-, and 5-year mortality, the areas under the receiver operating characteristic curves of the SEMMELWEIS-CRT score were 0.768 (95% CI: 0.674-0.861; P < 0.001), 0.793 (95% CI: 0.718-0.867; P < 0.001), 0.785 (95% CI: 0.711-0.859; P < 0.001), 0.776 (95% CI: 0.703-0.849; P < 0.001), and 0.803 (95% CI: 0.733-0.872; P < 0.001), respectively. The discriminative ability of our model was superior to other evaluated scores.
Conclusion
The SEMMELWEIS-CRT score (available at semmelweiscrtscore.com) exhibited good discriminative capabilities for the prediction of all-cause death in CRT patients and outperformed the already existing risk scores. By capturing the non-linear association of predictors, the utilization of ML approaches may facilitate optimal candidate selection and prognostication of patients undergoing CRT implantation.

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

Eur Heart J: 09 Jan 2020; epub ahead of print
Tokodi M, Schwertner WR, Kovács A, Tősér Z, ... Merkely B, Kosztin A
Eur Heart J: 09 Jan 2020; epub ahead of print | PMID: 31923316
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Abstract

Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort.

Ho JE, Zern EK, Lau ES, Wooster L, ... Malhotra R, Lewis GD
Background
Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear.
Objectives
This study sought to investigate the association of exPH with clinical determinants and outcomes.
Methods
The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality.
Results
Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both).
Conclusions
Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.

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

J Am Coll Cardiol: 06 Jan 2020; 75:17-26
Ho JE, Zern EK, Lau ES, Wooster L, ... Malhotra R, Lewis GD
J Am Coll Cardiol: 06 Jan 2020; 75:17-26 | PMID: 31918830
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Impact:
Abstract

Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening.

Bhuva AN, D\'Silva A, Torlasco C, Jones S, ... Hughes AD, Manisty CH
Background
Aging increases aortic stiffness, contributing to cardiovascular risk even in healthy individuals. Aortic stiffness is reduced through supervised training programs, but these are not easily generalizable.
Objectives
The purpose of this study was to determine whether real-world exercise training for a first-time marathon can reverse age-related aortic stiffening.
Methods
Untrained healthy individuals underwent 6 months of training for the London Marathon. Assessment pre-training and 2 weeks post-marathon included central (aortic) blood pressure and aortic stiffness using cardiovascular magnetic resonance distensibility. Biological \"aortic age\" was calculated from the baseline chronological age-stiffness relationship. Change in stiffness was assessed at the ascending (Ao-A) and descending aorta at the pulmonary artery bifurcation (Ao-P) and diaphragm (Ao-D). Data are mean changes (95% confidence intervals [CIs]).
Results
A total of 138 first-time marathon completers (age 21 to 69 years, 49% male) were assessed, with an estimated training schedule of 6 to 13 miles/week. At baseline, a decade of chronological aging correlated with a decrease in Ao-A, Ao-P, and Ao-D distensibility by 2.3, 1.9, and 3.1 × 10 mm Hg, respectively (p < 0.05 for all). Training decreased systolic and diastolic central (aortic) blood pressure by 4 mm Hg (95% CI: 2.8 to 5.5 mm Hg) and 3 mm Hg (95% CI: 1.6 to 3.5 mm Hg). Descending aortic distensibility increased (Ao-P: 9%; p = 0.009; Ao-D: 16%; p = 0.002), while remaining unchanged in the Ao-A. These translated to a reduction in \"aortic age\" by 3.9 years (95% CI: 1.1 to 7.6 years) and 4.0 years (95% CI: 1.7 to 8.0 years) (Ao-P and Ao-D, respectively). Benefit was greater in older, male participants with slower running times (p < 0.05 for all).
Conclusions
Training for and completing a marathon even at relatively low exercise intensity reduces central blood pressure and aortic stiffness-equivalent to a ∼4-year reduction in vascular age. Greater rejuvenation was observed in older, slower individuals.

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

J Am Coll Cardiol: 06 Jan 2020; 75:60-71
Bhuva AN, D'Silva A, Torlasco C, Jones S, ... Hughes AD, Manisty CH
J Am Coll Cardiol: 06 Jan 2020; 75:60-71 | PMID: 31918835
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Abstract

Diastolic Blood Pressure and Heart Rate Are Independently Associated With Mortality in Chronic Aortic Regurgitation.

Yang LT, Pellikka PA, Enriquez-Sarano M, Scott CG, ... Schaff HV, Michelena HI
Background
The prognostic significance of diastolic blood pressure (DBP) and resting heart rate (RHR) in patients with hemodynamically significant aortic regurgitation (AR) is unknown.
Objectives
This study sought to investigate the association of DBP and RHR with all-cause mortality in patients with AR.
Methods
Consecutive patients with ≥ moderate to severe AR were retrospectively identified from 2006 to 2017. The association between all-cause mortality and routinely measured DBP and RHR was examined.
Results
Of 820 patients (age 59 ± 17 years; 82% men) followed for 5.5 ± 3.5 years, 104 died under medical management, and 400 underwent aortic valve surgery (AVS). Age, symptoms, left ventricular ejection fraction (LVEF), LV end-systolic diameter-index (LVESDi), DBP, and RHR were univariable predictors of all-cause mortality (all p ≤ 0.002). When adjusted for demographics, comorbidities, and surgical triggers (symptoms, LVEF, and LVESDi), baseline DBP (adjusted-hazard ratio [HR]: 0.79 [95% confidence interval: 0.66 to 0.94] per 10 mm Hg increase, p = 0.009) and baseline RHR (adjusted HR: 1.23 [95% confidence interval: 1.03 to 1.45] per 10 beat per min [bpm] increase, p = 0.01) were independently associated with all-cause mortality. These associations persisted after adjustment for presence of hypertension, medications, time-dependent AVS, and using average DBP and RHR (all p ≤ 0.02). Compared with the general population, patients with AR exhibited excess mortality (relative risk of death >1), which rose steeply in inverse proportion (p nonlinearity = 0.002) to DBP starting at 70 mm Hg and peaking at 55 mm Hg and in direct proportion to RHR starting at 60 bpm.
Conclusions
In patients with chronic hemodynamically significant AR, routinely measured DBP and RHR demonstrate a robust association with all-cause death, independent of demographics, comorbidities, guideline-based surgical triggers, presence of hypertension, and use of medications. Therefore, DBP and RHR should be integrated into comprehensive clinical decision-making for these patients.

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

J Am Coll Cardiol: 06 Jan 2020; 75:29-39
Yang LT, Pellikka PA, Enriquez-Sarano M, Scott CG, ... Schaff HV, Michelena HI
J Am Coll Cardiol: 06 Jan 2020; 75:29-39 | PMID: 31918832
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Impact:
Abstract

Persistent Proarrhythmic Neural Remodeling Despite Recovery From Premature Ventricular Contraction-Induced Cardiomyopathy.

Tan AY, Elharrif K, Cardona-Guarache R, Mankad P, ... Minisi AJ, Huizar JF
Background
The presence and significance of neural remodeling in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown.
Objectives
This study aimed to characterize cardiac sympathovagal balance and proarrhythmia in a canine model of PVC-CM.
Methods
In 12 canines, the investigators implanted epicardial pacemakers and radiotelemetry units to record cardiac rhythm and nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus (VNA), and arterial blood pressure. Bigeminal PVCs (200 ms coupling) were applied for 12 weeks to induce PVC-CM in 7 animals then disabled for 4 weeks to allow complete recovery of left ventricular ejection fraction (LVEF), versus 5 sham controls.
Results
After 12 weeks of PVCs, LVEF (p = 0.006) and dP/dT (p = 0.007) decreased. Resting SNA (p = 0.002) and VNA (p = 0.04), exercise SNA (p = 0.01), SNA response to evoked PVCs (p = 0.005), heart rate (HR) at rest (p = 0.003), and exercise (p < 0.04) increased, whereas HR variability (HRV) decreased (p = 0.009). There was increased spontaneous atrial (p = 0.02) and ventricular arrhythmias (p = 0.03) in PVC-CM. Increased SNA preceded both atrial (p = 0.0003) and ventricular (p = 0.009) arrhythmia onset. Clonidine suppressed SNA and abolished all arrhythmias. After disabling PVC for 4 weeks, LVEF (p = 0.01), dP/dT (p = 0.047), and resting VNA (p = 0.03) recovered to baseline levels. However, SNA, resting HR, HRV, and atrial (p = 0.03) and ventricular (p = 0.03) proarrhythmia persisted. There was sympathetic hyperinnervation in stellate ganglia (p = 0.02) but not ventricles (p = 0.2) of PVC-CM and recovered animals versus sham controls.
Conclusions
Neural remodeling in PVC-CM is characterized by extracardiac sympathetic hyperinnervation and sympathetic neural hyperactivity that persists despite normalization of LVEF. The altered cardiac sympathovagal balance is an important trigger and substrate for atrial and ventricular proarrhythmia.

Published by Elsevier Inc.

J Am Coll Cardiol: 06 Jan 2020; 75:1-13
Tan AY, Elharrif K, Cardona-Guarache R, Mankad P, ... Minisi AJ, Huizar JF
J Am Coll Cardiol: 06 Jan 2020; 75:1-13 | PMID: 31918815
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Impact:
Abstract

Management of Acute and Recurrent Pericarditis: JACC State-of-the-Art Review.

Chiabrando JG, Bonaventura A, Vecchié A, Wohlford GF, ... Imazio M, Abbate A

Pericarditis refers to the inflammation of the pericardial layers, resulting from a variety of stimuli triggering a stereotyped immune response, and characterized by chest pain associated often with peculiar electrocardiographic changes and, at times, accompanied by pericardial effusion. Acute pericarditis is generally self-limited and not life-threatening; yet, it may cause significant short-term disability, be complicated by either a large pericardial effusion or tamponade, and carry a significant risk of recurrence. The mainstay of treatment of pericarditis is represented by anti-inflammatory drugs. Anti-inflammatory treatments vary, however, in both effectiveness and side-effect profile. The objective of this review is to summarize the up-to-date management of acute and recurrent pericarditis.

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

J Am Coll Cardiol: 06 Jan 2020; 75:76-92
Chiabrando JG, Bonaventura A, Vecchié A, Wohlford GF, ... Imazio M, Abbate A
J Am Coll Cardiol: 06 Jan 2020; 75:76-92 | PMID: 31918837
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Impact:
Abstract

DP1 Activation Reverses Age-Related Hypertension via NEDD4L-Mediated T-bet Degradation in T Cells.

Kong D, Wan Q, Li J, Zuo S, ... Breyer RM, Yu Y

Blood pressure (BP) often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of pro-inflammatory cytokines increases in T lymphocyte. Prostaglandin (PG) D, a pro-resolution mediator, suppresses Th1 cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of PGD/DP1 axis in T cells on age-related hypertension.To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants and CD4 T cells were sorted for gene expression, PG production and western bot assays. Mice BP was quantified by invasive telemetric monitor.PGD/DP1 axis was down-regulated in CD4 T cells from older humans and aged mice, DP1 deletion in CD4+ T cells (TDP1KO) augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling and CD4 T cells infiltration, superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. TNFα neutralization or IFNγ deletion ameliorated the age-related hypertension in TDP1KO mice. Mechanistically, DP1 inhibited Th1 activity via the Gαs/PKA/p-Sp1/NEDD4L pathway-mediated T-bet ubiquitination. T-bet deletion or forced NEDD4L expression in CD4 T cell attenuated age-related hypertension in TDP1KO mice. DP1 receptor activation by BW245C prevented age-associated BP elevation and reduced vascular/renal superoxide production in male mice.PGD/DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension in males.



Circulation: 01 Jan 2020; epub ahead of print
Kong D, Wan Q, Li J, Zuo S, ... Breyer RM, Yu Y
Circulation: 01 Jan 2020; epub ahead of print | PMID: 31893939
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Abstract

S-Nitrosylation of Muscle LIM Protein Facilitates Myocardial Hypertrophy Through Toll-Like Receptor 3-Mediated Receptor-Interacting Protein Kinase 3 and NLRP3 Inflammasome Activation.

Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of S-nitrosylation of muscle LIM protein (MLP) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. S-nitrosylation sites were further identified through liquid chromatography-tandem mass spectrometry (LCMS/MS). Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase (GSNOR) was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry (MS) and confirmed by co-immunoprecipitation. Recruitment of toll-like receptor 3 (TLR3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA (siRNA)-transfected neonatal rat cardiomyocytes (NRCMs) and in TLR3 knockout mouse model.SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction (TAC). The level of SNO-MLP also increased in angiotensin II (Ang II) or phenylephrine (PE)-treated NRCMs. S-nitrosylated site of MLP at cysteine (Cys) 79 was identified by LCMS/MS and further confirmed in NRCMs. Mutation of Cys79 significantly reduced hypertrophic growth in Ang II or PE-treated NRCMs and TAC mice. Reducing MLP Snitrosylation level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, MLP S-nitrosylation stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupting this interaction by downregulating TLR3 attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and receptor-interacting protein kinase 3 (RIP3). This interaction in turn induced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a novel therapeutic target for myocardial hypertrophy and heart failure.



Circulation: 05 Jan 2020; epub ahead of print
Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902237
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Abstract

Inverse transition of labyrinthine domain patterns in ferroelectric thin films.

Nahas Y, Prokhorenko S, Fischer J, Xu B, ... Garcia V, Bellaiche L

Phase separation is a cooperative process, the kinetics of which underpin the orderly morphogenesis of domain patterns on mesoscopic scales. Systems of highly degenerate frozen states may exhibit the rare and counterintuitive inverse-symmetry-breaking phenomenon. Proposed a century ago, inverse transitions have been found experimentally in disparate materials, ranging from polymeric and colloidal compounds to high-transition-temperature superconductors, proteins, ultrathin magnetic films, liquid crystals and metallic alloys, with the notable exception of ferroelectric oxides, despite extensive theoretical and experimental work on the latter. Here we show that following a subcritical quench, the non-equilibrium self-assembly of ferroelectric domains in ultrathin films of Pb(ZrTi)O results in a maze, or labyrinthine pattern, featuring meandering stripe domains. Furthermore, upon increasing the temperature, this highly degenerate labyrinthine phase undergoes an inverse transition whereby it transforms into the less-symmetric parallel-stripe domain structure, before the onset of paraelectricity at higher temperatures. We find that this phase sequence can be ascribed to an enhanced entropic contribution of domain walls, and that domain straightening and coarsening is predominantly driven by the relaxation and diffusion of topological defects. Computational modelling and experimental observation of the inverse dipolar transition in BiFeO suggest the universality of the phenomenon in ferroelectric oxides. The multitude of self-patterned states and the various topological defects that they embody may be used beyond current domain and domain-wall-based technologies by enabling fundamentally new design principles and topologically enhanced functionalities within ferroelectric films.



Nature: 30 Dec 2019; 577:47-51
Nahas Y, Prokhorenko S, Fischer J, Xu B, ... Garcia V, Bellaiche L
Nature: 30 Dec 2019; 577:47-51 | PMID: 31894148
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Abstract

Spectroscopic confirmation of a mature galaxy cluster at a redshift of 2.

Willis JP, Canning REA, Noordeh ES, Allen SW, ... Stanford SA, Brammer G

Galaxy clusters are the most massive virialized structures in the Universe and are formed through the gravitational accretion of matter over cosmic time. The discovery of an evolved galaxy cluster at redshift z = 2, corresponding to a look-back time of 10.4 billion years, provides an opportunity to study its properties. The galaxy cluster XLSSC 122 was originally detected as a faint, extended X-ray source in the XMM Large Scale Structure survey and was revealed to be coincident with a compact over-density of galaxies with photometric redshifts of 1.9 ± 0.2. Subsequent observations at millimetre wavelengths detected a Sunyaev-Zel\'dovich decrement along the line of sight to XLSSC 122, thus confirming the existence of hot intracluster gas, while deep imaging spectroscopy from the European Space Agency\'s X-ray Multi-Mirror Mission (XMM-Newton) revealed an extended, X-ray-bright gaseous atmosphere with a virial temperature of 60 million Kelvin, enriched with metals to the same extent as are local clusters. Here we report optical spectroscopic observations of XLSSC 122 and identify 37 member galaxies at a mean redshift of 1.98, corresponding to a look-back time of 10.4 billion years. We use photometry to determine a mean, dust-free stellar age of 2.98 billion years, indicating that star formation commenced in these galaxies at a mean redshift of 12, when the Universe was only 370 million years old. The full range of inferred formation redshifts, including the effects of dust, covers the interval from 7 to 13. These observations confirm that XLSSC 122 is a remarkably mature galaxy cluster with both evolved stellar populations in the member galaxies and a hot, metal-rich gas composing the intracluster medium.



Nature: 30 Dec 2019; 577:39-41
Willis JP, Canning REA, Noordeh ES, Allen SW, ... Stanford SA, Brammer G
Nature: 30 Dec 2019; 577:39-41 | PMID: 31894143
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Impact:
Abstract

The past and future of global river ice.

Yang X, Pavelsky TM, Allen GH

More than one-third of Earth\'s landmass is drained by rivers that seasonally freeze over. Ice transforms the hydrologic, ecologic, climatic and socio-economic functions of river corridors. Although river ice extent has been shown to be declining in many regions of the world, the seasonality, historical change and predicted future changes in river ice extent and duration have not yet been quantified globally. Previous studies of river ice, which suggested that declines in extent and duration could be attributed to warming temperatures, were based on data from sparse locations. Furthermore, existing projections of future ice extent are based solely on the location of the 0-°C isotherm. Here, using satellite observations, we show that the global extent of river ice is declining, and we project a mean decrease in seasonal ice duration of 6.10 ± 0.08 days per 1-°C increase in global mean surface air temperature. We tracked the extent of river ice using over 400,000 clear-sky Landsat images spanning 1984-2018 and observed a mean decline of 2.5 percentage points globally in the past three decades. To project future changes in river ice extent, we developed an observationally calibrated and validated model, based on temperature and season, which reduced the mean bias by 87 per cent compared with the 0-degree-Celsius isotherm approach. We applied this model to future climate projections for 2080-2100: compared with 2009-2029, the average river ice duration declines by 16.7 days under Representative Concentration Pathway (RCP) 8.5, whereas under RCP 4.5 it declines on average by 7.3 days. Our results show that, globally, river ice is measurably declining and will continue to decline linearly with projected increases in surface air temperature towards the end of this century.



Nature: 30 Dec 2019; 577:69-73
Yang X, Pavelsky TM, Allen GH
Nature: 30 Dec 2019; 577:69-73 | PMID: 31894147
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Abstract

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J

Orai1 is a critical ion channel subunit, best recognized as a mediator of storeoperated Ca entry (SOCE) in non-excitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop JPIII, a small-molecule Orai1 channel inhibitor suitable fordelivery.Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. 5 weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and pro-hypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca signaling alterations (increased SOCE, decreased [Ca]i transients amplitude and decay rate, lower SR Ca load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from CdnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.



Circulation: 06 Jan 2020; epub ahead of print
Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J
Circulation: 06 Jan 2020; epub ahead of print | PMID: 31906693
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Abstract

International evaluation of an AI system for breast cancer screening.

McKinney SM, Sieniek M, Godbole V, Godwin J, ... De Fauw J, Shetty S

Screening mammography aims to identify breast cancer at earlier stages of the disease, when treatment can be more successful. Despite the existence of screening programmes worldwide, the interpretation of mammograms is affected by high rates of false positives and false negatives. Here we present an artificial intelligence (AI) system that is capable of surpassing human experts in breast cancer prediction. To assess its performance in the clinical setting, we curated a large representative dataset from the UK and a large enriched dataset from the USA. We show an absolute reduction of 5.7% and 1.2% (USA and UK) in false positives and 9.4% and 2.7% in false negatives. We provide evidence of the ability of the system to generalize from the UK to the USA. In an independent study of six radiologists, the AI system outperformed all of the human readers: the area under the receiver operating characteristic curve (AUC-ROC) for the AI system was greater than the AUC-ROC for the average radiologist by an absolute margin of 11.5%. We ran a simulation in which the AI system participated in the double-reading process that is used in the UK, and found that the AI system maintained non-inferior performance and reduced the workload of the second reader by 88%. This robust assessment of the AI system paves the way for clinical trials to improve the accuracy and efficiency of breast cancer screening.



Nature: 30 Dec 2019; 577:89-94
McKinney SM, Sieniek M, Godbole V, Godwin J, ... De Fauw J, Shetty S
Nature: 30 Dec 2019; 577:89-94 | PMID: 31894144
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Abstract

Prevention of tuberculosis in macaques after intravenous BCG immunization.

Darrah PA, Zeppa JJ, Maiello P, Hackney JA, ... Flynn JL, Seder RA

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.



Nature: 30 Dec 2019; 577:95-102
Darrah PA, Zeppa JJ, Maiello P, Hackney JA, ... Flynn JL, Seder RA
Nature: 30 Dec 2019; 577:95-102 | PMID: 31894150
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Abstract

Incidence, Trends and Outcomes of Type 2 Myocardial Infarction in a Community Cohort.

Raphael CE, Roger VL, Sandoval Y, Singh M, ... Jaffe AS, Gulati R

Type 2 myocardial infarction (T2MI) occurs due to an acute imbalance in myocardial oxygen supply and demand in the absence of athero-thrombosis. Despite being frequently encountered in clinical practice, the population-based incidence and trends remain unknown and the long-term outcomes incompletely characterized.We prospectively recruited residents of Olmsted County, Minnesota who experienced an event associated with a cardiac troponin T (cTnT) >99th percentile of a normal reference population (≥0.01 ng/mL) between 1/1/2003 and 12/31/2012. Events were retrospectively classified into type 1 MI (T1MI, atherothombotic event), T2MI or myocardial injury (troponin rise not meeting criteria for MI) using the universal definition. Outcomes were long term all-cause and cardiovascular mortality and recurrent MI. T2MI was further subclassified by inciting event for supply/demand mismatch.A total of 5460 patients had at least one cTnT ≥0.01 ng/mL, of whom 1365 were classified as index T1MI (age 68.5±14.8 years, 63% male) and 1054 T2MI (age 73.7±15.8 years, 46% male). The annual incidence of T1MI decreased markedly from 202 to 84 per 100,000 persons between 2003 and 2012 (p<0.001), while the incidence of T2MI declined from 130 to 78 per 100,000 persons (p=0.02). Compared to T1MI, patients with T2MI had higher long-term all-cause mortality after adjustment for age and sex, driven by early and non-cardiovascular death. Rates of cardiovascular death were similar after either type of MI (HR 0.8, 95% CI 0.7-1.0, p=0.11). Sub-classification of T2MI by etiology demonstrated a more favorable prognosis when the principal provoking mechanism was arrhythmia, compared with post-operative status, hypotension, anemia and hypoxia. After index T2MI, the most common MI during follow-up was a recurrent T2MI while the occurrence of a new T1MI was relatively rare (estimated rates 9.7% and 1.7% at 5 years).There has been an evolution in type of MI occurring in the community over a decade, with the incidence of T2MI now being similar to T1MI. Mortality after T2MI is higher and driven by early and non-cardiovascular death. The provoking mechanism of supply/demand mismatch affects long-term survival. These findings underscore the healthcare burden of T2MI and provide benchmarks for clinical trial design.



Circulation: 05 Jan 2020; epub ahead of print
Raphael CE, Roger VL, Sandoval Y, Singh M, ... Jaffe AS, Gulati R
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902228
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Abstract

Assessing progress towards sustainable development over space and time.

Xu Z, Chau SN, Chen X, Zhang J, ... Li Y, Liu J

To address global challenges, 193 countries have committed to the 17 United Nations Sustainable Development Goals (SDGs). Quantifying progress towards achieving the SDGs is essential to track global efforts towards sustainable development and guide policy development and implementation. However, systematic methods for assessing spatio-temporal progress towards achieving the SDGs are lacking. Here we develop and test systematic methods to quantify progress towards the 17 SDGs at national and subnational levels in China. Our analyses indicate that China\'s SDG Index score (an aggregate score representing the overall performance towards achieving all 17 SDGs) increased at the national level from 2000 to 2015. Every province also increased its SDG Index score over this period. There were large spatio-temporal variations across regions. For example, eastern China had a higher SDG Index score than western China in the 2000s, and southern China had a higher SDG Index score than northern China in 2015. At the national level, the scores of 13 of the 17 SDGs improved over time, but the scores of four SDGs declined. This study suggests the need to track the spatio-temporal dynamics of progress towards SDGs at the global level and in other nations.



Nature: 30 Dec 2019; 577:74-78
Xu Z, Chau SN, Chen X, Zhang J, ... Li Y, Liu J
Nature: 30 Dec 2019; 577:74-78 | PMID: 31894145
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Abstract

Field-resolved infrared spectroscopy of biological systems.

Pupeza I, Huber M, Trubetskov M, Schweinberger W, ... Žigman M, Krausz F

The proper functioning of living systems and physiological phenotypes depends on molecular composition. Yet simultaneous quantitative detection of a wide variety of molecules remains a challenge. Here we show how broadband optical coherence opens up opportunities for fingerprinting complex molecular ensembles in their natural environment. Vibrationally excited molecules emit a coherent electric field following few-cycle infrared laser excitation, and this field is specific to the sample\'s molecular composition. Employing electro-optic sampling, we directly measure this global molecular fingerprint down to field strengths 10 times weaker than that of the excitation. This enables transillumination of intact living systems with thicknesses of the order of 0.1 millimetres, permitting broadband infrared spectroscopic probing of human cells and plant leaves. In a proof-of-concept analysis of human blood serum, temporal isolation of the infrared electric-field fingerprint from its excitation along with its sampling with attosecond timing precision results in detection sensitivity of submicrograms per millilitre of blood serum and a detectable dynamic range of molecular concentration exceeding 10. This technique promises improved molecular sensitivity and molecular coverage for probing complex, real-world biological and medical settings.



Nature: 30 Dec 2019; 577:52-59
Pupeza I, Huber M, Trubetskov M, Schweinberger W, ... Žigman M, Krausz F
Nature: 30 Dec 2019; 577:52-59 | PMID: 31894146
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Abstract

Atomic imaging of the edge structure and growth of a two-dimensional hexagonal ice.

Ma R, Cao D, Zhu C, Tian Y, ... Wang EG, Jiang Y

The formation and growth of water-ice layers on surfaces and of low-dimensional ice under confinement are frequent occurrences. This is exemplified by the extensive reporting of two-dimensional (2D) ice on metals, insulating surfaces, graphite and graphene and under strong confinement. Although structured water adlayers and 2D ice have been imaged, capturing the metastable or intermediate edge structures involved in the 2D ice growth, which could reveal the underlying growth mechanisms, is extremely challenging, owing to the fragility and short lifetime of those edge structures. Here we show that noncontact atomic-force microscopy with a CO-terminated tip (used previously to image interfacial water with minimal perturbation), enables real-space imaging of the edge structures of 2D bilayer hexagonal ice grown on a Au(111) surface. We find that armchair-type edges coexist with the zigzag edges usually observed in 2D hexagonal crystals, and freeze these samples during growth to identify the intermediate edge structures. Combined with simulations, these experiments enable us to reconstruct the growth processes that, in the case of the zigzag edge, involve the addition of water molecules to the existing edge and a collective bridging mechanism. Armchair edge growth, by contrast, involves local seeding and edge reconstruction and thus contrasts with conventional views regarding the growth of bilayer hexagonal ices and 2D hexagonal matter in general.



Nature: 30 Dec 2019; 577:60-63
Ma R, Cao D, Zhu C, Tian Y, ... Wang EG, Jiang Y
Nature: 30 Dec 2019; 577:60-63 | PMID: 31894149
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Abstract

Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association.

Kociol RD, Cooper LT, Fang JC, Moslehi JJ, ... Vardeny O,

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.



Circulation: 05 Jan 2020:CIR0000000000000745; epub ahead of print
Kociol RD, Cooper LT, Fang JC, Moslehi JJ, ... Vardeny O,
Circulation: 05 Jan 2020:CIR0000000000000745; epub ahead of print | PMID: 31902242
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Abstract

Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.

Ford TJ, Corcoran D, Padmanabhan S, Aman A, ... Davenport AP, Berry C
Aims
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD).
Methods and results
Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status.
Conclusion
We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina.
Trial registration
ClinicalTrials.gov: NCT03193294.

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: 22 Jan 2020; epub ahead of print
Ford TJ, Corcoran D, Padmanabhan S, Aman A, ... Davenport AP, Berry C
Eur Heart J: 22 Jan 2020; epub ahead of print | PMID: 31972008
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Abstract

OUTSMART HF: A Randomized Controlled Trial of Routine Versus Selective Cardiac Magnetic Resonance for Patients with Non-Ischemic Heart Failure (IMAGE-HF 1B).

Paterson DI, Wells G, Erthal F, Mielniczuk L, ... Chan KL,

Cardiac magnetic resonance (CMR) is a recommended imaging test for patients with heart failure (HF), however there is a lack of evidence showing incremental benefit over transthoracic echocardiography. Hypothesis: Routine use of CMR will yield more specific diagnoses in non-ischemic HF. Secondary hypothesis: Routine use of CMR will improve patient outcomes.Patients with non-ischemic HF were randomized to Routine versus Selective CMR. Patients in the Routine strategy underwent echo and CMR whereas those assigned to Selective use underwent echo with or without CMR according to the clinical presentation. HF etiology was classified from the imaging data as well as by the treating physician at 3 months (primary outcome). Clinical events were collected for 12 months.500 patients (344 male), mean age 59±13, were randomized. The Routine and Selective CMR strategies had similar rates of specific HF etiologies at 3 months clinical follow-up, 44% vs. 50% respectively, p=0.22. At image interpretation, rates of specific HF etiology were also not different between Routine and Selective CMR, 34% vs. 30% respectively, p=0.34. However, 24% of patients in the Selective group underwent a non-protocol CMR. Patients with specific HF etiologies had more clinical events than those with non-specific etiologies based on imaging classification, 19% vs. 12% respectively, p=0.02, but not on clinical assessment, 15% vs. 14%, p=0.49.In patients with non-ischemic HF, Routine CMR does not yield more specific HF etiologies on clinical assessment. Patients with specific HF etiologies from imaging had worse outcomes whereas HF etiologies defined clinically did not.URL: https://clinicaltrials.gov. Unique Identifier: NCT01281384.



Circulation: 07 Jan 2020; epub ahead of print
Paterson DI, Wells G, Erthal F, Mielniczuk L, ... Chan KL,
Circulation: 07 Jan 2020; epub ahead of print | PMID: 31910649
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Abstract

Elagolix for Heavy Menstrual Bleeding in Women with Uterine Fibroids.

Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, ... Watts NB, Muneyyirci-Delale O
Background
Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding.
Methods
We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal \"add-back\" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation.
Results
A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy.
Conclusions
Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:328-340
Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, ... Watts NB, Muneyyirci-Delale O
N Engl J Med: 22 Jan 2020; 382:328-340 | PMID: 31971678
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Abstract

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

Marshall HS, McMillan M, Koehler AP, Lawrence A, ... Vadivelu K, Richmond P
Background
The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain.
Methods
We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing(group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for(encoding porin protein A) andgenogroups. Secondary outcomes included carriage prevalence and acquisition of alland individual disease-causing genogroups. Risk factors for carriage were assessed at baseline.
Results
A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causingbetween the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causingincluded later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified.
Conclusions
Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:318-327
Marshall HS, McMillan M, Koehler AP, Lawrence A, ... Vadivelu K, Richmond P
N Engl J Med: 22 Jan 2020; 382:318-327 | PMID: 31971677
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Abstract

Vaccination of Infants with Meningococcal Group B Vaccine (4CMenB) in England.

Ladhani SN, Andrews N, Parikh SR, Campbell H, ... Borrow R, Ramsay ME
Background
In September 2015, the United Kingdom introduced the multicomponent meningococcal group B vaccine (4CMenB, Bexsero) into its publicly funded national immunization program at a reduced two-dose priming schedule for infants, with a 12-month booster.
Methods
Using data from enhanced national surveillance of invasive meningococcal disease in England, we evaluated the effect of vaccination on the incidence of meningococcal group B disease during the first 3 years of the program. The effect of vaccination was assessed by comparing the observed incidence of disease with the expected incidence based on the incidence during the 4-year prevaccination period in equivalent cohorts and with the use of disease trends in cohorts of children younger than 5 years of age who were not eligible to receive the vaccine. Vaccine effectiveness was estimated with the use of the indirect screening method.
Results
4CMenB uptake in England remained consistently high; data from the first 3 months of 2018 showed that 92.5% of children had completed the primary immunizations by their first birthday and 87.9% had received all three doses by 2 years. From September 2015 through August 2018, the incidence of meningococcal group B disease in England (average annual birth cohort, approximately 650,000 infants) was significantly lower in vaccine-eligible cohorts than the expected incidence (63 observed cases as compared with 253 expected cases; incidence rate ratio, 0.25; 95% confidence interval [CI], 0.19 to 0.36), with a 75% reduction in age groups that were fully eligible for vaccination. The adjusted vaccine effectiveness against meningococcal group B disease was 52.7% (95% CI, -33.5 to 83.2) with a two-dose priming schedule for infants and 59.1% (95% CI, -31.1 to 87.2) with a two-dose priming schedule plus a booster at 1 year). Over the 3-year period, there were 169 cases of meningococcal group B disease in the vaccine-eligible cohorts, and an estimated 277 cases (95% CI, 236 to 323) were prevented.
Conclusions
The 4CMenB program was associated with continued positive effect against meningococcal group B disease in children in England, and protection after three doses of the vaccine was sustained for at least 2 years. (Funded by Public Health England.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:309-317
Ladhani SN, Andrews N, Parikh SR, Campbell H, ... Borrow R, Ramsay ME
N Engl J Med: 22 Jan 2020; 382:309-317 | PMID: 31971676
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Abstract

Teprotumumab for the Treatment of Active Thyroid Eye Disease.

Douglas RS, Kahaly GJ, Patel A, Sile S, ... Holt RJ, Smith TJ
Background
Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease.
Methods
In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves\' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful).
Results
A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation.
Conclusions
Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 22 Jan 2020; 382:341-352
Douglas RS, Kahaly GJ, Patel A, Sile S, ... Holt RJ, Smith TJ
N Engl J Med: 22 Jan 2020; 382:341-352 | PMID: 31971679
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Abstract

A Novel Coronavirus from Patients with Pneumonia in China, 2019.

Zhu N, Zhang D, Wang W, Li X, ... Tan W,

In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 23 Jan 2020; epub ahead of print
Zhu N, Zhang D, Wang W, Li X, ... Tan W,
N Engl J Med: 23 Jan 2020; epub ahead of print | PMID: 31978945
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Abstract

Improved Survival with Extracorporeal Cardiopulmonary Resuscitation Despite Progressive Metabolic Derangement Associated with Prolonged Resuscitation.

Bartos JA, Grunau B, Carlson C, Duval S, ... Aufderheide TP, Yannopoulos D

Likelihood of neurologically favorable survival declines with prolonged resuscitation. However, the ability of extracorporeal cardiopulmonary resuscitation (ECPR) to modulate this decline is unknown. We aimed to examine the effects of resuscitation duration on survival and metabolic profile in patients who undergo ECPR for refractory ventricular fibrillation/ventricular tachycardia out-of-hospital cardiac arrest (VF/VT OHCA).We retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT OHCA treated with the UMN-ECPR protocol (transport with ongoing CPR to the cardiac catheterization laboratory for ECPR) compared with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial. We evaluated the metabolic changes and rate of survival in relation to duration of CPR in UMN-ECPR patients.Neurologically favorable survival was significantly higher in UMN-ECPR patients vs. ALPS patients (33% vs. 23%; p = 0.01) overall. The mean duration of CPR was also significantly longer for UMN-ECPR patients vs. ALPS patients (60 vs. 35 min; p < 0.001). Analysis of the effect of CPR duration on neurologically favorable survival demonstrated significantly higher neurologically favorable survival for UMN-ECPR patients compared to ALPS patients at each CPR duration interval less than 60 minutes; however, longer CPR duration was associated with progressive decline in neurologically favorable survival in both groups. All UMN-ECPR patients with 20-29 minutes of CPR (8/8) survived with neurologically favorable status compared to 24% (24/102) for ALPS patients with the same duration of CPR. There were no neurologically favorable survivors in the ALPS cohort with CPR {greater than or equal to}40 minutes, whereas neurologically favorable survival was 25% (9/36) for UMN-ECPR patients with 50-59 minutes of CPR and 19% with {greater than or equal to}60 minutes. Relative risk of mortality or poor neurologic function was significantly reduced in UMN-ECPR patients with CPR duration {greater than or equal to} 60 minutes, Significant metabolic changes included decline in pH, increased lactic acid and paCO2, and thickened left ventricular wall with prolonged professional CPR.ECPR was associated with improved neurologically favorable survival at all CPR durations less than 60 minutes despite severe progressive metabolic derangement. However, CPR duration remains a critical determinate of survival.



Circulation: 02 Jan 2020; epub ahead of print
Bartos JA, Grunau B, Carlson C, Duval S, ... Aufderheide TP, Yannopoulos D
Circulation: 02 Jan 2020; epub ahead of print | PMID: 31896278
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Abstract

Long-Distance Skiing and Incidence of Hypertension: A Cohort Study of 206,889 Participants in a Long-Distance Cross-Country Skiing Event.

Andersen K, Hållmarker U, James S, Sundström J

Hypertension is the leading risk factor for death worldwide and high levels of physical activity is associated with lower incidence of hypertension. The associations of excessive levels of exercise and incidence of hypertension is less known. We aim to compare the incidence of hypertension among 206,889 participants in a long-distance cross-country skiing event and 505,542 persons randomly sampled from the general population (matched to the skiers on age sex and place of residence).Skiers best performance (in per cent of winning time) and number of completed races during the study period were associated to incidence of hypertension after participation in . Hypertension was defined as prescription of blood pressure-lowering drugs as obtained from the national drug registry. Models were adjusted for sex, age, education and income (total effect).During a median time-of-risk of 8.3 years skiers had lower incidence of hypertension compared to non-skiers (HR 0.59; 95% confidence interval [CI] 0.58-0.60). Among the skiers, better performance (in % of winning time) inwas strongly associated with lower incidence of hypertension (Fastest fifth: HR 0.41; 95% CI 0.39-0.42. Slowest fifth: 0.78 CI 0.75-0.81). The association was near linear and did not differ between sexes. Among the skiers, a weaker association of number of completed races during the study period with incidence of hypertension (1 race: HR 0.63; 95% CI 0.62-0.65.>5 races: HR 0.51; 95% CI 0.50-0.53). A sub-analysis of 10,804 participants including adjustment for lifestyle factors showed similar results.Participation in a long-distance skiing event was associated with 41% lower incidence of hypertension over the next 8 years, compared to non-participation; and the better the performance, the lower the incidence of hypertension. This adds to the list of beneficial effects of intensive training, as hypertension is the leading risk factor of premature death globally.



Circulation: 05 Jan 2020; epub ahead of print
Andersen K, Hållmarker U, James S, Sundström J
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902224
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Abstract

First in Human Experience with Peritoneal Direct Sodium Removal Using a Zero Sodium Solution: A New Candidate Therapy for Volume Overload.

Rao VS, Turner JM, Griffin M, Mahoney D, ... Finkelstein F, Testani JM

Loop diuretics have well described toxicities and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Non-renal removal of sodium directly across the peritoneal membrane (direct sodium removal, DSR) using a sodium free osmotic solution should result in extraction of large quantities of sodium with limited off target solute removal.This report describes the pre-clinical development and first-in-human proof of concept for DSR. Sodium free 10% dextrose was utilized as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, scalability, and to determine the effect of experimental HF. In the human study, participants with end stage renal disease (ESRD) on peritoneal dialysis (PD) underwent randomization and crossover to either a two-hour dwell with one liter of DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary endpoint was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary endpoint was difference in sodium removal between DSR and standard PD solution.Porcine experiments revealed that one liter of DSR solution removed 4.1±0.4 grams of sodium in 2 hours with negligible off target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (p=0.005). In the setting of experimental HF with elevated right atrial pressure, sodium removal was ~4 times greater than in healthy animals (p<0.001). In the human proof of concept study, DSR solution was well-tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable and off target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 grams) compared to standard PD solution (1.0±0.3 grams, p<0.0001).DSR was well-tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in HF is warranted.URL: https://clinicaltrials.gov Unique identifier: NCT03801226.



Circulation: 07 Jan 2020; epub ahead of print
Rao VS, Turner JM, Griffin M, Mahoney D, ... Finkelstein F, Testani JM
Circulation: 07 Jan 2020; epub ahead of print | PMID: 31910658
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Abstract

Microvascular Disease in Chronic Thromboembolic Pulmonary Hypertension: Hemodynamic Phenotyping and Histomorphometric Assessment.

Gerges C, Gerges M, Friewald R, Fesler P, ... Klepetko W, Lang IM

Pulmonary endarterectomy (PEA) is the gold standard treatment for patients with operable chronic thromboembolic pulmonary hypertension (CTEPH). However, persistent pulmonary hypertension (PH) after PEA remains a major determinant of poor prognosis. A concomitant small-vessel arteriopathy in addition to major pulmonary artery obstruction has been suggested to play an important role in the development of persistent PH and survival after PEA. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence and severity of small-vessel arteriopathy. Using the pulmonary artery occlusion technique, we sought to assess the presence and degree of smallvessel disease in CTEPH patients undergoing PEA in order to predict postoperative outcome before surgery.Based on pulmonary artery occlusion waveforms yielding an estimate of the effective capillary pressure (P), we partitioned pulmonary vascular resistance in larger arterial (R, upstream resistance) and small arterial plus venous components (R, downstream resistance) in 90 patients prior to PEA. For validation, lung wedge biopsies were taken from non-obstructed and obstructed lung territories during PEA in 49 cases. Biopsy sites were chosen according to the pulmonary angiogram still frames that were mounted in the operating room. All vessels per specimen were measured, in each patient. Percent media (%MT) (arteries) and intima thickness (%IT) (arteries, veins, and indeterminate vessels) were calculated relative to external vessel diameter.Decreased R was an independent predictor of persistent PH (OR per 10%: 0.40 [0.23-0.69]; p=0.001) and survival (HR per 10%: 0.03 [0.00-0.33]; p=0.004). Arterial %MT and %IT of non-obstructed lung territories and venous %IT of obstructed lung territories were significantly increased in patients with persistent PH and non-survivors. R correlated inversely with %MT (r=-0.72, p<0.001) and %IT (r=-0.62, p<0.001) of arteries from nonobstructed lung territories and with %IT (r=-0.44, p=0.024) of veins from obstructed lung territories. Receiver operating characteristic analysis disclosed that R <66% predicted persistent PH after PEA, while R <60% identified patients with poor prognosis after PEA.Pulmonary artery occlusion waveform analysis with estimation of R seems to be a valuable technique for assessing the degree of small-vessel disease and postoperative outcome after PEA in CTEPH.



Circulation: 02 Jan 2020; epub ahead of print
Gerges C, Gerges M, Friewald R, Fesler P, ... Klepetko W, Lang IM
Circulation: 02 Jan 2020; epub ahead of print | PMID: 31896275
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Abstract

Marijuana Use in Patients With Cardiovascular Disease: JACC Review Topic of the Week.

DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M

Marijuana use is increasing as more states are legalizing cannabis for both medicinal and recreational purposes. National survey data estimate that >2 million Americans with established cardiovascular diseases currently use or have used marijuana in its variety of forms, including inhalation and vaping. Cannabinoid receptors are distributed in multiple tissue beds and cells, including platelets, adipose tissue, and myocytes. Observational data suggest associations between marijuana and a broad range of adverse cardiovascular risks. Marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco. Synthetic cannabinoids have been linked to more sustained and deleterious pharmacodynamic effects. Marijuana is classified as a Schedule I substance, thus limiting its rigorous study for cardiovascular health effects. This review summarizes cardiovascular considerations related to marijuana use, pharmacological interactions, and future steps to provide clearer guidance regarding its cardiovascular safety. Screening for marijuana use is encouraged, especially in young patients presenting with cardiovascular disease.

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

J Am Coll Cardiol: 27 Jan 2020; 75:320-332
DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M
J Am Coll Cardiol: 27 Jan 2020; 75:320-332 | PMID: 31976871
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Abstract

Extracellular Myocardial Volume in Patients With Aortic Stenosis.

Everett RJ, Treibel TA, Fukui M, Lee H, ... Moon JC, Dweck MR
Background
Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis.
Objectives
This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes.
Methods
Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery-based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters.
Results
Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013).
Conclusions
In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.

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

J Am Coll Cardiol: 27 Jan 2020; 75:304-316
Everett RJ, Treibel TA, Fukui M, Lee H, ... Moon JC, Dweck MR
J Am Coll Cardiol: 27 Jan 2020; 75:304-316 | PMID: 31976869
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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
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Abstract

Coronary Artery Target Selection and Survival After Bilateral Internal Thoracic Artery Grafting.

Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
Background
The importance of a coronary artery, based on the myocardial mass it perfuses, is well documented, but little is known about the importance of a vessel that has been bypassed and its effect on survival in the context of bilateral internal thoracic artery (BITA) grafting.
Objectives
This study determined the effect of a dominant left anterior descending (LAD) artery and important non-LAD targets on outcomes after BITA grafting.
Methods
From January 1972 to January 2011, of 6,127 patients who underwent BITA grafting, 2,551 received 1 ITA grafted to the LAD and had an evaluable coronary angiogram. A dominant LAD was defined as one that was wrapped around the left ventricular apex. Non-LAD targets were graded based on their terminal reach toward the apex: important: >75% (n = 1,698); and less important: ≤75% (n = 853). Mean follow-up was 14 ± 8.7 years. Multivariable analysis was performed to identify risk factors for time-related mortality.
Results
A dominant LAD was present more frequently in patients with less important additional targets (51% vs. 35%; p < 0.0001). A total of 179 patients (7.0%) received a second ITA to multiple targets, 77 (43%) of which were to multiple important target vessels. Unadjusted late survival was similar regardless of degree of importance of the second ITA target-77% at 15 years (p = 0.70) for the important and less important targets, respectively. In the multivariable model, grafting the second ITA to multiple important targets was associated with better long-term survival (p = 0.005). In patients with a nondominant LAD, a second ITA grafted to a less important artery was associated with higher risk of operative mortality (2.4% vs. 0.51%; p = 0.007). A saphenous vein graft to an important or less important target did not influence long-term survival.
Conclusions
In BITA grafting, bypassing multiple important targets to maximize myocardium supplied by ITAs improved long-term survival. In patients with a nondominant LAD, selecting an important target for the second ITA lowered operative mortality.

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

J Am Coll Cardiol: 27 Jan 2020; 75:258-268
Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
J Am Coll Cardiol: 27 Jan 2020; 75:258-268 | PMID: 31976863
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Abstract

Embolic Stroke of Undetermined Source: JACC Review Topic of the Week.

Ntaios G

The term embolic stroke of undetermined source (ESUS) was introduced in 2014 to describe patients with a nonlacunar ischemic stroke and no convincing etiology. The terms ESUS and cryptogenic stroke are not synonyms, as the latter also includes patients with multiple stroke etiologies or incomplete diagnostic work-up. ESUS involves approximately 17% of all ischemic stroke patients, and these patients are typically younger with mild strokes and an annual rate of stroke recurrence of 4% to 5%. It was hypothesized that oral anticoagulation may decrease the risk of stroke recurrence in ESUS, which was tested in 2 large randomized controlled trials: the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) and the RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source). The present review discusses the trials of anticoagulation in patients with ESUS, suggests potential explanations for their neutral results, and highlights the rationale that supports ongoing and future research in this population aiming to reduce the associated risk for stroke recurrence.

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

J Am Coll Cardiol: 27 Jan 2020; 75:333-340
Ntaios G
J Am Coll Cardiol: 27 Jan 2020; 75:333-340 | PMID: 31976872
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Abstract

Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.

Furtado RHM, Nicolau JC, Guo J, Im K, ... Newby LK, Giugliano RP
Background
Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial.
Objectives
This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls.
Methods
Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days.
Results
In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; p = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; p = 0.46).
Conclusions
When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).

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

J Am Coll Cardiol: 27 Jan 2020; 75:289-300
Furtado RHM, Nicolau JC, Guo J, Im K, ... Newby LK, Giugliano RP
J Am Coll Cardiol: 27 Jan 2020; 75:289-300 | PMID: 31976867
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Abstract

The structural basis for cohesin-CTCF-anchored loops.

Li Y, Haarhuis JHI, Cacciatore ÁS, Oldenkamp R, ... Rowland BD, Panne D

Cohesin catalyses the folding of the genome into loops that are anchored by CTCF. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 Å crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL. Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.



Nature: 05 Jan 2020; epub ahead of print
Li Y, Haarhuis JHI, Cacciatore ÁS, Oldenkamp R, ... Rowland BD, Panne D
Nature: 05 Jan 2020; epub ahead of print | PMID: 31905366
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Abstract

In vitro characterization of the human segmentation clock.

Diaz-Cuadros M, Wagner DE, Budjan C, Hubaud A, ... Touboul J, Pourquié O

The segmental organization of the vertebral column is established early in embryogenesis, when pairs of somites are rhythmically produced by the presomitic mesoderm (PSM). The tempo of somite formation is controlled by a molecular oscillator known as the segmentation clock. Although this oscillator has been well-characterized in model organisms, whether a similar oscillator exists in humans remains unknown. Genetic analyses of patients with severe spine segmentation defects have implicated several human orthologues of cyclic genes that are associated with the mouse segmentation clock, suggesting that this oscillator might be conserved in humans. Here we show that human PSM cells derived in vitro-as well as those of the mouse-recapitulate the oscillations of the segmentation clock. Human PSM cells oscillate with a period two times longer than that of mouse cells (5 h versus 2.5 h), but are similarly regulated by FGF, WNT, Notch and YAP signalling. Single-cell RNA sequencing reveals that mouse and human PSM cells in vitro follow a developmental trajectory similar to that of mouse PSM in vivo. Furthermore, we demonstrate that FGF signalling controls the phase and period of oscillations, expanding the role of this pathway beyond its classical interpretation in \'clock and wavefront\' models. Our work identifying the human segmentation clock represents an important milestone in understanding human developmental biology.



Nature: 07 Jan 2020; epub ahead of print
Diaz-Cuadros M, Wagner DE, Budjan C, Hubaud A, ... Touboul J, Pourquié O
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915384
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Abstract

Microbiota-targeted maternal antibodies protect neonates from enteric infection.

Zheng W, Zhao W, Wu M, Song X, ... Mekalanos JJ, Kasper DL

Although maternal antibodies protect newborn babies from infection, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates.



Nature: 07 Jan 2020; epub ahead of print
Zheng W, Zhao W, Wu M, Song X, ... Mekalanos JJ, Kasper DL
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915378
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Abstract

Coupling delay controls synchronized oscillation in the segmentation clock.

Yoshioka-Kobayashi K, Matsumiya M, Niino Y, Isomura A, ... Miyawaki A, Kageyama R

Individual cellular activities fluctuate but are constantly coordinated at the population level via cell-cell coupling. A notable example is the somite segmentation clock, in which the expression of clock genes (such as Hes7) oscillates in synchrony between the cells that comprise the presomitic mesoderm (PSM). This synchronization depends on the Notch signalling pathway; inhibiting this pathway desynchronizes oscillations, leading to somite fusion. However, how Notch signalling regulates the synchronicity of HES7 oscillations is unknown. Here we establish a live-imaging system using a new fluorescent reporter (Achilles), which we fuse with HES7 to monitor synchronous oscillations in HES7 expression in the mouse PSM at a single-cell resolution. Wild-type cells can rapidly correct for phase fluctuations in HES7 oscillations, whereas the absence of the Notch modulator gene lunatic fringe (Lfng) leads to a loss of synchrony between PSM cells. Furthermore, HES7 oscillations are severely dampened in individual cells of Lfng-null PSM. However, when Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of HES7 oscillations were almost normal, which suggests that LFNG is involved mostly in cell-cell coupling. Mixed cultures of control and Lfng-null PSM cells, and an optogenetic Notch signalling reporter assay, revealed that LFNG delays the signal-sending process of intercellular Notch signalling transmission. These results-together with mathematical modelling-raised the possibility that Lfng-null PSM cells shorten the coupling delay, thereby approaching a condition known as the oscillation or amplitude death of coupled oscillators. Indeed, a small compound that lengthens the coupling delay partially rescues the amplitude and synchrony of HES7 oscillations in Lfng-null PSM cells. Our study reveals a delay control mechanism of the oscillatory networks involved in somite segmentation, and indicates that intercellular coupling with the correct delay is essential for synchronized oscillation.



Nature: 07 Jan 2020; epub ahead of print
Yoshioka-Kobayashi K, Matsumiya M, Niino Y, Isomura A, ... Miyawaki A, Kageyama R
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915376
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Abstract

Nearest neighbours reveal fast and slow components of motor learning.

Kollmorgen S, Hahnloser RHR, Mante V

Changes in behaviour resulting from environmental influences, development and learning are commonly quantified on the basis of a few hand-picked features (for example, the average pitch of acoustic vocalizations), assuming discrete classes of behaviours (such as distinct vocal syllables). However, such methods generalize poorly across different behaviours and model systems and may miss important components of change. Here we present a more-general account of behavioural change that is based on nearest-neighbour statistics, and apply it to song development in a songbird, the zebra finch. First, we introduce the concept of \'repertoire dating\', whereby each rendition of a behaviour (for example, each vocalization) is assigned a repertoire time, reflecting when similar renditions were typical in the behavioural repertoire. Repertoire time isolates the components of vocal variability that are congruent with long-term changes due to vocal learning and development, and stratifies the behavioural repertoire into \'regressions\', \'anticipations\' and \'typical renditions\'. Second, we obtain a holistic, yet low-dimensional, description of vocal change in terms of a stratified \'behavioural trajectory\', revealing numerous previously unrecognized components of behavioural change on fast and slow timescales, as well as distinct patterns of overnight consolidation across the behavioral repertoire. We find that diurnal changes in regressions undergo only weak consolidation, whereas anticipations and typical renditions consolidate fully. Because of its generality, our nonparametric description of how behaviour evolves relative to itself-rather than to a potentially arbitrary, experimenter-defined goal-appears well suited for comparing learning and change across behaviours and species, as well as biological and artificial systems.



Nature: 07 Jan 2020; epub ahead of print
Kollmorgen S, Hahnloser RHR, Mante V
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915383
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Abstract

The emergence of transcriptional identity in somatosensory neurons.

Sharma N, Flaherty K, Lezgiyeva K, Wagner DE, Klein AM, Ginty DD

More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.



Nature: 07 Jan 2020; epub ahead of print
Sharma N, Flaherty K, Lezgiyeva K, Wagner DE, Klein AM, Ginty DD
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915380
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Abstract

TGF-β orchestrates fibrogenic and developmental EMTs via the RAS effector RREB1.

Su J, Morgani SM, David CJ, Wang Q, ... Hadjantonakis AK, Massagué J

Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer. EMTs are driven by SNAIL, ZEB and TWIST transcription factors together with microRNAs that balance this regulatory network. Transforming growth factor β (TGF-β) is a potent inducer of developmental and fibrogenic EMTs. Aberrant TGF-β signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer. TGF-β depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector, as a key partner of TGF-β-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-β-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-β-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-β pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.



Nature: 07 Jan 2020; epub ahead of print
Su J, Morgani SM, David CJ, Wang Q, ... Hadjantonakis AK, Massagué J
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915377
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Abstract

A Galactic-scale gas wave in the solar neighborhood.

Alves J, Zucker C, Goodman AA, Speagle JS, ... Schlafly EF, Green GM

For the past 150 years, the prevailing view of the local interstellar medium was based on a peculiarity known as Gould\'s Belt, an expanding ring of young stars, gas and dust, tilted about 20 degrees to the Galactic plane. Still, the physical relation between local gas clouds has remained practically unknown because the distance accuracy to clouds is of the same order as, or larger than, their sizes. With the advent of large photometric surveys and astrometric survey this situation has changed. Here we report the three-dimensional structure of all local cloud complexes. We find a narrow and coherent 2.7-kiloparsec arrangement of dense gas in the solar neighbourhood that contains many of the clouds thought to be associated with the Gould Belt. This finding is inconsistent with the notion that these clouds are part of a ring, disputing the Gould Belt model. The new structure comprises the majority of nearby star-forming regions, has an aspect ratio of about 1:20, and contains about three million solar masses of gas. Remarkably, the new structure appears to be undulating and its three-dimensional structure is well described by a damped sinusoidal wave on the plane of the Milky Way, with an average period of about 2 kiloparsecs and a maximum amplitude of about 160 parsecs.



Nature: 06 Jan 2020; epub ahead of print
Alves J, Zucker C, Goodman AA, Speagle JS, ... Schlafly EF, Green GM
Nature: 06 Jan 2020; epub ahead of print | PMID: 31910431
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Abstract

Activation of the GLP-1 receptor by a non-peptidic agonist.

Zhao P, Liang YL, Belousoff MJ, Deganutti G, ... Sexton PM, Wootten D

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors.



Nature: 07 Jan 2020; epub ahead of print
Zhao P, Liang YL, Belousoff MJ, Deganutti G, ... Sexton PM, Wootten D
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915381
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Abstract

A repeating fast radio burst source localized to a nearby spiral galaxy.

Marcote B, Nimmo K, Hessels JWT, Tendulkar SP, ... Vanderlinde K, Zwaniga AV

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes. Their physical origin remains unknown, but dozens of possible models have been postulated. Some FRB sources exhibit repeat bursts. Although over a hundred FRB sources have been discovered, only four have been localized and associated with a host galaxy, and just one of these four is known to emit repeating FRBs. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.



Nature: 05 Jan 2020; epub ahead of print
Marcote B, Nimmo K, Hessels JWT, Tendulkar SP, ... Vanderlinde K, Zwaniga AV
Nature: 05 Jan 2020; epub ahead of print | PMID: 31907402
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Abstract

Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition.

Xue JY, Zhao Y, Aronowitz J, Mai TT, ... Risso D, Lito P

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma. KRAS(G12C) inhibitors are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation, and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.



Nature: 07 Jan 2020; epub ahead of print
Xue JY, Zhao Y, Aronowitz J, Mai TT, ... Risso D, Lito P
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915379
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Abstract

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer\'s disease.

Gate D, Saligrama N, Leventhal O, Yang AC, ... Davis MM, Wyss-Coray T

Alzheimer\'s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function. However, little is known about the contribution of the adaptive immune response in Alzheimer\'s disease. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer\'s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer\'s disease that consists of increased numbers of CD8 T effector memory CD45RA (T) cells. In a second cohort, we found that CD8 T cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8 T cells in the cerebrospinal fluid of patients with Alzheimer\'s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer\'s disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer\'s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.



Nature: 07 Jan 2020; epub ahead of print
Gate D, Saligrama N, Leventhal O, Yang AC, ... Davis MM, Wyss-Coray T
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915375
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Abstract

Ocean acidification does not impair the behaviour of coral reef fishes.

Clark TD, Raby GD, Roche DG, Binning SA, ... Jutfelt F, Sundin J

The partial pressure of CO in the oceans has increased rapidly over the past century, driving ocean acidification and raising concern for the stability of marine ecosystems. Coral reef fishes are predicted to be especially susceptible to end-of-century ocean acidification on the basis of several high-profile papers that have reported profound behavioural and sensory impairments-for example, complete attraction to the chemical cues of predators under conditions of ocean acidification. Here, we comprehensively and transparently show that-in contrast to previous studies-end-of-century ocean acidification levels have negligible effects on important behaviours of coral reef fishes, such as the avoidance of chemical cues from predators, fish activity levels and behavioural lateralization (left-right turning preference). Using data simulations, we additionally show that the large effect sizes and small within-group variances that have been reported in several previous studies are highly improbable. Together, our findings indicate that the reported effects of ocean acidification on the behaviour of coral reef fishes are not reproducible, suggesting that behavioural perturbations will not be a major consequence for coral reef fishes in high CO oceans.



Nature: 07 Jan 2020; epub ahead of print
Clark TD, Raby GD, Roche DG, Binning SA, ... Jutfelt F, Sundin J
Nature: 07 Jan 2020; epub ahead of print | PMID: 31915382
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Abstract

Adhesion-related readmissions after open and laparoscopic surgery: a retrospective cohort study (SCAR update).

Krielen P, Stommel MWJ, Pargmae P, Bouvy ND, ... van Goor H, Ten Broek RPG
Background
Adhesions are the most common driver of long-term morbidity after abdominal surgery. Although laparoscopy can reduce adhesion formation, the effect of minimally invasive surgery on long-term adhesion-related morbidity remains unknown. We aimed to assess the impact of laparoscopy on adhesion-related readmissions in a population-based cohort.
Methods
We did a retrospective cohort study of patients of any age who had abdominal or pelvic surgery done using laparoscopic or open approaches between June 1, 2009, and June 30, 2011, using validated population data from the Scottish National Health Service. All patients who had surgery were followed up until Dec 31, 2017. The primary outcome measure was the incidence of hospital readmissions directly related to adhesions in the laparoscopic and open surgery cohorts at 5 years. Readmissions were categorised as directly related to adhesions, possibly related to adhesions, and readmissions for an operation that was potentially complicated by adhesions. We did subgroup analyses of readmissions by anatomical site of surgery and used Kaplan-Meier analyses to assess differences in survival across subgroups. We used multivariable Cox-regression analysis to determine whether surgical approach was an independent and significant risk factor for adhesion-related readmissions.
Findings
Between June 1, 2009, and June 30, 2011, 72 270 patients had an index abdominal or pelvic surgery, of whom 21 519 (29·8%) had laparoscopic index surgery and 50 751 (70·2%) had open surgery. Of the 72 270 patients who had surgery, 2527 patients (3·5%) were readmitted within 5 years of surgery for disorders directly related to adhesions, 12 687 (17·6%) for disorders possibly related to adhesions, and 9436 (13·1%) for operations potentially complicated by adhesions. Of the 21 519 patients who had laparoscopic surgery, 359 (1·7% [95% CI 1·5-1·9]) were readmitted for disorders directly related to adhesions compared with 2168 (4·3% [4·1-4·5]) of 50 751 patients in the open surgery cohort (p<0·0001). 3443 (16·0% [15·6-16·4]) of 21 519 patients in the laparoscopic surgery cohort were readmitted for disorders possibly related to adhesions compared with 9244 (18·2% [17·8-18·6]) of 50 751 patients in the open surgery cohort (p<0·005). In multivariate analyses, laparoscopy reduced the risk of directly related readmissions by 32% (hazard ratio [HR] 0·68, 95% CI 0·60-0·77), and of possibly related readmissions by 11% (HR 0·89, 0·85-0·94) compared with open surgery. Procedure type, malignancy, sex, and age were also independently associated with risk of adhesion-related readmissions.
Interpretation
Laparoscopic surgery reduces the incidence of adhesion-related readmissions. However, the overall burden of readmissions associated with adhesions remains high. With further increases in the use of laparoscopic surgery expected in the future, the effect at the population level might become larger. Further steps remain necessary to reduce the incidence of adhesion-related postsurgical complications.
Funding
Dutch Adhesion Group and Nordic Pharma.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 03 Jan 2020; 395:33-41
Krielen P, Stommel MWJ, Pargmae P, Bouvy ND, ... van Goor H, Ten Broek RPG
Lancet: 03 Jan 2020; 395:33-41 | PMID: 31908284
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Abstract

Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure Overloaded Hearts.

Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K

Proinflammatory cytokines play an important role in the pathogenesis of heart failure. However, the mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of the mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in non-immune cells such as cardiomyocytes remains to be elucidated.To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Furthermore, interleukin-6 (IL-6) signaling was inhibited by the administration with its receptor antibody. Finally, overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared to the control littermates. Four weeks after TAC, themRNA level was upregulated, but not other cytokine mRNAs including tumor necrosis factor-α in Regnase-1-deficient hearts. Although themRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction ofmRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9- mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.



Circulation: 13 Jan 2020; epub ahead of print
Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931613
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Abstract

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis Following Myocardial Infarction.

Sreejit G, Abdel-Latif A, Athmanathan B, Annabathula R, ... Murphy AJ, Nagareddy PR

Myocardial infarction (MI) triggers myelopoiesis resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.Using a mouse model of the permanent ligation of the left anterior descending (LAD) artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of acute inflammatory response and the underlying signaling pathways. Utilizing a combination of genetic and pharmacological strategies, we identified the sequalae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indices of neutrophilia with major adverse cardiovascular events (MACE) was studied in a cohort of acute MI patients.Induction of MI resulted in a rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll Like Receptor (TLR) 4 and prime the Nod Like Receptor (NLR) family Pyrin Domain-Containing 3 (Nlrp3) inflammasome in naïve neutrophils and promote interleukin 1 (IL-1β) secretion. The released IL-1β interact with its receptor (Interleukin 1 Receptor Type 1, IL1R1) on hematopoietic stem and progenitor cells in the bone marrow (BM), and stimulate granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and its downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome (ACS), higher neutrophil count on admission and post-revascularization correlates positively with major adverse cardiovascular disease (CVD) outcomes.Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response following myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or its downstream mediators (e.g. Nlrp3, IL-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in ACS patients.



Circulation: 15 Jan 2020; epub ahead of print
Sreejit G, Abdel-Latif A, Athmanathan B, Annabathula R, ... Murphy AJ, Nagareddy PR
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941367
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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
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Abstract

Deficiency of Circulating Monocytes Ameliorates the Progression of Myxomatous Valve Degeneration in Marfan Syndrome.

Kim AJ, Xu N, Umeyama K, Hulin A, ... Nagashima H, Yutzey KE
Background
Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known.
Methods
We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (), gene-edited MFS pigs (), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages () were generated to determine the requirements of recruited macrophages to MVD progression.
Results
MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity.
Conclusions
All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.



Circulation: 13 Jan 2020; 141:132-146
Kim AJ, Xu N, Umeyama K, Hulin A, ... Nagashima H, Yutzey KE
Circulation: 13 Jan 2020; 141:132-146 | PMID: 31928435
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Abstract

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multi-Cohort Study.

Lewis AA, Ayers CR, Selvin E, Neeland I, ... deFilippi CR, de Lemos JA

A \"malignant\" subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk.Participants (n=15, 710) without prevalent cardiovascular disease were pooled from three population-based cohort studies, the Atherosclerosis Risk in Communities Study (ARIC), the Dallas Heart Study (DHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were classified into three groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT < 6 ng/L and NT-proBNP < 100 pg/mL), and those with ECGLVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF.Over the 10 year follow up period, HF occurred in 512 (3.3%) participants, with rates 5.2% among black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women vs white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI 2.1 to 3.5) in those with malignant LVH and 0.9 (95% CI 0.6 to 1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction (PAF) of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding PAF, were intermediate and similar among black women and white men and lowest among white women.A higher prevalence of malignant LVH may in part explain the higher risk of heart failure among blacks vs whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower heart failure risk and mitigate racial disparities.



Circulation: 13 Jan 2020; epub ahead of print
Lewis AA, Ayers CR, Selvin E, Neeland I, ... deFilippi CR, de Lemos JA
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931608
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Abstract

Time Trends in Cardiovascular Disease Mortality Across the BRICS: An Age-Period-Cohort Analysis of Key Nations with Emerging Economies Using the Global Burden of Disease Study 2017.

Zou Z, Cini K, Dong B, Ma Y, ... Burgner DP, Patton GC

Brazil, Russia, India, China and South Africa (BRICS) are emerging economies making up almost half the global population. We analyzed trends in cardiovascular disease (CVD) mortality across the BRICS, and associations with age, period and birth cohort.Mortality estimates were derived from the Global Burden of Disease Study 2017. We used age-period-cohort modeling to estimate cohort and period effects in CVD between 1992- 2016. Period was defined as survey year, and period effects reflect population wide exposure at a circumscribed point in time. Cohort effects are defined as differences in risks across birth cohort. Net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks were calculated.In 2016, there were 8.4 million CVD deaths across the BRICS. Between 1992 and 2016, the reduction in CVD age-standardized mortality rate (ASMR) in BRICS (-17%) was less than in North America (-39%). 88% of the increased number of all- cause deaths resulted from the increase in CVD deaths. ASMR from stroke and HHD declined by approximately one third across the BRICS, whereas IHD increased slightly (2%). Brazil had the largest ASMR reductions across all CVD categories, with both improvement over time and in recent birth cohorts. South Africa was the only country where CVD ASMR increased. Different age-related CVD mortality was seen in those aged ≥ 50 years in China, ≤ 40 years in Russia, 35-60 years in India, and ≥ 55 years in South Africa. Improving period and cohort risks for CVD mortality were generally found across countries, with the exception of worsening period effects in India and greater risks for IHD in Chinese cohorts born in the 1950s and 1960s.With the exception of Brazil, reductions of CVD mortality across the BRICS have been less than in North America, such that China, India and South Africa contribute an increasing proportion of global CVD deaths. Brazil\'s example suggests that prevention policies can both reduce the risks for younger birth cohorts and shift the risks for all age groups over time.



Circulation: 15 Jan 2020; epub ahead of print
Zou Z, Cini K, Dong B, Ma Y, ... Burgner DP, Patton GC
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941371
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Abstract

Dysfunctional HDLs are Associated with a Greater Incidence of Acute Coronary Syndrome in a Population at High Cardiovascular Risk: A Nested-Case Control Study.

Soria-Florido MT, Castañer O, Lassale C, Estruch R, ... Hernáez Á, Fitó M

Studies have failed to establish a clear link between high-density lipoprotein (HDL) cholesterol and cardiovascular disease, leading to the hypothesis that HDL atheroprotective role lies in its biological activity rather than in its cholesterol content. However, to date, the association between HDL functional characteristics and acute coronary syndrome has not been comprehensively investigated.We conducted a case-control study nested within the PREDIMED () cohort, originally a randomized trial where participants followed a Mediterranean or low-fat diet. Incident acute coronary syndrome cases (=167) were individually matched (1:2) to controls by sex, age, intervention group, body mass index, and follow-up time. We investigated its two individual manifestations (myocardial infarction, unstable angina) as secondary outcomes. We measured the following functional characteristics: HDL cholesterol concentration (in plasma); cholesterol efflux capacity; antioxidant ability measured by the HDL oxidative-inflammatory index; phospholipase A2 activity; and sphingosine-1-phosphate, apolipoproteins A-I and A-IV, serum amyloid A, and complement 3 protein (in apolipoprotein B-depleted plasma). We used conditional logistic regression models adjusted for HDL cholesterol levels and cardiovascular risk factors to estimate odds ratios (ORs) between one standard deviation increments in HDL functional characteristics and clinical outcomes.Low values of cholesterol efflux capacity (OR: 0.58, 95% CI: 0.40-0.83), and levels of sphingosine-1-phosphate (OR: 0.70, 95% CI: 0.52-0.92), and apolipoprotein A-I (OR: 0.58, 95% CI: 0.42-0.79) were associated with higher odds of acute coronary syndrome. Higher HDL oxidative inflammatory index values were marginally linked to acute coronary syndrome risk (OR: 1.27, 95% CI: 0.99-1.63). Low values of cholesterol efflux capacity (OR: 0.33, 95% CI: 0.18-0.61), sphingosine-1-phosphate (OR: 0.60, 95% CI: 0.40-0.89) and apolipoprotein A-I (OR: 0.59, 95% CI: 0.37-0.93) were particularly linked to myocardial infarction, whereas high HDL oxidative-inflammatory index values (OR: 1.53, 95% CI: 1.01-2.33) and low apolipoprotein A-I levels (OR: 0.52, 95% CI: 0.31-0.88) were associated with unstable angina.Low cholesterol efflux capacity values, pro-oxidant/pro-inflammatory HDL particles, and low HDL levels of sphingosine-1-phosphate and apolipoprotein A-I were associated with increased odds of acute coronary syndrome and its manifestations in high cardiovascular risk subjects.URL: http://www.controlled-trials.com Unique identifier: ISRCTN35739639.



Circulation: 15 Jan 2020; epub ahead of print
Soria-Florido MT, Castañer O, Lassale C, Estruch R, ... Hernáez Á, Fitó M
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941372
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Abstract

The Effect of Coconut Oil Consumption on Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Clinical Trials.

Neelakantan N, Seah JYH, van Dam RM

Coconut oil is high in saturated fat and may, therefore, raise serum cholesterol concentrations, but beneficial effects on other cardiovascular risk factors have also been suggested. Therefore, we conducted a systematic review of the effect of coconut oil consumption on blood lipids and other cardiovascular risk factors compared with other cooking oils using data from clinical trials.We searched PubMed, SCOPUS, Cochrane Registry, and Web of Science through June 2019. We selected trials that compared the effects of coconut oil consumption with other fats that lasted at least 2 weeks. Two reviewers independently screened articles, extracted data, and assessed the study quality according to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The main outcomes included low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), total cholesterol, triglycerides, measures of body fatness, markers of inflammation, and glycemia. Data were pooled using random-effects meta-analysis.16 articles were included in the meta-analysis. Results were available from all trials on blood lipids, 8 trials on body weight, 5 trials on percentage body fat, 4 trials on waist circumference, 4 trials on fasting plasma glucose, and 5 trials on C-reactive protein. Coconut oil consumption significantly increased LDL-cholesterol by 10.47 mg/dL (95% CI: 3.01, 17.94;= 84%, N=16) and HDL-cholesterol by 4.00 mg/dL (95% CI: 2.26, 5.73;= 72%, N=16) as compared with nontropical vegetable oils. These effects remained significant after excluding nonrandomized trials, or trials of poor quality (Jadad score <3). Coconut oil consumption did not significantly affect markers of glycemia, inflammation, and adiposity as compared with nontropical vegetable oils.Coconut oil consumption results in significantly higher LDL-cholesterol than nontropical vegetable oils. This should inform choices about coconut oil consumption.



Circulation: 12 Jan 2020; epub ahead of print
Neelakantan N, Seah JYH, van Dam RM
Circulation: 12 Jan 2020; epub ahead of print | PMID: 31928080
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Abstract

Orphan G-Protein-Coupled Receptor GPRC5B Controls Smooth Muscle Contractility and Differentiation by Inhibiting Prostacyclin Receptor Signaling.

Carvalho J, Chennupati R, Li R, Günther S, ... Offermanns S, Wettschureck N

G-protein-coupled receptors (GPCRs) are important regulators of contractility and differentiation in vascular smooth muscle cells (SMC), but the specific function of SMC-expressed orphan GPCR GPRC5B is unclear.We studied the role of GPRC5B in the regulation of contractility and dedifferentiation in human and murine SMC in vitro as well as in tamoxifen-inducible, SMC-specific knockout mice (iSM-Gprc5b-KO) under conditions of arterial hypertension and atherosclerosis in vivo.Mesenteric arteries from SMC-specific Gprc5b-KOs showed ex vivo significantly enhanced prostacyclin receptor (IP)-dependent relaxation, whereas responses to other relaxant or contractile factors were normal. In vitro, knockdown of GPRC5B in human aortic SMC resulted in increased IP-dependent cAMP production and consecutive facilitation of SMC relaxation. In line with this facilitation of IP-mediated relaxation, iSM-Gprc5b-KO mice were protected from arterial hypertension, and this protective effect was abrogated by IP antagonists. Mechanistically, we show that knockdown of GPRC5B increased the membrane localization of IP both in vitro and in vivo, and that GPRC5B, but not other GPCRs, physically interact with IP. Finally, we show that enhanced IP signaling in GPRC5B-deficient smooth muscle cells does not only facilitate relaxation, but also prevents dedifferentiation during atherosclerosis development, resulting in reduced plaque load and increased differentiation of SMC in the fibrous cap.Taken together, our data show that GPRC5B regulates vascular SMC tone and differentiation by negatively regulating IP signaling.



Circulation: 15 Jan 2020; epub ahead of print
Carvalho J, Chennupati R, Li R, Günther S, ... Offermanns S, Wettschureck N
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941358
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