Topic: Basic Research

Abstract

Emerging Techniques for Risk Stratification in Nonischemic Dilated Cardiomyopathy: JACC Review Topic of the Week.

Marrow BA, Cook SA, Prasad SK, McCann GP

Dilated cardiomyopathy (DCM) is a common condition, which carries significant mortality from sudden cardiac death and pump failure. Left ventricular ejection fraction has conventionally been used as a risk marker for sudden cardiac death, but has performed poorly in trials. There have been significant advances in the areas of cardiac magnetic resonance imaging and genetics, which are able to provide useful rick prediction in DCM. Biomarkers and cardiopulmonary exercise testing are well validated in the prediction of risk in heart failure; however, they have been tested less specifically in the DCM setting. This review will discuss these methods with a view toward multiparametric risk assessment in DCM with the hope of creating parametric risk models to predict sudden cardiac death and pump failure in the DCM population.

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

J Am Coll Cardiol: 16 Mar 2020; 75:1196-1207
Marrow BA, Cook SA, Prasad SK, McCann GP
J Am Coll Cardiol: 16 Mar 2020; 75:1196-1207 | PMID: 32164893
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Abstract

Cardiovascular Mortality After Type 1 and Type 2 Myocardial Infarction in Young Adults.

Singh A, Gupta A, DeFilippis EM, Qamar A, ... Bhatt DL, Blankstein R
Background
Type 2 myocardial infarction (MI) and myocardial injury are associated with increased short-term mortality. However, data regarding long-term mortality are lacking.
Objectives
This study compared long-term mortality among young adults with type 1 MI, type 2 MI, or myocardial injury.
Methods
Adults age 50 years or younger who presented with troponin >99th percentile or the International Classification of Diseases code for MI over a 17-year period were identified. All cases were adjudicated as type 1 MI, type 2 MI, or myocardial injury based on the Fourth Universal Definition of MI. Cox proportional hazards models were constructed for survival free from all-cause and cardiovascular death.
Results
The cohort consisted of 3,829 patients (median age 44 years; 30% women); 55% had type 1 MI, 32% had type 2 MI, and 13% had myocardial injury. Over a median follow-up of 10.2 years, mortality was highest for myocardial injury (45.6%), followed by type 2 MI (34.2%) and type 1 MI (12%) (p < 0.001). In an adjusted model, type 2 MI was associated with higher all-cause (hazard ratio: 1.8; 95% confidence interval: 1.2 to 2.7; p = 0.004) and cardiovascular mortality (hazard ratio: 2.7; 95% confidence interval: 1.4 to 5.1; p = 0.003) compared with type 1 MI. Those with type 2 MI or myocardial injury were younger and had fewer cardiovascular risk factors but had more noncardiovascular comorbidities. They were significantly less likely to be prescribed cardiovascular medications at discharge.
Conclusions
Young patients who experience a type 2 MI have higher long-term all-cause and cardiovascular mortality than those who experience type 1 MI, with nearly one-half of patients with myocardial injury and more than one-third of patients with type 2 MI dying within 10 years. These findings emphasize the need to provide more aggressive secondary prevention for patients who experience type 2 MI and myocardial injury.

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

J Am Coll Cardiol: 09 Mar 2020; 75:1003-1013
Singh A, Gupta A, DeFilippis EM, Qamar A, ... Bhatt DL, Blankstein R
J Am Coll Cardiol: 09 Mar 2020; 75:1003-1013 | PMID: 32138959
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Abstract

Sleep Irregularity and Risk of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

Huang T, Mariani S, Redline S
Background
The cardiovascular system exhibits strong circadian rhythms to maintain normal functioning. Irregular sleep schedules, characterized by high day-to-day variability in sleep duration or timing, represent possibly milder but much more common and chronic disruption of circadian rhythms in the general population than shift work.
Objectives
This study aimed to prospectively examine the association between sleep regularity and risk of cardiovascular disease (CVD).
Methods
In MESA (Multi-Ethnic Study of Atherosclerosis), 1,992 participants free of CVD completed 7-day wrist actigraphy for sleep assessment from 2010 to 2013 and were prospectively followed through 2016. The study assessed sleep regularity using the SD of actigraphy-measured sleep duration and sleep-onset timing across 7 days. Incident CVD included nonfatal and fatal cardiovascular events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incident CVD according to SD of sleep duration and timing, adjusted for traditional CVD risk factors (including CVD biomarkers) and other sleep-related factors (including average sleep duration).
Results
During a median follow-up of 4.9 years, 111 participants developed CVD events. The multivariable-adjusted HRs (95% confidence intervals) for CVD across categories of sleep duration SD were 1.00 (reference) for ≤60 min, 1.09 (0.62 to 1.92) for 61 to 90 min, 1.59 (0.91 to 2.76) for 91 to 120 min, and 2.14 (1.24 to 3.68) for >120 min (p trend = 0.002). Similarly, compared with participants with a sleep timing SD ≤30 min, the HRs (95% confidence intervals) for CVD were 1.16 (0.64 to 2.13) for 31 to 60 min, 1.52 (0.81 to 2.88) for 61 to 90 min, and 2.11 (1.13 to 3.91) for >90 min (p trend = 0.002). Exclusion of current shift workers yielded similar results.
Conclusions
Irregular sleep duration and timing may be novel risk factors for CVD, independent of traditional CVD risk factors and sleep quantity and/or quality.

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

J Am Coll Cardiol: 09 Mar 2020; 75:991-999
Huang T, Mariani S, Redline S
J Am Coll Cardiol: 09 Mar 2020; 75:991-999 | PMID: 32138974
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Abstract

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

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

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

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

Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.

Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
Background
Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure.
Objectives
The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies.
Methods
To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models.
Results
At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy.
Conclusions
The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

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

J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174
Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174 | PMID: 32164890
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Abstract

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction.

Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
Background
Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).
Objectives
The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.
Methods
In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).
Results
Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.
Conclusions
Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295
Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295 | PMID: 32192654
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Abstract

Sustainability of and Adherence to Preschool Health Promotion Among Children 9 to 13 Years Old.

Fernández-Jiménez R, Briceño G, Céspedes J, Vargas S, ... Carvajal I, Fuster V
Background
Long-term evaluations of child health promotion programs are required to assess their sustainability and the need for reintervention.
Objectives
This study sought to explore the long-term impact of a preschool health promotion intervention delivered in an urban low-income area of Colombia (phase 1) and to assess the effect of a new community-based intervention (phase 2).
Methods
In phase 1, a cross-sectional analysis of knowledge, attitudes, and habits (KAH) toward a healthy lifestyle and ideal cardiovascular health (ICH) scores of 1,216 children 9 to 13 years old was performed. Of the total, 596 had previously received a preschool health promotion intervention at 3 to 5 years old, whereas the remaining 620 were not previously intervened (intervention-naive group). In phase 2, all children were cluster randomized 1:1 to receive either a 4-month educational intervention (the SI! Program) to instill healthy behaviors in community centers (24 clusters, 616 children) or to control (24 clusters, 600 children). Previously intervened and intervention-naive children were not mixed in the same cluster. The primary outcomes were the change from baseline in KAH and ICH scores. Intervention effects were tested for with linear mixed-effects models.
Results
In phase 1, ∼85% of children had nonideal cardiovascular health, and those who previously received a preschool intervention showed a negligible residual effect compared with intervention-naive children. In phase 2, the between-group (control vs. intervention) differences in the change of the overall KAH and ICH scores were 0.92 points (95% confidence interval [CI]: -0.28 to 2.13; p = 0.133) and -0.20 points (95% CI: -0.43 to 0.03; p = 0.089), respectively. No booster effect was detected. However, a dose-response effect was observed, with maximal benefit in children attending >75% of the scheduled intervention; the difference in the change of KAH between the high- and low-adherence groups was 3.72 points (95% CI: 1.71 to 5.73; p < 0.001).
Conclusions
Although overall significant differences between the intervention and control groups were not observed, high adherence rates to health promotion interventions may improve effectiveness and outcomes in children. Reintervention strategies may be required at multiple stages to induce sustained health promotion effects (Salud Integral Colombia [SI! Colombia II]; NCT03119792).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 06 Apr 2020; 75:1565-1578
Fernández-Jiménez R, Briceño G, Céspedes J, Vargas S, ... Carvajal I, Fuster V
J Am Coll Cardiol: 06 Apr 2020; 75:1565-1578 | PMID: 32241373
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Abstract

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

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

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

J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534
Guo Y, Lane DA, Wang L, Zhang H, ... Lip GYH,
J Am Coll Cardiol: 06 Apr 2020; 75:1523-1534 | PMID: 32241367
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Abstract

Yoga-Based Cardiac Rehabilitation After Acute Myocardial Infarction: A Randomized Trial.

Prabhakaran D, Chandrasekaran AM, Singh K, Mohan B, ... Kinra S,
Background
Given the shortage of cardiac rehabilitation (CR) programs in India and poor uptake worldwide, there is an urgent need to find alternative models of CR that are inexpensive and may offer choice to subgroups with poor uptake (e.g., women and elderly).
Objectives
This study sought to evaluate the effects of yoga-based CR (Yoga-CaRe) on major cardiovascular events and self-rated health in a multicenter randomized controlled trial.
Methods
The trial was conducted in 24 medical centers across India. This study recruited 3,959 patients with acute myocardial infarction with a median and minimum follow-up of 22 and 6 months. Patients were individually randomized to receive either a Yoga-CaRe program (n = 1,970) or enhanced standard care involving educational advice (n = 1,989). The co-primary outcomes were: 1) first occurrence of major adverse cardiovascular events (MACE) (composite of all-cause mortality, myocardial infarction, stroke, or emergency cardiovascular hospitalization); and 2) self-rated health on the European Quality of Life-5 Dimensions-5 Level visual analogue scale at 12 weeks.
Results
MACE occurred in 131 (6.7%) patients in the Yoga-CaRe group and 146 (7.4%) patients in the enhanced standard care group (hazard ratio with Yoga-CaRe: 0.90; 95% confidence interval [CI]: 0.71 to 1.15; p = 0.41). Self-rated health was 77 in Yoga-CaRe and 75.7 in the enhanced standard care group (baseline-adjusted mean difference in favor of Yoga-CaRe: 1.5; 95% CI: 0.5 to 2.5; p = 0.002). The Yoga-CaRe group had greater return to pre-infarct activities, but there was no difference in tobacco cessation or medication adherence between the treatment groups (secondary outcomes).
Conclusions
Yoga-CaRe improved self-rated health and return to pre-infarct activities after acute myocardial infarction, but the trial lacked statistical power to show a difference in MACE. Yoga-CaRe may be an option when conventional CR is unavailable or unacceptable to individuals. (A study on effectiveness of YOGA based cardiac rehabilitation programme in India and United Kingdom; CTRI/2012/02/002408).

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

J Am Coll Cardiol: 06 Apr 2020; 75:1551-1561
Prabhakaran D, Chandrasekaran AM, Singh K, Mohan B, ... Kinra S,
J Am Coll Cardiol: 06 Apr 2020; 75:1551-1561 | PMID: 32241371
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Abstract

Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality.

Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF
Background
More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection.
Methods
Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events.
Results
With a median of 7.9 years of follow-up, the estimated cumulative incidence of hepatocellular carcinoma was 4.0% among aspirin users and 8.3% among nonusers of aspirin (difference, -4.3 percentage points; 95% confidence interval [CI], -5.0 to -3.6; adjusted hazard ratio, 0.69; 95% CI, 0.62 to 0.76). This inverse association appeared to be duration-dependent; as compared with short-term use (3 months to <1 year), the adjusted hazard ratios were 0.90 (95% CI, 0.76 to 1.06) for 1 to less than 3 years of use, 0.66 (95% CI, 0.56 to 0.78) for 3 to less than 5 years of use, and 0.57 (95% CI, 0.42 to 0.70) for 5 or more years of use. Ten-year liver-related mortality was 11.0% among aspirin users and 17.9% among nonusers (difference, -6.9 percentage points [95% CI, -8.1 to -5.7]; adjusted hazard ratio, 0.73 [95% CI, 0.67 to 0.81]). However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and nonusers of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, -0.6 to 2.4).
Conclusions
In a nationwide study of patients with chronic viral hepatitis in Sweden, use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver-related mortality than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 11 Mar 2020; 382:1018-1028
Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF
N Engl J Med: 11 Mar 2020; 382:1018-1028 | PMID: 32160663
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Abstract

Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy.

Nijst P, Martens P, Dauw J, Tang WHW, ... Dupont M, Mullens W
Background
The necessity of neurohumoral blockers in patients with heart failure who demonstrate normalized ejection fractions after cardiac resynchronization therapy remains unclear.
Objectives
The aim of this study was to investigate the feasibility and safety of neurohumoral blocker withdrawal in patients with normalized ejection fractions after cardiac resynchronization therapy.
Methods
In this prospective, open-label, randomized controlled pilot trial with a 2 × 2 factorial design, subjects were randomized to withdrawal of renin-angiotensin-aldosterone system inhibitors and/or beta-blockers versus continuation of treatment. The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular end-systolic volume index of >15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure-related hospitalizations, and incidence of sustained ventricular arrhythmias at 24 months.
Results
Eighty subjects were consecutively enrolled and randomized among 4 groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). Of the 80 subjects, 6 (7.5%) met the primary and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 subjects because of hypertension or supraventricular arrhythmias.
Conclusions
The incidence of the primary and secondary endpoints over a follow-up period of 2 years was low in both the control group and in the groups in which neurohumoral blockers were discontinued. However, neurohumoral blocker withdrawal was hampered by cardiac comorbidities. (Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients [STOP-CRT]; NCT02200822).

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

J Am Coll Cardiol: 30 Mar 2020; 75:1426-1438
Nijst P, Martens P, Dauw J, Tang WHW, ... Dupont M, Mullens W
J Am Coll Cardiol: 30 Mar 2020; 75:1426-1438 | PMID: 32216911
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Abstract

Intravenous Statin Administration During Myocardial Infarction Compared With Oral Post-Infarct Administration.

Mendieta G, Ben-Aicha S, Gutiérrez M, Casani L, ... Badimon L, Vilahur G
Background
Beyond lipid-lowering, statins exert cardioprotective effects. High-dose statin treatment seems to reduce cardiovascular complications in high-risk patients. The ideal timing and administration regime remain unknown.
Objectives
This study compared the cardioprotective effects of intravenous statin administration during myocardial infarction (MI) with oral administration immediately post-MI.
Methods
Hypercholesterolemic pigs underwent MI induction (90 min of ischemia) and were kept for 42 days. Animals were distributed in 3 arms (A): A1 received an intravenous bolus of atorvastatin during MI; A2 received an intravenous bolus of vehicle during MI; and A3 received oral atorvastatin within 2 h post-MI. A1 and A3 remained on daily oral atorvastatin for the following 42 days. Cardiac magnetic resonance analysis (days 3 and 42 post-MI) and molecular/histological studies were performed.
Results
At day 3, A1 showed a 10% reduction in infarct size compared with A3 and A2 and a 50% increase in myocardial salvage. At day 42, both A1 and A3 showed a significant decrease in scar size versus A2; however, A1 showed a further 24% reduction versus A3. Functional analyses revealed improved systolic performance in A1 compared with A2 and less wall motion abnormalities in the jeopardized myocardium versus both groups at day 42. A1 showed enhanced collagen content and AMP-activated protein kinase activation in the scar, increased vessel density in the penumbra, higher tumor necrosis factor α plasma levels and lower peripheral blood mononuclear cell activation versus both groups.
Conclusions
Intravenous administration of atorvastatin during MI limits cardiac damage, improves cardiac function, and mitigates remodeling to a larger extent than when administered orally shortly after reperfusion. This therapeutic approach deserves to be investigated in ST-segment elevation MI patients.

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

J Am Coll Cardiol: 30 Mar 2020; 75:1386-1402
Mendieta G, Ben-Aicha S, Gutiérrez M, Casani L, ... Badimon L, Vilahur G
J Am Coll Cardiol: 30 Mar 2020; 75:1386-1402 | PMID: 32216907
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Abstract

Transcatheter Correction of Superior Sinus Venosus Atrial Septal Defects as an Alternative to Surgical Treatment.

Hansen JH, Duong P, Jivanji SGM, Jones M, ... Qureshi SA, Rosenthal E
Background
The superior sinus venosus atrial septal defect (SVASD) is characterized by deficiency of the common wall between the superior vena cava (SVC) and the right upper pulmonary vein (RUPV), which is no longer committed to the left atrium.
Objectives
This study sought to evaluate the potential for redirecting the SVC and RUPV flow to the right and left atria, respectively, by implantation of a covered stent in the SVC.
Methods
Review of 48 consecutive adult SVASD patients undergoing assessment for correction. Pre-procedural evaluation included cross-sectional imaging and ex vivo simulation using printed or virtual 3-dimensional models.
Results
Transcatheter correction was performed in 25 patients, with a further 6 awaiting stent implantation. Only 8 patients were deemed technically unsuitable. The procedure involved balloon test inflation in the anticipated stent landing zone with simultaneous transesophageal echocardiography and pulmonary venography to confirm defect closure and unobstructed pulmonary venous drainage, followed by deployment of a 10-zig covered Cheatham platinum stent. Stents of lengths between 5 and 8 cm were implanted. A second, uncovered stent was used for anchoring in 9 patients. The RUPV was protected with a high-pressure balloon during stent implantation to prevent pulmonary venous obstruction in 4 patients. The median follow-up period was 1.4 (interquartile range: 0.8 to 1.7) years, with no mortality. Stent embolization occurred in 1 patient; another required drainage of hemopericardium. Cardiac computed tomography after 3 months confirmed unobstructed pulmonary venous return. At latest follow-up, a residual shunt was present in 1 patient.
Conclusions
Transcatheter correction of SVASD may be considered as an alternative to surgery in a substantial proportion of patients.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1266-1278
Hansen JH, Duong P, Jivanji SGM, Jones M, ... Qureshi SA, Rosenthal E
J Am Coll Cardiol: 23 Mar 2020; 75:1266-1278 | PMID: 32192652
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Abstract

Atrial Fibrillation: JACC Council Perspectives.

Chung MK, Refaat M, Shen WK, Kutyifa V, ... Lakkireddy DR,

Atrial fibrillation (AF) is an increasingly prevalent arrhythmia; its pathophysiology and progression are well studied. Stroke and bleeding risk models have been created and validated. Decision tools for stroke prophylaxis are evolving, with better options at hand. Utilization of various diagnostic tools offer insight into AF burden and thromboembolic risk. Rate control, rhythm control, and stroke prophylaxis are the cornerstones of AF therapy. Although antiarrhythmic drugs are useful, AF ablation has become a primary therapeutic strategy. Pulmonary vein isolation is the cornerstone of AF ablation, and methods to improve ablation safety and efficacy continue to progress. Ablation of nonpulmonary vein sites is increasingly being recognized as an important strategy for treating nonparoxysmal AF. Several new ablation techniques and technologies and stroke prophylaxis are being explored. This is a contemporary review on the prevalence, pathophysiology, risk prediction, prophylaxis, treatment options, new insights for optimizing treatment outcomes, and emerging concepts of AF.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 13 Apr 2020; 75:1689-1713
Chung MK, Refaat M, Shen WK, Kutyifa V, ... Lakkireddy DR,
J Am Coll Cardiol: 13 Apr 2020; 75:1689-1713 | PMID: 32273035
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Abstract

Short-Term Progression of Multiterritorial Subclinical Atherosclerosis.

López-Melgar B, Fernández-Friera L, Oliva B, García-Ruiz JM, ... Sanz J, Fuster V
Background
Atherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood.
Objectives
This study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk.
Methods
The study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk.
Results
Imaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): -1 to 3 plaques] by 2DVUS; 7.6 mm [IQR: -32.2 to 57.6 mm] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk.
Conclusions
With this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 13 Apr 2020; 75:1617-1627
López-Melgar B, Fernández-Friera L, Oliva B, García-Ruiz JM, ... Sanz J, Fuster V
J Am Coll Cardiol: 13 Apr 2020; 75:1617-1627 | PMID: 32273027
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Abstract

AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury.

Hinkel R, Ramanujam D, Kaczmarek V, Howe A, ... Kupatt C, Engelhardt S
Background
miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro-ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure.
Objectives
The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition.
Methods
Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis.
Results
AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment.
Conclusions
This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure.

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

J Am Coll Cardiol: 20 Apr 2020; 75:1788-1800
Hinkel R, Ramanujam D, Kaczmarek V, Howe A, ... Kupatt C, Engelhardt S
J Am Coll Cardiol: 20 Apr 2020; 75:1788-1800 | PMID: 32299591
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Abstract

The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy.

James CA, Syrris P, van Tintelen JP, Calkins H

Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiomyopathy characterized by frequent ventricular arrhythmias and progressive ventricular dysfunction. Risk of sudden cardiac death is elevated in ACM patients and can be the presenting symptom particularly in younger individuals and athletes. This review describes current understanding of the genetic architecture of ACM and molecular mechanisms of ACM pathogenesis. We consider an emerging threshold model for ACM inheritance in which multiple factors including pathogenic variants in known ACM genes, genetic modifiers, and environmental exposures, particularly exercise, are required to reach a threshold for disease expression. We also review best practices for integrating genetics-including recent discoveries-in caring for ACM families and emphasize the utility of genotype for both management of affected individuals and predictive testing in family members.

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: 18 Mar 2020; epub ahead of print
James CA, Syrris P, van Tintelen JP, Calkins H
Eur Heart J: 18 Mar 2020; epub ahead of print | PMID: 32191298
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Abstract

Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure.

Zhou W, Brown JM, Bajaj NS, Chandra A, ... O\'Gara P, Di Carli MF
Aims
Hypertension is a well-established heart failure (HF) risk factor, especially in the context of adverse left ventricular (LV) remodelling. We aimed to use myocardial flow reserve (MFR) and global longitudinal strain (GLS), markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive HF risk assessment.
Methods and results
Consecutive patients undergoing symptom-prompted stress cardiac positron emission tomography (PET)-computed tomography and transthoracic echocardiogram within 90 days without reduced left ventricular ejection fraction (<40%) or flow-limiting coronary artery disease (summed stress score ≥ 3) were included. Global MFR was quantified by PET, and echocardiograms were retrospectively analysed for cardiac structure and function. Patients were followed over a median 8.75 (Q1-3 4.56-10.04) years for HF hospitalization and a composite of death, HF hospitalization, MI, or stroke. Of 194 patients, 155 had adaptive LV remodelling while 39 had maladaptive remodelling, which was associated with lower MFR and impaired GLS. Across the remodelling spectrum, diastolic parameters, GLS, and N-terminal pro-B-type natriuretic peptide were independently associated with MFR. Maladaptive LV remodelling was associated with increased adjusted incidence of HF hospitalization and death. Importantly, the combination of abnormal MFR and GLS was associated with a higher rate of HF hospitalization compared to normal MFR and GLS [adjusted hazard ratio (HR) 3.21, 95% confidence interval (CI) 1.09-9.45, P = 0.034), including in the adaptive remodelling subset (adjusted HR 3.93, 95% CI 1.14-13.56, P = 0.030).
Conclusion
We have demonstrated important associations between coronary microvascular dysfunction and myocardial mechanics that refine disease characterization and HF risk assessment of patients with hypertension based on subclinical target organ injury.

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: 27 Mar 2020; epub ahead of print
Zhou W, Brown JM, Bajaj NS, Chandra A, ... O'Gara P, Di Carli MF
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221588
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Abstract

Management of Acute Ischemic Stroke Due to Large-Vessel Occlusion: JACC Focus Seminar.

Ospel JM, Holodinsky JK, Goyal M

Acute ischemic stroke is a severe and life-threatening disease, particularly when caused by a large-vessel occlusion. The only available 2 treatment options are intravenous alteplase and endovascular therapy (mechanical clot removal), both of which are highly time-dependent. Thus, rapid patient transfer, diagnosis, and treatment are crucial, and time-consuming imaging methods and overly selective treatment selection criteria should be avoided. A combined endovascular therapy approach using stent-retrievers and aspiration is the most effective way to achieve fast first-pass complete reperfusion and should thus be used. To diagnose and treat patients as fast as possible, the organization of existing systems of care, and particularly pre-hospital transfer systems, have to be changed. Several different transport models are currently in use because the optimal patient transfer paradigm is highly dependent on local geography and hospital efficiency.

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

J Am Coll Cardiol: 20 Apr 2020; 75:1832-1843
Ospel JM, Holodinsky JK, Goyal M
J Am Coll Cardiol: 20 Apr 2020; 75:1832-1843 | PMID: 32299595
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Abstract

The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development.

Demetz E, Tymoszuk P, Hilbe R, Volani C, ... Tancevski I, Weiss G
Aims
Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice.
Methods and results
Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability.
Conclusion
Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.

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: 29 Mar 2020; epub ahead of print
Demetz E, Tymoszuk P, Hilbe R, Volani C, ... Tancevski I, Weiss G
Eur Heart J: 29 Mar 2020; epub ahead of print | PMID: 32227235
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Abstract

Simple electrocardiographic measures improve sudden arrhythmic death prediction in coronary disease.

Chatterjee NA, Tikkanen JT, Panicker GK, Narula D, ... Albert CM,
Aims
To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD).
Methods and results
The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1-1.9] and 6.2% (95% CI 4.5-8.3) in those with a low- and high-risk ECG score, respectively (P for Δ < 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7-49%), P = 0.009].
Conclusion
For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF.
Clinical trial registration
https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.

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: 06 Apr 2020; epub ahead of print
Chatterjee NA, Tikkanen JT, Panicker GK, Narula D, ... Albert CM,
Eur Heart J: 06 Apr 2020; epub ahead of print | PMID: 32259257
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Abstract

Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease.

Spertus JA, Jones PG, Maron DJ, O\'Brien SM, ... Mark DB,
Background
In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients.
Methods
We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency.
Results
At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina).
Conclusions
In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Spertus JA, Jones PG, Maron DJ, O'Brien SM, ... Mark DB,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227753
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Abstract

Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease.

Spertus JA, Jones PG, Maron DJ, Mark DB, ... Bangalore S,
Background
In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status.
Methods
We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy.
Results
Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4).
Conclusions
Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Spertus JA, Jones PG, Maron DJ, Mark DB, ... Bangalore S,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227754
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Abstract

KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2.

Maguy A, Kucera JP, Wepfer JP, Forest V, Charpentier F, Li J
Background
Patients with long QT syndrome (LQTS) are predisposed to life-threatening arrhythmias. A delay in cardiac repolarization is characteristic of the disease. Pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation are part of the current treatment options, but no targeted therapy for LQTS exists to date. Previous studies indicate that induced autoimmunity against the voltage-gated KCNQ1 K channels accelerates cardiac repolarization.
Objectives
However, a causative relationship between KCNQ1 antibodies and the observed electrophysiological effects has never been demonstrated, and thus presents the aim of this study.
Methods
The authors purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as single-channel recordings on Chinese hamster ovary cells overexpressing I channels. The effect of purified KCNQ1 antibodies on human cardiomyocytes derived from induced pluripotent stem cells was then studied.
Results
The study demonstrated that KCNQ1 antibodies underlie the previously observed increase in repolarizing I current. The antibodies shift the voltage dependence of activation and slow the deactivation of I. At the single-channel level, KCNQ1 antibodies increase the open time and probability of the channel. In models of LQTS type 2 (LQTS2) using human induced pluripotent stem cell-derived cardiomyocytes, KCNQ1 antibodies reverse the prolonged cardiac repolarization and abolish arrhythmic activities.
Conclusions
Here, the authors provide the first direct evidence that KCNQ1 antibodies act as agonists on I channels. Moreover, KCNQ1 antibodies were able to restore alterations in cardiac repolarization and most importantly to suppress arrhythmias in LQTS2. KCNQ1 antibody therapy may thus present a novel promising therapeutic approach for LQTS2.

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

J Am Coll Cardiol: 04 May 2020; 75:2140-2152
Maguy A, Kucera JP, Wepfer JP, Forest V, Charpentier F, Li J
J Am Coll Cardiol: 04 May 2020; 75:2140-2152 | PMID: 32354382
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Abstract

Extracellular Matrix in Ischemic Heart Disease, Part 4/4: JACC Focus Seminar.

Frangogiannis NG, Kovacic JC

Myocardial ischemia and infarction, both in the acute and chronic phases, are associated with cardiomyocyte loss and dramatic changes in the cardiac extracellular matrix (ECM). It has long been appreciated that these changes in the cardiac ECM result in altered mechanical properties of ischemic or infarcted myocardial segments. However, a growing body of evidence now clearly demonstrates that these alterations of the ECM not only affect the structural properties of the ischemic and post-infarct heart, but they also play a crucial and sometimes direct role in mediating a range of biological pathways, including the orchestration of inflammatory and reparative processes, as well as the pathogenesis of adverse remodeling. This final part of a 4-part JACC Focus Seminar reviews the evidence on the role of the ECM in relation to the ischemic and infarcted heart, as well as its contribution to cardiac dysfunction and adverse clinical outcomes.

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

J Am Coll Cardiol: 04 May 2020; 75:2219-2235
Frangogiannis NG, Kovacic JC
J Am Coll Cardiol: 04 May 2020; 75:2219-2235 | PMID: 32354387
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Abstract

Omics phenotyping in heart failure: the next frontier.

Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, ... Emdin M, Januzzi JL

This state-of-the-art review aims to provide an up-to-date look at breakthrough omic technologies that are helping to unravel heart failure (HF) disease mechanisms and heterogeneity. Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and physiology involved in HF than achieved by either one alone and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible and can be validated across multiple independent populations to ensure confidence in clinical decision-making.

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: 25 Apr 2020; epub ahead of print
Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, ... Emdin M, Januzzi JL
Eur Heart J: 25 Apr 2020; epub ahead of print | PMID: 32337540
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Abstract

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.

Karam S, Margaria JP, Bourcier A, Mika D, ... Leroy J, Vandecasteele G

The cAMP-hydrolyzing phosphodiesterase 4B (PDE4B) is a key negative regulator of cardiac β-adrenergic receptor (β-AR) stimulation. PDE4B deficiency leads to abnormal Ca handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure (HF).We measured PDE4B expression in human cardiac tissues, developed two transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B (PDE4B-TG), and an adeno-associated virus serotype 9 encoding PDE4B (AAV9-PDE4B). Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Cyclic AMP and PKA activity were monitored by Förster resonance energy transfer, I by whole cell patch-clamp, and cardiomyocyte shortening and Ca transients with an Ionoptix system. HF was induced by 2 weeks infusion of isoproterenol (Iso) or transverse aortic constriction (TAC). Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis and histology.PDE4B protein was decreased in human failing hearts. The first PDE4B-TG mouse line (TG15) had a ~15-fold increase in cardiac cAMP-PDE activity and a ~30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basalmyocardial function was unchanged, but β-AR stimulation of cardiac inotropy, cAMP, PKA, I, Ca transients and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion and fibrosis induced by chronic Iso treatment. In the second PDE4B-TG mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ~50-fold increase in cardiac cAMP-PDE activity caused a ~50% decrease in fractional shortening, hypertrophy, dilatation and premature death. In contrast, mice injected with AAV9-PDE4B (10 viral particles/mouse) had a ~50% increase in cardiac cAMP-PDE activity which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis and fibrosis, while attenuating hypertrophy induced by chronic Iso infusion. Similarly, AAV9-PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion and prevented apoptosis and fibrotic remodeling in TAC.Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat HF.



Circulation: 07 Apr 2020; epub ahead of print
Karam S, Margaria JP, Bourcier A, Mika D, ... Leroy J, Vandecasteele G
Circulation: 07 Apr 2020; epub ahead of print | PMID: 32264695
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Abstract

From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases.

Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Lüscher TF

Nucleic acid-based therapeutics are currently developed at large scale for prevention and management of cardiovascular diseases (CVDs), since: (i) genetic studies have highlighted novel therapeutic targets suggested to be causal for CVD; (ii) there is a substantial recent progress in delivery, efficacy, and safety of nucleic acid-based therapies; (iii) they enable effective modulation of therapeutic targets that cannot be sufficiently or optimally addressed using traditional small molecule drugs or antibodies. Nucleic acid-based therapeutics include (i) RNA-targeted therapeutics for gene silencing; (ii) microRNA-modulating and epigenetic therapies; (iii) gene therapies; and (iv) genome-editing approaches (e.g. CRISPR-Cas-based): (i) RNA-targeted therapeutics: several large-scale clinical development programmes, using antisense oligonucleotides (ASO) or short interfering RNA (siRNA) therapeutics for prevention and management of CVD have been initiated. These include ASO and/or siRNA molecules to lower apolipoprotein (a) [apo(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoCIII, ANGPTL3, or transthyretin (TTR) for prevention and treatment of patients with atherosclerotic CVD or TTR amyloidosis. (ii) MicroRNA-modulating and epigenetic therapies: novel potential therapeutic targets are continually arising from human non-coding genome and epigenetic research. First microRNA-based therapeutics or therapies targeting epigenetic regulatory pathways are in clinical studies. (iii) Gene therapies: EMA/FDA have approved gene therapies for non-cardiac monogenic diseases and LDL receptor gene therapy is currently being examined in patients with homozygous hypercholesterolaemia. In experimental studies, gene therapy has significantly improved cardiac function in heart failure animal models. (iv) Genome editing approaches: these technologies, such as using CRISPR-Cas, have proven powerful in stem cells, however, important challenges are remaining, e.g. low rates of homology-directed repair in somatic cells such as cardiomyocytes. In summary, RNA-targeted therapies (e.g. apo(a)-ASO and PCSK9-siRNA) are now in large-scale clinical outcome trials and will most likely become a novel effective and safe therapeutic option for CVD in the near future. MicroRNA-modulating, epigenetic, and gene therapies are tested in early clinical studies for CVD. CRISPR-Cas-mediated genome editing is highly effective in stem cells, but major challenges are remaining in somatic cells, however, this field is rapidly advancing.

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: 28 Apr 2020; epub ahead of print
Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Lüscher TF
Eur Heart J: 28 Apr 2020; epub ahead of print | PMID: 32350510
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Abstract

Atrial myxomas arise from multipotent cardiac stem cells.

Scalise M, Torella M, Marino F, Ravo M, ... Ellison-Hughes GM, Torella D
Aims
Cardiac myxomas usually develop in the atria and consist of an acid-mucopolysaccharide-rich myxoid matrix with polygonal stromal cells scattered throughout. These human benign tumours are a valuable research model because of the rarity of cardiac tumours, their clinical presentation and uncertain origin. Here, we assessed whether multipotent cardiac stem/progenitor cells (CSCs) give rise to atrial myxoma tissue.
Methods and results
Twenty-three myxomas were collected and analysed for the presence of multipotent CSCs. We detected myxoma cells positive for c-kit (c-kitpos) but very rare Isl-1 positive cells. Most of the c-kitpos cells were blood lineage-committed CD45pos/CD31pos cells. However, c-kitpos/CD45neg/CD31neg cardiac myxoma cells expressed stemness and cardiac progenitor cell transcription factors. Approximately ≤10% of the c-kitpos/CD45neg/CD31neg myxoma cells also expressed calretinin, a characteristic of myxoma stromal cells. In vitro, the c-kitpos/CD45neg/CD31neg myxoma cells secrete chondroitin-6-sulfate and hyaluronic acid, which are the main components of gelatinous myxoma matrix in vivo. In vitro, c-kitpos/CD45neg/CD31neg myxoma cells have stem cell properties being clonogenic, self-renewing, and sphere forming while exhibiting an abortive cardiac differentiation potential. Myxoma-derived CSCs possess a mRNA and microRNA transcriptome overall similar to normal myocardium-derived c-kitpos/CD45neg/CD31negCSCs , yet showing a relatively small and relevant fraction of dysregulated mRNA/miRNAs (miR-126-3p and miR-335-5p, in particular). Importantly, myxoma-derived CSCs but not normal myocardium-derived CSCs, seed human myxoma tumours in xenograft\'s in immunodeficient NOD/SCID mice.
Conclusion
Myxoma-derived c-kitpos/CD45neg/CD31neg CSCs fulfill the criteria expected of atrial myxoma-initiating stem cells. The transcriptome of these cells indicates that they belong to or are derived from the same lineage as the atrial multipotent c-kitpos/CD45neg/CD31neg CSCs. Taken together the data presented here suggest that human myxomas could be the first-described CSC-related human heart disease.

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

Eur Heart J: 23 Apr 2020; epub ahead of print
Scalise M, Torella M, Marino F, Ravo M, ... Ellison-Hughes GM, Torella D
Eur Heart J: 23 Apr 2020; epub ahead of print | PMID: 32330934
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Abstract

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

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

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



Circulation: 30 Mar 2020; epub ahead of print
Marstrand P, Han L, Day SM, Olivotto I, ... Ho CY,
Circulation: 30 Mar 2020; epub ahead of print | PMID: 32228044
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Abstract

Association between Mental Disorders and Subsequent Medical Conditions.

Momen NC, Plana-Ripoll O, Agerbo E, Benros ME, ... Prior A, McGrath JJ
Background
Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions.
Methods
We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses.
Results
A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder.
Conclusions
Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Apr 2020; 382:1721-1731
Momen NC, Plana-Ripoll O, Agerbo E, Benros ME, ... Prior A, McGrath JJ
N Engl J Med: 29 Apr 2020; 382:1721-1731 | PMID: 32348643
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Abstract

Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization.

Cecelja M, Keehn L, Ye L, Spector TD, Hughes AD, Chowienczyk P
Aims
Haemodynamic determinants of blood pressure (BP) include cardiac output (CO), systemic vascular resistance (SVR), and arterial stiffness. We investigated the heritability of these phenotypes, their association with BP-related single-nucleotide polymorphisms (SNPs), and the causal association between BP and arterial stiffness.
Methods and results
We assessed BP, central BP components, and haemodynamic properties (during a single visit) including CO, SVR, and pulse wave velocity (PWV, measure of arterial stiffness) in 3531 (1934 monozygotic, 1586 dizygotic) female TwinsUK participants. Heritability was estimated using structural equation modelling. Association with 984 BP-associated SNP was examined using least absolute shrinkage and selection operator (LASSO) and generalized estimating equation regression. One and two-sample Mendelian randomization (MR) was used to estimate the causal direction between BP and arterial stiffness including data on 436 419 UK Biobank participants. We found high heritability for systolic and pulsatile components of BP (>50%) and PWV (65%) with overlapping genes accounting for >50% of their observed correlation. Environmental factors explained most of the variability of CO and SVR (>80%). Regression identified SNPs (n = 5) known to be associated with BP to also be associated with PWV. One-sample MR showed evidence of bi-directional causal association between BP and PWV in TwinsUK participants. Two-sample MR, confirmed a bi-directional causal effect of PWV on BP (inverse variance weighted (IVW) beta = 0.11, P < 0.02) and BP on arterial stiffness (IVW beta = 0.004, P < 0.0001).
Conclusion
The genetic basis of BP is mediated not only by genes regulating BP but also by genes that influence arterial stiffness. Mendelian randomization indicates a bi-directional causal association between BP and arterial stiffness.

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: 30 Apr 2020; epub ahead of print
Cecelja M, Keehn L, Ye L, Spector TD, Hughes AD, Chowienczyk P
Eur Heart J: 30 Apr 2020; epub ahead of print | PMID: 32357239
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Abstract

When genetic burden reaches threshold.

Walsh R, Tadros R, Bezzina CR

Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.

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

Eur Heart J: 28 Apr 2020; epub ahead of print
Walsh R, Tadros R, Bezzina CR
Eur Heart J: 28 Apr 2020; epub ahead of print | PMID: 32350504
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Abstract

Disruptive Modifications to Cardiac Critical Care Delivery During the Covid-19 Pandemic: An International Perspective.

Katz JN, Sinha SS, Alviar CL, Dudzinski DM, ... Morrow DA, van Diepen S

The COVID-19 pandemic has presented a major unanticipated stress on our workforce, organizational structure, systems of care, and critical resource supply. In order to ensure provider safety, maximize efficiency, and optimize patient outcomes, health systems need to be agile. Critical care cardiologists may be uniquely positioned to treat the numerous respiratory and cardiovascular complications of the SARS-CoV-2 virus and support clinicians without critical care training who may be suddenly asked to care for critically ill patients. This manuscript draws upon the experiences of colleagues from heavily impacted regions of the United States and Europe as well as lessons learned from military mass casualty medicine. We offer pragmatic suggestions on how to implement scalable models for critical care delivery, cultivate educational tools for team training, and embrace technologies such as telemedicine to enable effective collaboration despite social distancing imperatives.

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

J Am Coll Cardiol: 13 Apr 2020; epub ahead of print
Katz JN, Sinha SS, Alviar CL, Dudzinski DM, ... Morrow DA, van Diepen S
J Am Coll Cardiol: 13 Apr 2020; epub ahead of print | PMID: 32305402
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Abstract

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

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

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



Circulation: 11 Mar 2020; epub ahead of print
Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, ... Wallentin L, Granger CB
Circulation: 11 Mar 2020; epub ahead of print | PMID: 32160801
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Abstract

Infections Associated with Resterilized Pacemakers and Defibrillators.

Khairy TF, Lupien MA, Nava S, Baez FV, ... Macle L, Khairy P
Background
Access to pacemakers and defibrillators is problematic in places with limited resources. Resterilization and reuse of implantable cardiac devices obtained post mortem from patients in wealthier nations have been undertaken, but uncertainty around the risk of infection is a concern.
Methods
A multinational program was initiated in 1983 to provide tested and resterilized pacemakers and defibrillators to underserved nations; a prospective registry was established in 2003. Patients who received reused devices in this program were matched in a 1:3 ratio with control patients who received new devices implanted in Canada. The primary outcome was infection or device-related death, with mortality from other causes modeled as a competing risk.
Results
Resterilized devices were implanted in 1051 patients (mean [±SD] age, 63.2±18.5 years; 43.6% women) in Mexico (36.0%), the Dominican Republic (28.1%), Guatemala (26.6%), and Honduras (9.3%). Overall, 85% received pacemakers and 15% received defibrillators, with one (55.5%), two (38.8%), or three (5.7%) leads. Baseline characteristics did not differ between these patients and the 3153 matched control patients. At 2 years of follow-up, infections had occurred in 21 patients (2.0%) with reused devices and in 38 (1.2%) with new devices (hazard ratio, 1.66; 95% confidence interval, 0.97 to 2.83; P = 0.06); there were no device-related deaths. The most common implicated pathogens wereand .
Conclusions
Among patients in underserved countries who received a resterilized and reused pacemaker or defibrillator, the incidence of infection or device-related death at 2 years was 2.0%, an incidence that did not differ significantly from that seen among matched control patients with new devices in Canada.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 06 May 2020; 382:1823-1831
Khairy TF, Lupien MA, Nava S, Baez FV, ... Macle L, Khairy P
N Engl J Med: 06 May 2020; 382:1823-1831 | PMID: 32374963
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Abstract

Atorvastatin Reduces First and Subsequent Vascular Events Across Vascular Territories in the SPARCL Trial.

Szarek M, Amarenco P, Callahan A, DeMicco D, ... Welch KM,
Background
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial compared atorvastatin with placebo in 4,731 participants with recent stroke or transient ischemic attack and no known coronary heart disease. Atorvastatin reduced the first occurrence of stroke and the first occurrence of a composite of vascular events.
Objectives
This post hoc analysis assessed the occurrence of all (first and subsequent) vascular events and the effect of atorvastatin to reduce these events by vascular territory (cerebrovascular, coronary, or peripheral) in SPARCL.
Methods
Treatment effects on total adjudicated vascular events, overall and by vascular territory, were summarized by marginal proportional hazards models. Vascular event rates were estimated for each treatment group with cumulative incidence functions.
Results
The placebo group had an estimated 41.2 first and 62.7 total vascular events per 100 participants over six years. There were 164 fewer first and 390 fewer total vascular events in the atorvastatin group (total events hazard ratio 0.68, 95% confidence interval 0.60 to 0.77). The total events reduction included 177 fewer cerebrovascular, 170 fewer coronary, and 43 fewer peripheral events. Over six years, an estimated 20 vascular events per 100 participants were avoided with atorvastatin treatment.
Conclusions
In participants with recent stroke or transient ischemic attack, the total number of vascular events prevented with atorvastatin was more than twice the number of first events prevented. Total event reduction provides a comprehensive metric to capture the totality of atorvastatin clinical efficacy in reducing disease burden after stroke or transient ischemic attack.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 10 Mar 2020; epub ahead of print
Szarek M, Amarenco P, Callahan A, DeMicco D, ... Welch KM,
J Am Coll Cardiol: 10 Mar 2020; epub ahead of print | PMID: 32194196
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Abstract

Lysine-Specific Demethylase-1 Deficiency Increases Agonist Signaling Via the Mineralocorticoid Receptor.

Treesaranuwattana T, Wong KYH, Brooks DL, Tay CS, ... Williams JS, Pojoga LH

LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency () in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies inmice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency-mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased inmouse kidney tissues, aldosterone secretion fromglomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.



Hypertension: 30 Mar 2020; 75:1045-1053
Treesaranuwattana T, Wong KYH, Brooks DL, Tay CS, ... Williams JS, Pojoga LH
Hypertension: 30 Mar 2020; 75:1045-1053 | PMID: 32160100
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Abstract

Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

Liao B, Geng L, Zhang F, Shu L, ... Wang K, Hoo RLC
Aims
Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood-brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious effects.
Methods and results
Circulating A-FABP and its cerebral expression were increased in mice after middle cerebral artery occlusion. Genetic deletion and pharmacological inhibition of A-FABP alleviated cerebral ischaemia injury with reduced infarction volume, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by reduced degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9). In patients with acute IS, elevated circulating A-FABP levels positively correlated with those of MMP-9 and cerebral infarct volume. Mechanistically, ischaemia-induced elevation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral resident microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signalling, enhancing degradation of tight junction proteins and BBB leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9.
Conclusion
A-FABP is a key mediator of cerebral ischaemia injury promoting MMP-9-mediated BBB disruption. Inhibition of A-FABP is a potential strategy to improve IS outcome.

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

Eur Heart J: 28 Apr 2020; epub ahead of print
Liao B, Geng L, Zhang F, Shu L, ... Wang K, Hoo RLC
Eur Heart J: 28 Apr 2020; epub ahead of print | PMID: 32350521
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Abstract

Heart-Specific Immune Responses in an Animal Model of AutoimmuneRelated Myocarditis Mitigated by an Immunoproteasome Inhibitor and Genetic Ablation.

Bockstahler M, Fischer A, Goetzke CC, Neumaier HL, ... Kaya Z, Beling A

Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1, control the threshold of self-antigen responses directed against cardiac troponin I (TnI). Here, we aimed at identifying how the immunoproteasome, the main proteolytic machinery in immune cells harboring three distinct protease activities in the LMP2, LMP7 and MECL1 subunit, affects TnI-directed autoimmune pathology of the heart.TnI-directed autoimmune myocarditis (TnI-AM), a CD4 T cell-mediated disease, was induced in mice lacking all three immunoproteasome subunits, triple-ip, or lacking either the LMP2 or LMP7 gene, by immunization with a cardiac TnI peptide. Alternatively, prior to induction of TnI-AM or after establishment of AM, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in both experimental TnI-AM and in two cases of ICI-related myocarditis.All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower pro-inflammatory and chemotactic cytokines, less IL-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7 mice involved a changed balance between effector and regulatory CD4 T cells in the spleen, with CD4 T cells from LMP7 mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 and TLR7/8-engaged CD14 monocytes with ONX 0914, diminished pro-inflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4 T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing both the induction and progression of TnI-AM, when self-reactive CD4 T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulinG deposition, IL-17 production in heart tissue and TnI-directed humoral autoimmune responses, was also present in two cases of ICI-related myocarditis, thus demonstrating the activation of heart-specific autoimmune reactions by ICI therapy.By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including cases with ICI-related heart-specific autoimmunity.



Circulation: 11 Mar 2020; epub ahead of print
Bockstahler M, Fischer A, Goetzke CC, Neumaier HL, ... Kaya Z, Beling A
Circulation: 11 Mar 2020; epub ahead of print | PMID: 32160764
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Abstract

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial.

Bhatt DL, Briggs AH, Reed SD, Annemans L, ... Gabriel Steg P,
Background
Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.
Objectives
This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.
Methods
A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.
Results
Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.
Conclusions
In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).

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

J Am Coll Cardiol: 11 May 2020; 75:2297-2308
Bhatt DL, Briggs AH, Reed SD, Annemans L, ... Gabriel Steg P,
J Am Coll Cardiol: 11 May 2020; 75:2297-2308 | PMID: 32381160
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Abstract

Incidence and Long-Term Outcomes of Hypertensive Disorders of Pregnancy.

Garovic VD, White WM, Vaughan L, Saiki M, ... Weaver A, Mielke MM
Background
Hypertensive disorders of pregnancy (HDP) are associated with increased risks for cardiovascular disease later in life. The HDP incidence is commonly assessed using diagnostic codes, which are not reliable; and typically are expressed per-pregnancy, which may underestimate the number of women with an HDP history after their reproductive years.
Objectives
This study sought to determine the incidence of HDP expressed as both per-pregnancy and per-woman, and to establish their associations with future chronic conditions and multimorbidity, a measure of accelerated aging, in a population-based cohort study.
Methods
Using the Rochester Epidemiology Project medical record-linkage system, the authors identified residents of Olmsted County, Minnesota, who delivered between 1976 and 1982. The authors classified pregnancies into normotensive, gestational hypertension, pre-eclampsia, eclampsia, pre-eclampsia superimposed on chronic hypertension, and chronic hypertension using a validated electronic algorithm, and calculated the incidence of HDP both per-pregnancy and per-woman. The risk of chronic conditions between women with versus those without a history of HDP (age and parity 1:2 matched) was quantified using the hazard ratio and corresponding 95% confidence interval estimated from a Cox model.
Results
Among 9,862 pregnancies, we identified 719 (7.3%) with HDP and 324 (3.3%) with pre-eclampsia. The incidence of HDP and pre-eclampsia doubled when assessed on a per-woman basis: 15.3% (281 of 1,839) and 7.5% (138 of 1,839), respectively. Women with a history of HDP were at increased risk for subsequent diagnoses of stroke (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.37 to 3.76), coronary artery disease (HR: 1.89; 95% CI: 1.26 to 2.82), cardiac arrhythmias (HR: 1.62; 95% CI: 1.28 to 2.05), chronic kidney disease (HR: 2.41; 95% CI: 1.54 to 3.78), and multimorbidity (HR: 1.25; 95% CI: 1.15 to 1.35).
Conclusions
The HDP population-based incidence expressed per-pregnancy underestimates the number of women affected by this condition during their reproductive years. A history of HDP confers significant increase in risks for future chronic conditions and multimorbidity.

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

J Am Coll Cardiol: 11 May 2020; 75:2323-2334
Garovic VD, White WM, Vaughan L, Saiki M, ... Weaver A, Mielke MM
J Am Coll Cardiol: 11 May 2020; 75:2323-2334 | PMID: 32381164
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Abstract

Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale.

Turc G, Lee JY, Brochet E, Kim JS, ... Mas JL,
Background
In patients with patent foramen ovale (PFO)-associated stroke, the presence of large shunt or atrial septal aneurysm (ASA) has been suggested to convey a high risk of stroke recurrence.
Objectives
The purpose of this study was to assess the respective influence of PFO size and ASA status on stroke recurrence under medical therapy in patients with recent PFO-associated stroke without alternative cause.
Methods
The authors pooled individual patient data from 2 prospective observational studies and the medical arms of 2 randomized trials, in which shunt size and ASA status was assessed by independent reading of echocardiographic images. Associations between PFO anatomical features and recurrent ischemic stroke were assessed by mixed effects Cox models.
Results
Of 898 patients (mean age 45.3 years), 178 (19.8%) had ASA with large PFO, 71 (7.9%) ASA with nonlarge PFO, 397 (44.2%) large PFO without ASA, and 252 (28.1%) nonlarge PFO without ASA. Over a median follow-up of 3.8 years (interquartile range: 2.6 to 5.5 years), 47 (5.2%) patients experienced a recurrent stroke. There was a heterogeneity across studies for the association between PFO size and stroke recurrence (p = 0.01). In a model accounting for age, hypertension, antithrombotic therapy, and PFO anatomy, ASA was independently associated with recurrent stroke (adjusted hazard ratio: 3.27; 95% confidence interval: 1.82 to 5.86; p < 0.0001), whereas large PFO was not (average adjusted hazard ratio across studies: 1.43; 95% confidence interval: 0.50 to 4.03; p = 0.50).
Conclusions
In patients with PFO-associated stroke, ASA is a more important predictor of recurrent stroke than shunt size. These results can help to better identify those patients with a high risk of stroke recurrence under medical therapy who may derive the most benefit from PFO closure. (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence [CLOSE]; NCT00562289) (Device Closure versus Medical Therapy in Patients with Cryptogenic Stroke and High-Risk Patent Foramen Ovale [DEFENSE-PFO]; NCT01550588).

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

J Am Coll Cardiol: 11 May 2020; 75:2312-2320
Turc G, Lee JY, Brochet E, Kim JS, ... Mas JL,
J Am Coll Cardiol: 11 May 2020; 75:2312-2320 | PMID: 32381162
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Abstract

Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study.

Zabel M, Willems R, Lubinski A, Bauer A, ... Merkely B,
Aims 
The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy.
Methods and results 
We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537-0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class Conclusion 
In contemporary ICM/DCM patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a 27% lower mortality after adjustment. There appear to be patients with less survival advantage, such as older patients or diabetics.

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

Eur Heart J: 05 May 2020; epub ahead of print
Zabel M, Willems R, Lubinski A, Bauer A, ... Merkely B,
Eur Heart J: 05 May 2020; epub ahead of print | PMID: 32372094
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Abstract

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.

Geleris J, Sun Y, Platt J, Zucker J, ... Sobieszczyk ME, Schluger NW
Background
Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use.
Methods
We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score.
Results
Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses.
Conclusions
In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 06 May 2020; epub ahead of print
Geleris J, Sun Y, Platt J, Zucker J, ... Sobieszczyk ME, Schluger NW
N Engl J Med: 06 May 2020; epub ahead of print | PMID: 32379955
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Abstract

Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation.

Li S, Nguyen NUN, Xiao F, Menendez-Montes I, ... Hill JA, Sadek HA

Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement, rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. Interestingly, the mechanism of LV dysfunction in primary severe MR is entirely unknown.Here we developed the first mouse model of severe MR. Valvular damage was achieved by severing the MV leaflets and chords using iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow-up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocytes morphology, LV fibrosis and cell death. Finally, assessment of dysregulated pathways was done by RNA-seq analysis and immunofluorescence.In the ensuing 15 weeks following induction of MR, gradual LV dilatation and dysfunction occurred resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass, and increased cardiomyocyte length, but not width, with EM evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mTOR and calcineurin pathways. Intriguingly, inhibition of mTOR signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Interestingly, EM images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts.These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.



Circulation: 09 Apr 2020; epub ahead of print
Li S, Nguyen NUN, Xiao F, Menendez-Montes I, ... Hill JA, Sadek HA
Circulation: 09 Apr 2020; epub ahead of print | PMID: 32272846
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Abstract

DPP (Dipeptidyl Peptidase)-4 Inhibitor Attenuates Ang II (Angiotensin II)-Induced Cardiac Hypertrophy via GLP (Glucagon-Like Peptide)-1-Dependent Suppression of Nox (Nicotinamide Adenine Dinucleotide Phosphate Oxidase) 4-HDAC (Histone Deacetylase) 4 Pathway.

Okabe K, Matsushima S, Ikeda S, Ikeda M, ... Ide T, Tsutsui H

Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II-induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II-induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II-induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II-induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II-induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes.



Hypertension: 30 Mar 2020; 75:991-1001
Okabe K, Matsushima S, Ikeda S, Ikeda M, ... Ide T, Tsutsui H
Hypertension: 30 Mar 2020; 75:991-1001 | PMID: 32160098
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Abstract

Research Priorities for Heart Failure With Preserved Ejection Fraction: National Heart, Lung, and Blood Institute Working Group Summary.

Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, ... Desvigne-Nickens P, Adhikari BB

Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.



Circulation: 23 Mar 2020; 141:1001-1026
Shah SJ, Borlaug BA, Kitzman DW, McCulloch AD, ... Desvigne-Nickens P, Adhikari BB
Circulation: 23 Mar 2020; 141:1001-1026 | PMID: 32202936
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Abstract

Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure.

Chirinos JA, Zhao L, Jia Y, Frej C, ... Cappola TP, Javaheri A

Apolipoprotein M (APOM) mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). APOM exerts anti-inflammatory and cardio-protective effects in animal models.In a subset of Penn-HF study (PHFS) participants (=297), we measured APOM by ELISA. We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between APOM and HDL-associated S1P. We confirmed the relationship between APOM and outcomes using modified aptamer-based APOM measurements, among 2,170 adults in the PHFS and 2 independent cohorts: the Washington University HF registry (n=173) and a subset of the TOPCAT trial (n=218). Finally, we examined the relationship between APOM and ~5000 other proteins (SomaScan assay) to identify biological pathways associated with APOM in HF.In the PHFS, APOM was inversely associated with the risk of death (Standardized Hazard Ratio=0.56; 95%CI=0.51-0.61; <0.0001) and the composite of death/ventricular assist device or heart transplant (Standardized HR=0.62; 95%CI=0.58-0.67; <0.0001). This relationship was independent of HDL-C or APOA-I levels. APOM remained associated with death (HR=0.78; 0.69-0.88; <0.0001) and the composite of death/ventricular assist device/heart transplant (HR=0.85; 95%CI=0.76-0.94; =0.001) in models that adjusted for multiple confounders. This association was present in both HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, and was replicated in the Washington University cohort and a HFpEF-only cohort (TOPCAT). The S1P and APOM content of isolated HDL particles strongly correlated (R=0.81; <0.0001). The top canonical pathways associated with APOM were inflammation (negative association), the coagulation system (negative association) and LXR/RXR activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays.Reduced circulating APOM is independently associated with adverse outcomes across the spectrum of human HF. Further research is needed to assess whether the APOM/S1P axis is a suitable therapeutic target in HF.



Circulation: 01 Apr 2020; epub ahead of print
Chirinos JA, Zhao L, Jia Y, Frej C, ... Cappola TP, Javaheri A
Circulation: 01 Apr 2020; epub ahead of print | PMID: 32237898
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Abstract

Reducing Hypermuscularization of the Transitional Segment between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage.

Ratelade J, Klug NR, Lombardi D, Angelim MKSC, ... Nelson MT, Joutel A

Spontaneous deep intracerebral hemorrhage (ICH) is a devastating subtype of stroke without specific treatments. It has been thought that smooth muscle cell (SMC) degeneration at the site of arteriolar wall rupture may be sufficient to cause hemorrhage. However, deep ICHs are rare in some aggressive small vessel diseases that are characterized by significant arteriolar SMC degeneration. Here we hypothesized that a second cellular defect may be required for the occurrence of ICH.We studied a genetic model of spontaneous deep ICH usingandmouse lines that are mutated for the alpha1 chain of Collagen type IV. We analyzed cerebroretinal microvessels, performed genetic rescue experiments, vascular reactivity analysis and computational modeling. We examined post-mortem brain tissues from patients with sporadic deep ICH.We identified in the normal cerebroretinal vasculature a novel segment between arterioles and capillaries, herein called the transitional segment (TS), that is covered by mural cells distinct from SMCs and pericytes. Inmutant mice, this TS was hypermuscularized, with a hyperplasia of mural cells expressing more contractile proteins, whereas the upstream arteriole exhibited a loss of SMCs. Mechanistically, TS showed a transient increase in proliferation of mural cells during post-natal maturation. Mutant brain microvessels, unlike mutant arteries, displayed a significant upregulation of SM genes andtarget genes, and genetic reduction ofinmice protected against ICH. Retina analysis showed that hypermuscularization of the TS was attenuated but arteriolar SMC loss unchanged in ,mice. Moreover, hypermuscularization of the retinal TS increased its contractility and tone and raised the intravascular pressure in the upstream feeding arteriole. We similarly found hypermuscularization of the TS and focal arteriolar SMC loss in brain tissues from patients with sporadic deep ICH.Our results suggest that hypermuscularization of the TS, via increased Notch3 activity, is involved in the occurrence of ICH inmutant mice, by raising the intravascular pressure in the upstream feeding arteriole and promoting its rupture at the site of SMC loss. Our human data indicate that these 2 mutually reinforcing vascular defects may represent a general mechanism of deep ICH.



Circulation: 17 Mar 2020; epub ahead of print
Ratelade J, Klug NR, Lombardi D, Angelim MKSC, ... Nelson MT, Joutel A
Circulation: 17 Mar 2020; epub ahead of print | PMID: 32183562
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Abstract

Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets.

Xu Y, Jiang H, Li L, Chen F, ... Sun H, Liu J

Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with a risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown.The activity of human platelets from healthy subjects before and after ingestion of BCAAs were measured. Protein phosphatase 2Cm (PP2Cm) specifically dephosphorylates branched-chain α-keto acid dehydrogenase, and thereby activates BCAA catabolism. PP2Cm deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation.We found that ingestion of BCAAs significantly promoted human platelet activity (n=5, P<0.001) and arterial thrombosis formation in mice (n=9, P<0.05). We also found that the valine catabolite α-ketoisovaleric acid (KIV) and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/KIV catabolic pathway plays a major role in BCAA-facilitated platelet activation. PP2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5, P<0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbβ3-mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or CHO cells expressing integrin αIIbβ3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbβ3-mediated BCAA-facilitated platelet activation and thrombosis formation. Additionally, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from type 2 diabetes mellitus patients are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity inmice (n=4, P<0.05).BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome-associated thrombophilia.



Circulation: 22 Mar 2020; epub ahead of print
Xu Y, Jiang H, Li L, Chen F, ... Sun H, Liu J
Circulation: 22 Mar 2020; epub ahead of print | PMID: 32200651
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Abstract

Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension.

Potus F, Pauciulo MW, Cook EK, Zhu N, ... Rauh MJ, Archer SL

Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations inand 16 other genes. However, these mutations occur in under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation and adverse vascular remodeling. The role ofin PAH is unknown.To test for a role of , we utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantifiedexpression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic evidence of PAH in hematopoietic -knockout mice.We observed an increased burden of rare, predicted deleterious, germline variants inin PAH patients of European ancestry (9/1832) compared to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients had 12mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients withmutations were older (71±7 years versus 48±19 years, p<0.0001) unresponsive to vasodilator challenge (0/7 vs 140/1055 (13.2%)), had lower PVR (5.2±3.1 versus 10.5±7.0 Woods units, p=0.02) and had increased inflammation (including elevation of IL-1β). Circulatingexpression did not correlate with age and was decreased in >86% of PAH patients. -knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling and inflammation, with elevated levels of cytokines, including IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed PAH.PAH is the first human disease related to potentialgermline mutations. Inherited and acquired abnormalities ofoccur in 0.39% of PAH cases. Decreasedexpression is ubiquitous and has potential as a PAH biomarker.



Circulation: 19 Mar 2020; epub ahead of print
Potus F, Pauciulo MW, Cook EK, Zhu N, ... Rauh MJ, Archer SL
Circulation: 19 Mar 2020; epub ahead of print | PMID: 32192357
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Abstract

Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes.

Hoyer FF, Zhang X, Coppin E, Vasamsetti SB, ... Dutta P, Nahrendorf M

Diabetes is a prevalent public health problem that affects about one third of the U.S. population and leads to serious vascular complications with increased risk for coronary artery disease. How bone marrow hematopoiesis contributes to diabetes complications is incompletely understood. We thus investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.In three types of mouse diabetes, including streptozotocin, high fat diet and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC) and endothelial cells in the bone marrow with flow cytometry and expression profiling.In diabetes, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less , a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (). Unexpectedly, we found enhanced HSPC proliferation and increased myeloid cell production inmice compared to wild type mice with diabetes. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes. Inflammatory myeloid cells accumulated more in skin wounds of diabeticmice, significantly delaying wound closure. Atherosclerosis accelerated inmice, leading to larger and more inflamed atherosclerotic lesions in the aorta.In diabetes, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Specifically, diabetes reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We also describe a previously unknown counter-regulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.



Circulation: 21 Apr 2020; epub ahead of print
Hoyer FF, Zhang X, Coppin E, Vasamsetti SB, ... Dutta P, Nahrendorf M
Circulation: 21 Apr 2020; epub ahead of print | PMID: 32316750
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Abstract

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019.

Shi S, Qin M, Cai Y, Liu T, ... Yang B, Huang C
Aims
To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19).
Methods and results
We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years. Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors. Risk factors of death and myocardial injury were analysed using multivariable regression models. A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs. 9.7%; P < 0.001) than survivors. The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001]. The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively. In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury.
Conclusion
The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities.

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

Eur Heart J: 10 May 2020; epub ahead of print
Shi S, Qin M, Cai Y, Liu T, ... Yang B, Huang C
Eur Heart J: 10 May 2020; epub ahead of print | PMID: 32391877
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Abstract

Global, Regional, and National Burden of Calcific Aortic Valve and Degenerative Mitral Valve Diseases, 1990-2017.

Yadgir S, Johnson CO, Aboyans V, Adebayo OM, ... Yonemoto N, Roth GA

Non-rheumatic valvular heart diseases (NRVDs) are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease (GBD) 2017 study, mortality, prevalence, and disability-adjusted life years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease (DMVD), and other NRVD were estimated for 195 countries and territories from 1990 to 2017.Vital registration data, epidemiological survey data, and administrative hospital data were used to estimate disease burden using the GBD modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimates disease for all countries, as data on NRVD are extremely limited for some regions of the world, such as sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for each sex, five-year age group, location, and year from 1990 to 2017.Globally, CAVD and DMVD caused 102,700 (95% uncertainty interval [UI] 82,700 to 107,900) and 35,700 (95% UI 30,500 to 42,500) deaths, and had 12.6 million (95% UI 11.4 million to 13.8 million) and 18.1 million (95% UI 17.6 million to 18.6 million) prevalent cases in 2017, respectively. 1.5 million (95% UI 1.4 million to 1.6 million) DALYs were estimated as due to NRVD, globally, representing 0.26% (95% UI 0.22% to 0.27%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and DMVD between 1990 and 2017, by 123% (95% UI 101% to 137%) and 64% (95% UI 50% to 75%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries.These global and national estimates demonstrate that CAVD and DMVD are important causes of disease burden among older adults. Efforts to better understand modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.



Circulation: 28 Mar 2020; epub ahead of print
Yadgir S, Johnson CO, Aboyans V, Adebayo OM, ... Yonemoto N, Roth GA
Circulation: 28 Mar 2020; epub ahead of print | PMID: 32223336
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Abstract

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson\'s Disease.

Schweitzer JS, Song B, Herrington TM, Park TY, ... Carter BS, Kim KS

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson\'s disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson\'s disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson\'s disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 May 2020; 382:1926-1932
Schweitzer JS, Song B, Herrington TM, Park TY, ... Carter BS, Kim KS
N Engl J Med: 13 May 2020; 382:1926-1932 | PMID: 32402162
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Abstract

The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis.

Martinez L, Cords O, Horsburgh CR, Andrews JR
Background
Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.
Methods
In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).
Findings
In total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit.
Interpretation
The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches.
Funding
National Institutes of Health.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 20 Mar 2020; 395:973-984
Martinez L, Cords O, Horsburgh CR, Andrews JR
Lancet: 20 Mar 2020; 395:973-984 | PMID: 32199484
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Abstract

Addressing Social Determinants of Health in the Care of Patients With Heart Failure: A Scientific Statement From the American Heart Association.

White-Williams C, Rossi LP, Bittner VA, Driscoll A, ... Shirey M,

Heart failure is a clinical syndrome that affects >6.5 million Americans, with an estimated 550 000 new cases diagnosed each year. The complexity of heart failure management is compounded by the number of patients who experience adverse downstream effects of the social determinants of health (SDOH). These patients are less able to access care and more likely to experience poor heart failure outcomes over time. Many patients face additional challenges associated with the cost of complex, chronic illness management and must make difficult decisions about their own health, particularly when the costs of medications and healthcare appointments are at odds with basic food and housing needs. This scientific statement summarizes the SDOH and the current state of knowledge important to understanding their impact on patients with heart failure. Specifically, this document includes a definition of SDOH, provider competencies, and SDOH assessment tools and addresses the following questions: (1) What models or frameworks guide healthcare providers to address SDOH? (2) What are the SDOH affecting the delivery of care and the interventions addressing them that affect the care and outcomes of patients with heart failure? (3) What are the opportunities for healthcare providers to address the SDOH affecting the care of patients with heart failure? We also include a case study (Data Supplement) that highlights an interprofessional team effort to address and mitigate the effects of SDOH in an underserved patient with heart failure.



Circulation: 29 Apr 2020:CIR0000000000000767; epub ahead of print
White-Williams C, Rossi LP, Bittner VA, Driscoll A, ... Shirey M,
Circulation: 29 Apr 2020:CIR0000000000000767; epub ahead of print | PMID: 32349541
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Abstract

Small molecules, big impact: 20 years of targeted therapy in oncology.

Bedard PL, Hyman DM, Davids MS, Siu LL

The identification of molecular targets and the growing knowledge of their cellular functions have led to the development of small molecule inhibitors as a major therapeutic class for cancer treatment. Both multitargeted and highly selective kinase inhibitors are used for the treatment of advanced treatment-resistant cancers, and many have also achieved regulatory approval for early clinical settings as adjuvant therapies or as first-line options for recurrent or metastatic disease. Lessons learned from the development of these agents can accelerate the development of next-generation inhibitors to optimise the therapeutic index, overcome drug resistance, and establish combination therapies. The future of small molecule inhibitors is promising as there is the potential to investigate novel difficult-to-drug targets, to apply predictive non-clinical models to select promising drug candidates for human evaluation, and to use dynamic clinical trial interventions with liquid biopsies to deliver precision medicine.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 27 Mar 2020; 395:1078-1088
Bedard PL, Hyman DM, Davids MS, Siu LL
Lancet: 27 Mar 2020; 395:1078-1088 | PMID: 32222192
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Abstract

Cyclodextrin Prevents Abdominal Aortic Aneurysm via Activation of Vascular Smooth Muscle Cell TFEB.

Lu H, Sun J, Liang W, Chang Z, ... Chen YE, Fan Y

Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA.The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Utilizing vascular smooth muscle cell (VSMC)-selectiveknockout mice and employing different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator on AAA .We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2 (BCL2). BCL2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. Consistently, we observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-β-cyclodextrin (HPβCD), a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Finally, we found that HPβCD inhibits AAA in a VSMC TFEB-dependent manner in mouse models.Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by HPβCD may be a promising therapeutic strategy for the prevention and treatment of AAA.



Circulation: 30 Apr 2020; epub ahead of print
Lu H, Sun J, Liang W, Chang Z, ... Chen YE, Fan Y
Circulation: 30 Apr 2020; epub ahead of print | PMID: 32354235
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Abstract

Construction of a human cell landscape at single-cell level.

Han X, Zhou Z, Fei L, Sun H, ... Zhang D, Guo G

Single-cell analysis is a valuable tool to dissect cellular heterogeneity in complex systems. Yet, a comprehensive single-cell atlas has not been achieved for humans. We used single-cell mRNA sequencing to determine the cell-type composition of all major human organs and constructed a scheme for the human cell landscape (HCL). We revealed a single-cell hierarchy for many tissues that have not been well characterised. We established a \'single-cell HCL analysis\' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from both human and mouse to reveal the conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, while the differentiated cells are more distinct. Our study provides a valuable resource for human biology.



Nature: 24 Mar 2020; epub ahead of print
Han X, Zhou Z, Fei L, Sun H, ... Zhang D, Guo G
Nature: 24 Mar 2020; epub ahead of print | PMID: 32214235
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Abstract

Population flow drives spatio-temporal distribution of COVID-19 in China.

Jia JS, Lu X, Yuan Y, Xu G, Jia J, Christakis NA

Sudden, large-scale, and diffuse human migration can amplify localized outbreaks into widespread epidemics. Rapid and accurate tracking of aggregate population flows may therefore be epidemiologically informative. Here, we use mobile-phone-data-based counts of 11,478,484 people egressing or transiting through the prefecture of Wuhan between 1 January and 24 January 2020 as they moved to 296 prefectures throughout China. First, we document the efficacy of quarantine in ceasing movement. Second, we show that the distribution of population outflow from Wuhan accurately predicts the relative frequency and geographic distribution of COVID-19 infections through February 19, 2020, across all of China. Third, we develop a spatio-temporal \"risk source\" model that leverages population flow data (which operationalizes risk emanating from epidemic epicenters) to not only forecast confirmed cases, but also to identify high-transmission-risk locales at an early stage. Fourth, we use this risk source model to statistically derive the geographic spread of COVID-19 and the growth pattern based on the population outflow from Wuhan; the model yields a benchmark trend and an index for assessing COVID-19 community transmission risk over time for different locations. This approach can be used by policy-makers in any nation with available data to make rapid and accurate risk assessments and to plan allocation of limited resources ahead of ongoing outbreaks.



Nature: 28 Apr 2020; epub ahead of print
Jia JS, Lu X, Yuan Y, Xu G, Jia J, Christakis NA
Nature: 28 Apr 2020; epub ahead of print | PMID: 32349120
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Abstract

Associations Between Cardiovascular Risk, Structural Brain Changes, and Cognitive Decline.

Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
Background
The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear.
Objectives
This study aimed to examine whether cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences.
Methods
Within the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models.
Results
In all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (β = -0.019; 95% confidence interval [CI]: -0.035 to -0.003), episodic memory (β = -0.023; 95% CI: -0.041 to -0.004), working memory (β = -0.021; 95% CI: -0.035 to -0.007), and perceptual speed (β = -0.027; 95% CI: -0.042 to -0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β = -0.021; 95% CI: -0.042 to -0.000), gray matter (β = -1.569; 95% CI: -2.757 to -0.382), and total brain (β = -1.588; 95% CI: -2.832 to -0.344), and greater volume of white matter hyperintensities (β = 0.035; 95% CI: 0.001 to 0.069).
Conclusions
Higher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.

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

J Am Coll Cardiol: 25 May 2020; 75:2525-2534
Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
J Am Coll Cardiol: 25 May 2020; 75:2525-2534 | PMID: 32439001
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Abstract

Temperate rainforests near the South Pole during peak Cretaceous warmth.

Klages JP, Salzmann U, Bickert T, Hillenbrand CD, ... Dziadek R,

The mid-Cretaceous period was one of the warmest intervals of the past 140 million years, driven by atmospheric carbon dioxide levels of around 1,000 parts per million by volume. In the near absence of proximal geological records from south of the Antarctic Circle, it is disputed whether polar ice could exist under such environmental conditions. Here we use a sedimentary sequence recovered from the West Antarctic shelf-the southernmost Cretaceous record reported so far-and show that a temperate lowland rainforest environment existed at a palaeolatitude of about 82° S during the Turonian-Santonian age (92 to 83 million years ago). This record contains an intact 3-metre-long network of in situ fossil roots embedded in a mudstone matrix containing diverse pollen and spores. A climate model simulation shows that the reconstructed temperate climate at this high latitude requires a combination of both atmospheric carbon dioxide concentrations of 1,120-1,680 parts per million by volume and a vegetated land surface without major Antarctic glaciation, highlighting the important cooling effect exerted by ice albedo under high levels of atmospheric carbon dioxide.



Nature: 30 Mar 2020; 580:81-86
Klages JP, Salzmann U, Bickert T, Hillenbrand CD, ... Dziadek R,
Nature: 30 Mar 2020; 580:81-86 | PMID: 32238944
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Abstract

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.

Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Aims
Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive.
Methods and results
Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs.
Conclusions
ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

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: 17 May 2020; epub ahead of print
Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428930
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Abstract

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

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: 17 May 2020; epub ahead of print
Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428936
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Abstract

Centrosome anchoring regulates progenitor properties and cortical formation.

Shao W, Yang J, He M, Yu XY, ... Shi H, Shi SH

Radial glial progenitor cells (RGPs) are the major neural progenitor cells that generate neurons and glia in the developing mammalian cerebral cortex. In RGPs, the centrosome is positioned away from the nucleus at the apical surface of the ventricular zone of the cerebral cortex. However, the molecular basis and precise function of this distinctive subcellular organization of the centrosome are largely unknown. Here we show in mice that anchoring of the centrosome to the apical membrane controls the mechanical properties of cortical RGPs, and consequently their mitotic behaviour and the size and formation of the cortex. The mother centriole in RGPs develops distal appendages that anchor it to the apical membrane. Selective removal of centrosomal protein 83 (CEP83) eliminates these distal appendages and disrupts the anchorage of the centrosome to the apical membrane, resulting in the disorganization of microtubules and stretching and stiffening of the apical membrane. The elimination of CEP83 also activates the mechanically sensitive yes-associated protein (YAP) and promotes the excessive proliferation of RGPs, together with a subsequent overproduction of intermediate progenitor cells, which leads to the formation of an enlarged cortex with abnormal folding. Simultaneous elimination of YAP suppresses the cortical enlargement and folding that is induced by the removal of CEP83. Together, these results indicate a previously unknown role of the centrosome in regulating the mechanical features of neural progenitor cells and the size and configuration of the mammalian cerebral cortex.



Nature: 30 Mar 2020; 580:106-112
Shao W, Yang J, He M, Yu XY, ... Shi H, Shi SH
Nature: 30 Mar 2020; 580:106-112 | PMID: 32238932
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Abstract

Recapitulating the human segmentation clock with pluripotent stem cells.

Matsuda M, Yamanaka Y, Uemura M, Osawa M, ... Toguchida J, Alev C

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation. Despite recent advances in in vitro induction of major mesodermal lineages and cell types, experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR-Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.



Nature: 30 Mar 2020; 580:124-129
Matsuda M, Yamanaka Y, Uemura M, Osawa M, ... Toguchida J, Alev C
Nature: 30 Mar 2020; 580:124-129 | PMID: 32238941
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Abstract

Identification and characterization of Trajectories of Cardiac Allograft Vasculopathy After Heart Transplantation: A Population Based Study.

Loupy A, Coutance G, Bonnet G, Van Keer J, ... Jouven X, Kobashigawa J

Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant (HTx) recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and non-immune factors in CAV development.HTx recipients from four academic centers (Pitié-Salpêtrière & Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, Cedars-Sinai, Los Angeles; 2004 to 2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological and immunological parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality.A total of 1301 patients were included (815 and 486 in the European and US cohort, respectively). The median follow-up post-transplant was 6.6 (IQR = 4-9.1) years with 4710 coronary angiographies analyzed. We identified four distinct profiles of CAV trajectories over 10 years. The four trajectories were characterized by i) patients without CAV at one year and non-progression over time (56.3%), ii) patients without CAV at one year and late onset slow CAV progression (7.6%), iii) patients with mild CAV at one year and mild progression over time (23.1%) and iv) patients with mild CAV at one year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, six early independent predictors of these trajectories were identified: donor age (p<0.001), donor male gender (p<0.001), donor tobacco consumption (p=0.001), recipient dyslipidemia (p=0.009), class II anti-HLA donor-specific antibodies (p=0.004) and acute cellular rejection ≥2R (p=0.028). The four CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios and showed gradients for overall cause mortality (p<0.001). In a large multicenter and highly phenotyped prospective cohort of HTx recipients, we identified four CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of HTx patients for early risk stratification, patient monitoring and clinical trials.URL: https://clinicaltrials.gov Unique Identifier: NCT04117152.



Circulation: 03 May 2020; epub ahead of print
Loupy A, Coutance G, Bonnet G, Van Keer J, ... Jouven X, Kobashigawa J
Circulation: 03 May 2020; epub ahead of print | PMID: 32363949
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Abstract

CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities.

Han K, Pierce SE, Li A, Spees K, ... Winslow MM, Bassik MC

Cancer genomics studies have identified thousands of putative cancer driver genes. Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif from the α-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.



Nature: 30 Mar 2020; 580:136-141
Han K, Pierce SE, Li A, Spees K, ... Winslow MM, Bassik MC
Nature: 30 Mar 2020; 580:136-141 | PMID: 32238925
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Impact:
Abstract

First-wave COVID-19 transmissibility and severity in China outside Hubei after control measures, and second-wave scenario planning: a modelling impact assessment.

Leung K, Wu JT, Liu D, Leung GM
Background
As of March 18, 2020, 13 415 confirmed cases and 120 deaths related to coronavirus disease 2019 (COVID-19) in mainland China, outside Hubei province-the epicentre of the outbreak-had been reported. Since late January, massive public health interventions have been implemented nationwide to contain the outbreak. We provide an impact assessment of the transmissibility and severity of COVID-19 during the first wave in mainland Chinese locations outside Hubei.
Methods
We estimated the instantaneous reproduction number (R) of COVID-19 in Beijing, Shanghai, Shenzhen, Wenzhou, and the ten Chinese provinces that had the highest number of confirmed COVID-19 cases; and the confirmed case-fatality risk (cCFR) in Beijing, Shanghai, Shenzhen, and Wenzhou, and all 31 Chinese provinces. We used a susceptible-infectious-recovered model to show the potential effects of relaxing containment measures after the first wave of infection, in anticipation of a possible second wave.
Findings
In all selected cities and provinces, the R decreased substantially since Jan 23, when control measures were implemented, and have since remained below 1. The cCFR outside Hubei was 0·98% (95% CI 0·82-1·16), which was almost five times lower than that in Hubei (5·91%, 5·73-6·09). Relaxing the interventions (resulting in R >1) when the epidemic size was still small would increase the cumulative case count exponentially as a function of relaxation duration, even if aggressive interventions could subsequently push disease prevalence back to the baseline level.
Interpretation
The first wave of COVID-19 outside of Hubei has abated because of aggressive non-pharmaceutical interventions. However, given the substantial risk of viral reintroduction, particularly from overseas importation, close monitoring of R and cCFR is needed to inform strategies against a potential second wave to achieve an optimal balance between health and economic protection.
Funding
Health and Medical Research Fund, Hong Kong, China.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 07 Apr 2020; epub ahead of print
Leung K, Wu JT, Liu D, Leung GM
Lancet: 07 Apr 2020; epub ahead of print | PMID: 32277878
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Impact:
Abstract

Mortality and Paclitaxel-Coated Devices: An Individual Patient Data Meta-Analysis.

Rocha-Singh KJ, Duval S, Jaff MR, Schneider PA, ... Beckman JA,

Paclitaxel-containing devices (PTXD) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease (PAD). A recent aggregate-data meta-analysis reported increased late mortality in PAD patients treated with PTXD. We performed an individual patient data (IPD) meta-analysis to evaluate mortality.Manufacturers of FDA approved and commercially available devices in the United States provided de-identified IPD for independent analysis. Cox proportional hazards one-stage meta-analysis models using intention-to-treat (ITT) methods were used for the primary analysis. A secondary analysis of additionally recovered missing vital status data was performed. The impact of control crossover to PTXD, cause-specific mortality and drug dose-mortality were assessed.2,185 subjects and 386 deaths from eight PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% confidence interval [CI], 6% to 80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data the excess relative mortality risk was 27% (95% CI, 3% to 58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXD. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dosemortality association was identified.This IPD meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.



Circulation: 05 May 2020; epub ahead of print
Rocha-Singh KJ, Duval S, Jaff MR, Schneider PA, ... Beckman JA,
Circulation: 05 May 2020; epub ahead of print | PMID: 32370548
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Impact:
Abstract

Effects of Chronic Nicotine Inhalation on Systemic and Pulmonary Blood Pressure and Right Ventricular Remodeling in Mice.

Oakes JM, Xu J, Morris TM, Fried ND, ... Gardner JD, Yue X

Cigarette smoking is the single most important risk factor for the development of cardiovascular and pulmonary diseases; however, the role of nicotine in the pathogenesis of these diseases is incompletely understood. The purpose of this study was to examine the effects of chronic nicotine inhalation on the development of cardiovascular and pulmonary disease with a focus on blood pressure and cardiac remodeling. Male C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hour on/12 hour off) for 8 weeks. Systemic blood pressure was recorded weekly by radio-telemetry, and cardiac remodeling was monitored by echocardiography. At the end of the 8 weeks, mice were subjected to right heart catheterization to measure right ventricular systolic pressure. Nicotine-exposed mice exhibited elevated systemic blood pressure from weeks 1 to 3, which then returned to baseline from weeks 4 to 8, indicating development of tolerance to nicotine. At 8 weeks, significantly increased right ventricular systolic pressure was detected in nicotine-exposed mice compared with the air controls. Echocardiography showed that 8-week nicotine inhalation resulted in right ventricular (RV) hypertrophy with increased RV free wall thickness and a trend of increase in RV internal diameter. In contrast, there were no significant structural or functional changes in the left ventricle following nicotine exposure. Mechanistically, we observed increased expression of angiotensin-converting enzyme and enhanced activation of mitogen-activated protein kinase pathways in the RV but not in the left ventricle. We conclude that chronic nicotine inhalation alters both systemic and pulmonary blood pressure with the latter accompanied by RV remodeling, possibly leading to progressive and persistent pulmonary hypertension.



Hypertension: 15 Mar 2020:HYPERTENSIONAHA11914608; epub ahead of print
Oakes JM, Xu J, Morris TM, Fried ND, ... Gardner JD, Yue X
Hypertension: 15 Mar 2020:HYPERTENSIONAHA11914608; epub ahead of print | PMID: 32172623
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Abstract

Effect of non-pharmaceutical interventions to contain COVID-19 in China.

Lai S, Ruktanonchai NW, Zhou L, Prosper O, ... Yu H, Tatem AJ

On March 11, 2020, the World Health Organization declared COVID-19 a pandemic. The outbreak containment strategies in China based on non-pharmaceutical interventions (NPIs) appear to be effective, but quantitative research is still needed to assess the efficacy of NPIs and their timings. Using epidemiological and anonymised human movement data, here we develop a modelling framework that uses daily travel networks to simulate different outbreak and intervention scenarios across China. We estimated that there were a total of 114,325 COVID-19 cases (interquartile range 76,776 - 164,576) in mainland China as of February 29, 2020. Without NPIs, the COVID-19 cases would likely have shown a 67-fold increase (interquartile range 44 - 94) by February 29, 2020, with the effectiveness of different interventions varying. The early detection and isolation of cases was estimated to have prevented more infections than travel restrictions and contact reductions, but combined NPIs achieved the strongest and most rapid effect. The lifting of travel restrictions since February 17, 2020 does not appear to lead to an increase in cases across China if the social distancing interventions can be maintained, even at a limited level of 25% reduction on average through late April. Our findings contribute to an improved understanding of NPIs on COVID-19 and to inform response efforts across the World.



Nature: 03 May 2020; epub ahead of print
Lai S, Ruktanonchai NW, Zhou L, Prosper O, ... Yu H, Tatem AJ
Nature: 03 May 2020; epub ahead of print | PMID: 32365354
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Abstract

Metabolites released from apoptotic cells act as tissue messengers.

Medina CB, Mehrotra P, Arandjelovic S, Perry JSA, ... Lorenz U, Ravichandran KS

Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body, and regulates inflammation, cell proliferation, and tissue regeneration. How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung-graft rejection. These data advance the concept that apoptotic cells are not inert cells waiting for removal, but instead release metabolites as \'good-bye\' signals to actively modulate outcomes in tissues.



Nature: 30 Mar 2020; 580:130-135
Medina CB, Mehrotra P, Arandjelovic S, Perry JSA, ... Lorenz U, Ravichandran KS
Nature: 30 Mar 2020; 580:130-135 | PMID: 32238926
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Abstract

Parental-to-embryo switch of chromosome organization in early embryogenesis.

Collombet S, Ranisavljevic N, Nagano T, Varnai C, ... Ancelin K, Heard E

Paternal and maternal epigenomes undergo marked changes after fertilization. Recent epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifications and differences in chromosome organization and accessibility, both in gametes and after fertilization. However, these studies have led to very different conclusions: the global absence of local topological-associated domains (TADs) in gametes and their appearance in the embryo versus the pre-existence of TADs and loops in the zygote. The questions of whether parental structures can be inherited in the newly formed embryo and how these structures might relate to allele-specific gene regulation remain open. Here we map genomic interactions for each parental genome (including the X chromosome), using an optimized single-cell high-throughput chromosome conformation capture (HiC) protocol, during preimplantation in the mouse. We integrate chromosome organization with allelic expression states and chromatin marks, and reveal that higher-order chromatin structure after fertilization coincides with an allele-specific enrichment of methylation of histone H3 at lysine 27. These early parental-specific domains correlate with gene repression and participate in parentally biased gene expression-including in recently described, transiently imprinted loci. We also find TADs that arise in a non-parental-specific manner during a second wave of genome assembly. These de novo domains are associated with active chromatin. Finally, we obtain insights into the relationship between TADs and gene expression by investigating structural changes to the paternal X chromosome before and during X chromosome inactivation in preimplantation female embryos. We find that TADs are lost as genes become silenced on the paternal X chromosome but linger in regions that escape X chromosome inactivation. These findings demonstrate the complex dynamics of three-dimensional genome organization and gene expression during early development.



Nature: 30 Mar 2020; 580:142-146
Collombet S, Ranisavljevic N, Nagano T, Varnai C, ... Ancelin K, Heard E
Nature: 30 Mar 2020; 580:142-146 | PMID: 32238933
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Abstract

Fundamental bounds on the fidelity of sensory cortical coding.

Rumyantsev OI, Lecoq JA, Hernandez O, Zhang Y, ... Ganguli S, Schnitzer MJ

How the brain processes information accurately despite stochastic neural activity is a longstanding question. For instance, perception is fundamentally limited by the information that the brain can extract from the noisy dynamics of sensory neurons. Seminal experiments suggest that correlated noise in sensory cortical neural ensembles is what limits their coding accuracy, although how correlated noise affects neural codes remains debated. Recent theoretical work proposes that how a neural ensemble\'s sensory tuning properties relate statistically to its correlated noise patterns is a greater determinant of coding accuracy than is absolute noise strength. However, without simultaneous recordings from thousands of cortical neurons with shared sensory inputs, it is unknown whether correlated noise limits coding fidelity. Here we present a 16-beam, two-photon microscope to monitor activity across the mouse primary visual cortex, along with analyses to quantify the information conveyed by large neural ensembles. We found that, in the visual cortex, correlated noise constrained signalling for ensembles with 800-1,300 neurons. Several noise components of the ensemble dynamics grew proportionally to the ensemble size and the encoded visual signals, revealing the predicted information-limiting correlations. Notably, visual signals were perpendicular to the largest noise mode, which therefore did not limit coding fidelity. The information-limiting noise modes were approximately ten times smaller and concordant with mouse visual acuity. Therefore, cortical design principles appear to enhance coding accuracy by restricting around 90% of noise fluctuations to modes that do not limit signalling fidelity, whereas much weaker correlated noise modes inherently bound sensory discrimination.



Nature: 30 Mar 2020; 580:100-105
Rumyantsev OI, Lecoq JA, Hernandez O, Zhang Y, ... Ganguli S, Schnitzer MJ
Nature: 30 Mar 2020; 580:100-105 | PMID: 32238928
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Abstract

Cardiovascular Biology of Prostanoids and Drug Discovery.

Zhu L, Zhang Y, Guo Z, Wang M

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs, which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.



Arterioscler Thromb Vasc Biol: 15 Apr 2020:ATVBAHA119313234; epub ahead of print
Zhu L, Zhang Y, Guo Z, Wang M
Arterioscler Thromb Vasc Biol: 15 Apr 2020:ATVBAHA119313234; epub ahead of print | PMID: 32295420
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Abstract

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.

Bao L, Deng W, Huang B, Gao H, ... Wu G, Qin C

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the corona virus disease 2019 (COVID-19) cases in China and has become a public health emergency of international concern. Because angiotensin-converting enzyme 2 (ACE2) is the cell entry receptor of SARS-CoV, we used transgenic mice bearing human ACE2 and infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant macrophages and lymphocytes into the alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, macrophages and alveolar epithelia. The phenomenon was not found in wild-type mice with SARS-CoV-2 infection. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. The mouse model with SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutics and vaccines as well as understanding the pathogenesis of COVID-19.



Nature: 06 May 2020; epub ahead of print
Bao L, Deng W, Huang B, Gao H, ... Wu G, Qin C
Nature: 06 May 2020; epub ahead of print | PMID: 32380511
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Abstract

Monotherapy with a P2Y inhibitor or aspirin for secondary prevention in patients with established atherosclerosis: a systematic review and meta-analysis.

Chiarito M, Sanz-Sánchez J, Cannata F, Cao D, ... Ferrante G, Stefanini GG
Background
Antiplatelet therapy is recommended among patients with established atherosclerosis. We compared monotherapy with a P2Y inhibitor versus aspirin for secondary prevention.
Methods
In this systematic review and meta-analysis, all randomised trials comparing P2Y inhibitor with aspirin monotherapy for secondary prevention in patients with cerebrovascular, coronary, or peripheral artery disease were evaluated for inclusion. On Dec 18, 2019, we searched PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials. Additionally, we reviewed references from identified articles and searched abstracts from 2017 to 2019 presented at relevant scientific meetings. Data about year of publication, inclusion and exclusion criteria, sample size, baseline patients\' features including the baseline condition determining study inclusion (ie, cerebrovascular, coronary, or peripheral artery disease), P2Y inhibitor type and dosage, aspirin dosage, endpoint definitions, effect estimates, follow-up duration, and percentage of patients lost to follow-up were collected. Odds ratios (ORs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. Co-primary endpoints were myocardial infarction and stroke. Key secondary endpoints were all-cause death and vascular death. Heterogeneity was assessed with the I index. This study is registered with PROSPERO (CRD42018115037).
Findings
A total of nine randomised trials were identified and included in this study, and 42 108 patients randomly allocated to a P2Y inhibitor (n=21 043) or aspirin (n=21 065) were included in our analyses. Patients who received a P2Y inhibitor had a borderline reduction for the risk of myocardial infarction compared with those who received aspirin (OR 0·81 [95% CI 0·66-0·99]; I=10·9%). Risks of stroke (OR 0·93 [0·82-1·06]; I=34·5%), all-cause death (OR 0·98 [0·89-1·08]; I=0%), and vascular death (OR 0·97 [0·86-1·09]; I=0%) did not differ between patients who received a P2Y inhibitor and those who received aspirin. Similarly, the risk of major bleeding (OR 0·90 [0·74-1·10]; I=3·9%) did not differ between patients who received a P2Y inhibitor and those who received aspirin. The number needed to treat to prevent one myocardial infarction with P2Y inhibitor monotherapy was 244 patients. Findings were consistent regardless of the type of P2Y inhibitor used.
Interpretation
Compared with aspirin monotherapy, P2Y inhibitor monotherapy is associated with a risk reduction for myocardial infarction and a comparable risk of stroke in the setting of secondary prevention. The benefit of P2Y inhibitor monotherapy is of debatable clinical relevance, in view of the high number needed to treat to prevent a myocardial infarction and the absence of any effect on all-cause and vascular mortality.
Funding
Italian Ministry of Education.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 08 May 2020; 395:1487-1495
Chiarito M, Sanz-Sánchez J, Cannata F, Cao D, ... Ferrante G, Stefanini GG
Lancet: 08 May 2020; 395:1487-1495 | PMID: 32386592
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Abstract

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.

Packer M

The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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

Eur Heart J: 26 May 2020; epub ahead of print
Packer M
Eur Heart J: 26 May 2020; epub ahead of print | PMID: 32460327
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Abstract

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
Background
Patients withhamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative formutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
Methods
In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-typewho met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned forgermline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representativevariants.
Results
The existence of germlinevariants was first established in a family with wild-typewho had oligopolyposis and early-onset colon cancers. A validation series indicated thatgermline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germlinevariants, particularly theK740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritizedvariants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
Conclusions
In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms withoutgermline mutations, we confirmed the function ofas a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2103-2116
Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
N Engl J Med: 27 May 2020; 382:2103-2116 | PMID: 32459922
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Abstract

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
Background
Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
Methods
We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
Results
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
Conclusions
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 May 2020; epub ahead of print
Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
N Engl J Med: 26 May 2020; epub ahead of print | PMID: 32459919
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Abstract

FDA Initiative for Drug Facts Label for Over-the-Counter Naloxone.

Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
Background
The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use.
Methods
In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval.
Results
The results for performance on six primary end points met or exceeded thresholds, including the steps \"Check for a suspected overdose\" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and \"Give the first dose\" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of \"Call 911 immediately,\" but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of \"Check, give, and call 911 immediately\" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9).
Conclusions
Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2129-2136
Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
N Engl J Med: 27 May 2020; 382:2129-2136 | PMID: 32459923
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Abstract

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

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

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



Hypertension: 15 Mar 2020:HYPERTENSIONAHA11913404; epub ahead of print
Wu X, Yuan X, Wang W, Liu K, ... Zhou S, Song L
Hypertension: 15 Mar 2020:HYPERTENSIONAHA11913404; epub ahead of print | PMID: 32172622
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Abstract

Video-based AI for beat-to-beat assessment of cardiac function.

Ouyang D, He B, Ghorbani A, Yuan N, ... Ashley EA, Zou JY

Accurate assessment of cardiac function is crucial for the diagnosis of cardiovascular disease, screening for cardiotoxicity and decisions regarding the clinical management of patients with a critical illness. However, human assessment of cardiac function focuses on a limited sampling of cardiac cycles and has considerable inter-observer variability despite years of training. Here, to overcome this challenge, we present a video-based deep learning algorithm-EchoNet-Dynamic-that surpasses the performance of human experts in the critical tasks of segmenting the left ventricle, estimating ejection fraction and assessing cardiomyopathy. Trained on echocardiogram videos, our model accurately segments the left ventricle with a Dice similarity coefficient of 0.92, predicts ejection fraction with a mean absolute error of 4.1% and reliably classifies heart failure with reduced ejection fraction (area under the curve of 0.97). In an external dataset from another healthcare system, EchoNet-Dynamic predicts the ejection fraction with a mean absolute error of 6.0% and classifies heart failure with reduced ejection fraction with an area under the curve of 0.96. Prospective evaluation with repeated human measurements confirms that the model has variance that is comparable to or less than that of human experts. By leveraging information across multiple cardiac cycles, our model can rapidly identify subtle changes in ejection fraction, is more reproducible than human evaluation and lays the foundation for precise diagnosis of cardiovascular disease in real time. As a resource to promote further innovation, we also make publicly available a large dataset of 10,030 annotated echocardiogram videos.



Nature: 30 Mar 2020; 580:252-256
Ouyang D, He B, Ghorbani A, Yuan N, ... Ashley EA, Zou JY
Nature: 30 Mar 2020; 580:252-256 | PMID: 32269341
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Abstract

Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction.

Tang X, Miao Y, Luo Y, Sriram K, ... Zhong S, Chen ZB

Metabolic disorders such as obesity and diabetes can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs in adipose tissue function is not fully understood. Other than VEGF-VEGFR-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function , and the relevance to adipose tissue function and obesity.We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-KO) and their wild-type littermates (WT) to a fast-food-mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We employed crosslinking immunoprecipitation (iCLIP)- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy and obese/Type 2 diabetic donors.We identified an anti-obesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 (/TSP1), an anti-angiogenic and pro-inflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from obese and/or type 2 diabetic donors, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway.Our study suggests a novel mechanism by which ECs, through AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.



Circulation: 11 May 2020; epub ahead of print
Tang X, Miao Y, Luo Y, Sriram K, ... Zhong S, Chen ZB
Circulation: 11 May 2020; epub ahead of print | PMID: 32393053
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Impact:
Abstract

Respiratory disease in rhesus macaques inoculated with SARS-CoV-2.

Munster VJ, Feldmann F, Williamson BN, van Doremalen N, ... Fischer ER, de Wit E

An outbreak of a novel coronavirus, named SARS-CoV-2, causing respiratory disease and a ~2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.



Nature: 11 May 2020; epub ahead of print
Munster VJ, Feldmann F, Williamson BN, van Doremalen N, ... Fischer ER, de Wit E
Nature: 11 May 2020; epub ahead of print | PMID: 32396922
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Abstract

Transcriptional and Cellular Diversity of the Human Heart.

Tucker NR, Chaffin M, Fleming SJ, Hall AW, ... Stegmann CM, Ellinor PT

The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low input RNA-sequencing have allowed definitions of cellular transcriptomes at single cell resolution at scale, here we have applied these approaches to assess the cellular and transcriptional diversity of the non-failing human heart.Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from seven human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based upon transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data.We sequenced the transcriptomes of 287,269 single cardiac nuclei, revealing a total of 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblasts subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Finally, intersection of our dataset with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity.Using large-scale single nuclei RNA sequencing, we have defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.



Circulation: 13 May 2020; epub ahead of print
Tucker NR, Chaffin M, Fleming SJ, Hall AW, ... Stegmann CM, Ellinor PT
Circulation: 13 May 2020; epub ahead of print | PMID: 32403949
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Abstract

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis.

Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
Background
In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES).
Objectives
This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR.
Methods
The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses.
Results
A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types.
Conclusions
At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678
Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678 | PMID: 32466881
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