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Abstract

Outcomes of transcatheter aortic valve replacement without predilation of the aortic valve: Insights from 1544 patients included in the SOURCE 3 registry.

Dumonteil N, Terkelsen C, Frerker C, Collart F, ... Lefèvre T,
Aims
To investigate the impact of transcatheter aortic valve replacement (TAVR) without preliminary balloon aortic valvuloplasty (pre-BAV) on periprocedural outcomes in a large, real-world registry.
Methods and results
The SOURCE 3 registry was an observational, multi-center, single-arm study of patients with severe, symptomatic aortic stenosis at high surgical risk treated with the SAPIEN 3 transcatheter heart valve (THV). Procedural and 30-day outcomes were compared between two groups of 772 patients each (retrospectively matched) with or without pre-BAV. All baseline clinical, echocardiographic, and anatomical valve characteristics were comparable between groups except for Society of Thoracic Surgeons (STS) score, which was lower in the direct TAVR group (6.0 ± 5.9 vs 7.8 ± 8.3; p = 0.003). In the direct TAVR group, there were less post-dilatations (8.1% vs. 13.1%, p = 0.002), shorter procedural time (70.9 ± 39.8 min vs 73.0 ± 32.2 min, p = 0.033) and fluoroscopy time (13.4 ± 7.0 min vs 14.9 ± 7.4 min, p < 0.001). Other procedural outcomes and echocardiographic variables at 30 days did not differ significantly between the two groups: safety endpoint (10.4% with pre-BAV vs 13.5% with direct TAVR, p = 0.059), mortality (2.1% vs 2.3%, p = 0.730), disabling strokes (0.4% vs 0.5%, p = 0.704), and moderate to severe paravalvular leak (PVL) (3.2% vs 2.2%, p = 0.40). Unexpectedly, new permanent pacemaker implantation and life-threatening bleeds were less frequently observed with pre-BAV group than with direct TAVR (10.4% vs 13.9%, p = 0.032 and 3.5% vs 6.5%, p = 0.007, respectively).
Conclusion
In this large TAVR dataset, direct implantation of the SAPIEN 3 THV without pre-BAV was feasible and safe and resulted in shorter procedures, without impact on 30-day prosthesis function and PVL.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:32-37
Dumonteil N, Terkelsen C, Frerker C, Collart F, ... Lefèvre T,
Int J Cardiol: 30 Nov 2019; 296:32-37 | PMID: 31256993
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Abstract

Abstract 10613: Symptomatic Human Immunodeficiency Virus Infected Patients Receive Less Aggressive Revascularization Management After Acute Coronary Syndrome, a 5-year Nationwide Analysis.

Huang Lucas C, Wu L, Yue B, Bachoo N, ... Wei X, Herzog E

Cardiovascular disease is a leading cause of morbidity and mortality in human immunodeficiency virus (HIV) infected adults, and should be managed more aggressively.Prior studies highlighted treatment disparities for Acute Coronary Syndrome (ACS) among HIV patients. This study aims at examining these disparities with the latest large cohort data.HIV patient with ACS are as likely to receive cardiac revascularization related procedures compared to control group.We reviewed the Nationwide Inpatient Sample from 2013 to 2016 to identify patients with diagnosis of ACS (ST-elevation and non ST-elevation myocardial infarction, and unstable angina) to compare rates of cardiac procedures (Catheterization, Percutaneous Coronary Intervention - PCI - and Coronary Artery Bypass Graft - CABG) among groups of population of interest (control, asymptomatic HIV, symptomatic HIV).Overall, 515,016 patients with primary diagnosis of ACS where identified and among them 2066 (0.40%) of ACS patients had diagnosis of HIV (asymptomatic and symptomatic). Multivariate regression analysis showed statistically significant lower procedural rates for catheterization (OR: 0.62, 95% CI: [0.52, 0.73]), PCI (OR: 0.80, 95% CI: [0.67, 0.96]) and CABG (OR: 0.70, 95% CI: [0.52, 0.93]) in symptomatic HIV compared to control group. For asymptomatic HIV patient group, no significant change of procedural rates were found compared to control group for catheterization, PCI and CABG (respectively OR: 0.90, 95% CI: [0.78, 1.05], OR: 1.13, 95% CI: [1.00, 1.26] and OR: OR: 0.87, 95% CI: [0.72, 1.04]).Analysis shows a treatment disparity for ACS for symptomatic HIV patients only as symptomatic HIV affected patients received less aggressive catheterization and revascularization management after ACS, compared to control group. However, this effect was not present for the asymptomatic HIV patient group.



Circulation: 18 Nov 2019; 140:A10613
Huang Lucas C, Wu L, Yue B, Bachoo N, ... Wei X, Herzog E
Circulation: 18 Nov 2019; 140:A10613 | PMID: 31633997
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Abstract

The association between pulmonary hypertension and stroke: A systematic review and meta-analysis.

Shah TG, Sutaria JM, Vyas MV
Background
Pulmonary hypertension is associated with atrial fibrillation and paradoxical embolism. Yet, the association between pulmonary hypertension and stroke has not been well studied.
Methods
We reviewed Medline and Embase from inception to December 1, 2018, to identify observational studies reporting prevalence of stroke in adult patients with pulmonary hypertension. We sought studies that included patients with pulmonary hypertension secondary to any etiology except left heart failure, and excluded studies that reported rates of perioperative stroke. We conducted random effects meta-analyses to obtain pooled prevalence of stroke in patients with pulmonary hypertension, and pooled unadjusted odds ratio of stroke in patients with pulmonary hypertension compared to those without.
Results
We included 14 studies including 32,523 participants of which 2976 (9.2%) had pulmonary hypertension, and 727 (2.2%) had a stroke. The pooled prevalence of stroke in patients with pulmonary hypertension was 8.0% [95% confidence interval (CI), 5.1%-10.9%, I 91.9]. The pooled unadjusted odds ratio of stroke in patients with pulmonary hypertension compared to those without was 1.46 (95% CI, 1.07-1.99, I 55.6, n = 7 studies).
Conclusion
Stroke is a major non-cardiac morbidity in patients with pulmonary hypertension, requiring further evaluation to determine its etiology, and measures to reduce its risk.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:21-24
Shah TG, Sutaria JM, Vyas MV
Int J Cardiol: 14 Nov 2019; 295:21-24 | PMID: 31402157
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Abstract

Delayed prolongation of the QRS interval in patients with left ventricular dysfunction.

Rav-Acha M, Nujidat A, Farkash R, Medina A, ... Glikson M, Hasin T
Aims
Patients with left ventricular dysfunction (LVD) and prolonged QRS on surface electrocardiogram are at increased risk for heart failure and death and may benefit from resynchronization therapy. Patients with initial narrow QRS may prolong their QRS during the disease course. The occurrence of delayed QRS prolongation, its predictors and associated risk of heart failure hospitalizations (HFH) or death are currently unknown and the subject of this investigation.
Methods & results
Patients with LVD, QRS < 120 ms and available follow-up ECGs were retrospectively evaluated for persistent unprovoked QRS prolongation >130 ms. Impact on mortality or HFH was assessed using Cox regression with QRS > 130 ms as a time dependent covariate. Following 178 patients for 30 (10;59) median (IQR) months, 28 (16%) patients prolonged their QRS to >130 ms, reaching a QRS duration of 154 ± 29 ms; LBBB pattern was diagnosed among 14 (50%) patients. Patients with delayed QRS prolongation were older (71.9 ± 11.8 vs 64.4 ± 15.1 years p = 0.014), had larger left ventricle and left atrial diameters (6.3 ± 0.9 vs 5.7 ± 0.9 cm p = 0.010; 4.9 ± 0.6 vs 4.5 ± 0.7 cm p = 0.006, respectively) and wider baseline QRS (104.8 ± 12.6 vs 91.4 ± 14.5 ms p < 0.001) which was linearly associated with late QRS prolongation (p for trend<0.0001). In a multivariable model, age, baseline QRS width and left atrial diameter were significantly associated with delayed QRS prolongation. QRS prolongation at follow-up was independently associated with risk of death or HFH (HR 7.426, 95% CI3.017-18.280, p < 0.0001).
Conclusion
QRS prolongation occurs in a significant proportion of patients with LVD and portends adverse outcome. Advanced age, prolonged QRS and larger left atria are potential predictors. Routine monitoring is justified and physicians may choose to plan ahead for resynchronization therapy in patients at risk for QRS prolongation.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 30 Nov 2019; 296:71-75
Rav-Acha M, Nujidat A, Farkash R, Medina A, ... Glikson M, Hasin T
Int J Cardiol: 30 Nov 2019; 296:71-75 | PMID: 31327517
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Abstract

Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats.

Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y

Patients with pulmonary arterial hypertension (PAH) and right ventricular (RV) failure have a poor clinical outcome, but the mechanisms of PAH and RV failure development are not totally clear. PAH is associated with reduced NO bioavailability and increased endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). Dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays a critical role in ADMA degradation. Here we generated a novel DDAH1 deficiency rat strain using the CRISPR-Cas9 technique, and studied the effect of DDAH1 dysfunction on monocrotaline-induced PAH, lung vascular remodeling and RV hypertrophy. DDAH1 knockout resulted in abolished DDAH1 expression in various tissues, and significant increases of plasma and lung ADMA content. DDAH1 knockout has no detectable effect on cardiac and lung structure, and LV function under control conditions in rats. However, DDAH1 knockout significantly aggravated monocrotaline-induced lung and RV oxidative stress, lung vascular remodeling and fibrosis, pulmonary hypertension and RV hypertrophy in rats. DDAH1 KO resulted in significantly greater increases of plasma and lung ADMA content under control conditions. In the wild type rats monocrotaline resulted in significant increases of plasma and lung ADMA contents and reduction of lung eNOS protein content and these changes were more marked in DDAH1 KO rats. Together, our results demonstrated that DDAH1 plays an important role in attenuating monocrotaline-induced lung oxidative stress, pulmonary hypertension and RV hypertrophy in rats.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 14 Nov 2019; 295:14-20
Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y
Int J Cardiol: 14 Nov 2019; 295:14-20 | PMID: 31402164
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Abstract

CMR feature tracking left ventricular strain-rate predicts ventricular tachyarrhythmia, but not deterioration of ventricular function in patients with repaired tetralogy of Fallot.

Hagdorn QAJ, Vos JDL, Beurskens NEG, Gorter TM, ... Berger RMF, Willems TP
Background
Myocardial strain has been shown to predict outcome in various cardiovascular diseases, including congenital heart diseases. The aim of this study was to evaluate the predictive value of cardiac magnetic resonance (CMR) feature-tracking derived strain parameters in repaired tetralogy of Fallot (rTOF) patients for developing ventricular tachycardia (VT) and deterioration of ventricular function.
Methods
Patients with rTOF who underwent CMR investigation were included. Strain and strain-rate of both ventricles were assessed using CMR feature tracking. The primary outcome was a composite of the occurrence of sustained VT or non-sustained VT requiring invasive therapy. The secondary outcome was analyzed in patients that underwent a second CMR after 1.5 to 3.5 years. Deterioration was defined as reduction (≥10%) in right ventricular (RV) ejection fraction, reduction (≥10%) in left ventricular (LV) ejection fraction or increase (≥30 mL/m) in indexed RV end-diastolic volume compared to baseline.
Results
172 patients (median age 24.3 years, 54 patients <18 years) were included. Throughout a median follow-up of 7.4 years, 9 patients (4.5%) experienced the primary endpoint of VT. Multivariate Cox-regression analysis showed that LV systolic circumferential strain-rate was independently predictive of primary outcome (p = 0.023). 70 patients underwent a serial CMR, of whom 14 patients (20%) showed ventricular deterioration. Logistic regression showed no predictive value of strain and strain-rate parameters.
Conclusions
In patients with rTOF, LV systolic circumferential strain-rate is an independent predictor for the development of VT. Ventricular strain parameters did not predict deterioration of ventricular function in the studied population.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:1-6
Hagdorn QAJ, Vos JDL, Beurskens NEG, Gorter TM, ... Berger RMF, Willems TP
Int J Cardiol: 14 Nov 2019; 295:1-6 | PMID: 31402156
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Abstract

Impact of heart rate on coronary computed tomographic angiography interpretability with a third-generation dual-source scanner.

Miller RJH, Eisenberg E, Friedman J, Cheng V, ... Thomson L, Berman DS
Background
Guidelines suggest coronary computed tomography angiography (CCTA) should be performed with a heart rate (HR) below 60. Third-generation dual-source CT (DSCT) scanners, with improved temporal resolution, and end-systolic acquisition may facilitate imaging at higher HRs. We determined the influence of HR and end-systolic acquisition on image interpretability and quality with a third-generation DSCT.
Methods
Patients who underwent CCTA between July 2017 and December 2018 were retrospectively identified. All images were acquired using a SOMATOM Force scanner (Siemens Healthcare). The primary outcome was the presence of any uninterpretable coronary segment. The association between HR and CCTA with uninterpretable segments was assessed with multivariable logistic regression, correcting for demographics and imaging variables.
Results
In total, 2620 patients were included, mean age 61.4 ± 12.9 years and 61.2% male, with uninterpretable segments present in 229 (8.7%) scans. In multivariable analysis, HR 80-89 was associated with an increased likelihood of having a scan with uninterpretable segments (adjusted odds ratio [OR] 4.53, p < 0.001). However, no significant association was present with end-systolic acquisition (HR 80-89, adjusted OR 2.32, p = 0.125). HR ≥ 90 was associated with a decreased likelihood of good or excellent image quality (adjusted OR 0.26, 95% CI 0.11-0.63, p = 0.003).
Conclusions
With third-generation dual-source CT scanners, patients with HR 60-80 can be imaged without impacting image interpretability. End-systolic image acquisition facilitates imaging at HRs > 80 without increasing non-diagnostic scans. Routine use of systolic gating could omit the need for strict HR control and pre-test beta blockade currently required for CCTA.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:42-47
Miller RJH, Eisenberg E, Friedman J, Cheng V, ... Thomson L, Berman DS
Int J Cardiol: 14 Nov 2019; 295:42-47 | PMID: 31427117
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Abstract

Rheumatic fever and rheumatic heart disease: Facts and research progress in Africa.

Muhamed B, Mutithu D, Aremu O, Zühlke L, Sliwa K

In recent years, the devastating effect of rheumatic fever (RF) and rheumatic heart disease (RHD) in Africa has been acknowledged by Institutions such as the Pan-African Society of Cardiology, the African Union Commission, and the World Health Organization. Key priorities set to eradicate RF and RHD include diagnosing and managing RF and RHD, building registries, improving adequate supplies of benzathine penicillin, reproductive health services, and cardiac surgery, developing multi-sectoral RHD awareness programmes, understanding RHD pathogenesis and fostering international partnership for resource mobilization. There were volumes of peer reviewed publications focusing on the key priorities to fight RHD in different parts to Africa; both individually as well as through international collaborations. This article analyzed findings and reports from 1961 to 2018 on efforts to eradicate RF and RHD in Africa.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 14 Nov 2019; 295:48-55
Muhamed B, Mutithu D, Aremu O, Zühlke L, Sliwa K
Int J Cardiol: 14 Nov 2019; 295:48-55 | PMID: 31405583
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Abstract

Incidental abnormal ECG findings and long-term cardiovascular morbidity and all-cause mortality: A population based prospective study.

Goldman A, Hod H, Chetrit A, Dankner R
Background
The additional prognostic value of resting electrocardiogram (ECG) in long-term cardiovascular disease (CVD)-risk-assessment is unclear. We evaluated the association of incidental abnormal ECG findings with long-term CVD-risk and all-cause mortality, and assessed the additional prognostic value of ECG as a screening tool in adults without known CVD.
Methods
A cohort of 2601 Israeli men and women without known CVD were actively followed from 1976 to 1982 for 23-year cumulative CVD-incidence, and until May 2017 for all-cause mortality. At baseline and follow-up, participants underwent interviews, physical examinations, blood tests and ECG.
Results
At baseline, 1199 (46.1%) had incidental abnormal ECG findings (exposed-group). CVD cumulative incidence reached 31.6% among the 930 survivors who participated in the active follow-up (294/930). During a 31-year median follow-up, 1719 (66.1%) of the total cohort died. Incidental abnormal ECG findings were associated with 46% greater CVD-risk (odds ratio = 1.46, 95%CI = 1.09-1.97). The net reclassification improvement (NRI) of CVD-risk was 7.4% (95%CI = 1.5%-13.3%, p = 0.01) following the addition of ECG findings, but the C-index improvement was not statistically significant [C-index = 0.656 (0.619-0.694) vs. C-index = 0.666 (0.629-0.703), p = 0.14]. Multivariable Cox regression demonstrated an all-cause mortality hazard ratio (HR) of 1.18 (95%CI = 1.07-1.30) for exposed vs. unexposed individuals. Non-specific T-wave changes and left-axis deviation are the incidental ECG abnormalities that were associated with all-cause mortality [HR = 1.18 (95%CI = 1.05-1.33) and HR = 1.19 (95%CI = 1.00-1.42), respectively].
Conclusion
Incidental abnormal ECG findings, mainly non-specific T-wave changes and left-axis deviation, were associated with increased long-term CVD-risk and all-cause mortality among individuals without known CVD, and demonstrated net reclassification improvement for CVD-risk.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:36-41
Goldman A, Hod H, Chetrit A, Dankner R
Int J Cardiol: 14 Nov 2019; 295:36-41 | PMID: 31412991
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Abstract

Sarcopenia is common in adults with complex congenital heart disease.

Sandberg C, Johansson K, Christersson C, Hlebowicz J, Thilén U, Johansson B
Background
Adults with complex congenital heart disease (CHD) have reduced aerobic capacity and impaired muscle function. We therefore hypothesized that patients have a lower skeletal muscle mass and higher fat mass than controls.
Methods
Body composition was examined with full body Dual-Energy x-ray Absorptiometry (DXA) in 73 patients with complex CHD (mean age 35.8 ± 14.3, women n = 22) and 73 age and sex matched controls. Patients fulfilling criteria for low skeletal muscle mass in relation to their height and fat mass were defined as sarcopenic.
Results
Male patients (n = 51) were shorter (177.4 ± 6.6 cm vs. 180.9 ± 6.7 cm, p = 0.009) and weighed less (76.0 ± 10.8 kg vs. 82.0 ± 12.4 kg, p = 0.01) than controls. Also, patients had a lower appendicular lean mass-index (ALM-index) (7.57 ± 0.97 kg/mvs. 8.46 ± 0.90 kg/m, p < 0.001). Patients\' relative tissue fat mass (27.9 ± 7.0% vs. 25.4 ± 8.6%, p = 0.1) did not differ. Forty-seven percent of the men (n = 24) were classified as sarcopenic. Female patients (n = 22) were also shorter (163.5 ± 8.7 cm vs. 166.7 ± 5.9 cm, p = 0.05) but had a higher BMI (25.7 ± 4.2 vs. 23.0 ± 2.5, p = 0.02) than controls. Patients also had a lower ALM-index (6.30 ± 0.75 vs. 6.67 ± 0.55, p = 0.05), but their relative body fat mass (40.8 ± 7.6% vs. 32.0 ± 7.0%, p < 0.001) were higher. Fifty-nine percent of the women (n = 13) were classified as sarcopenic.
Conclusions
The body composition was altered toward lower skeletal muscle mass in patients with complex CHD. Approximately half of the patients were classified as sarcopenic. Contrary to men, the women had increased body fat and a higher BMI. Further research is required to assess the cause, possible adverse long-term effects and whether sarcopenia is preventable or treatable.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:57-62
Sandberg C, Johansson K, Christersson C, Hlebowicz J, Thilén U, Johansson B
Int J Cardiol: 30 Nov 2019; 296:57-62 | PMID: 31230936
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Abstract

Lipid levels achieved after a first myocardial infarction and the prediction of recurrent atherosclerotic cardiovascular disease.

Ohm J, Hjemdahl P, Skoglund PH, Discacciati A, ... Jernberg T, Svensson P
Background
Low density lipoprotein cholesterol (LDL-C) goals post-myocardial infarction (MI) are debated, and the significance of achieved blood lipid levels for predicting a first recurrent atherosclerotic cardiovascular disease (rASCVD) event post-MI is unclear.
Methods
This was a cohort study on first-ever MI survivors aged ≤76 years attending 4-14 week revisits throughout Sweden 2005-2013. Personal-level data was collected from SWEDEHEART and linked national registries. Exposures were quintiles of LDL-C, high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TGs) at the revisit. Group level associations with rASCVD (nonfatal MI or coronary heart disease death or fatal or nonfatal ischemic stroke) were estimated in Cox regression models. Predictive capacity was estimated by differences in C-statistic, integrated discriminatory improvement, and net reclassification improvement when adding each blood lipid to a validated risk prediction model.
Results
25,643 patients, 96.9% on statin therapy, were followed during a mean of 4.1 years. rASCVD occurred in 2173 patients (8.5%). For LDL-C and TC, moderate associations with rASCVD were observed only in the 5th vs. the lowest (referent) quintiles. For TGs and HDL-C increased risks were observed in quintiles 3-5 vs. the lowest. Minor predictive improvements were observed when lipid fractions were added to the risk model but the discrimination overall was poor (C-statistics <0.6).
Conclusions
Our data question the importance of LDL-C levels achieved at first revisit post-MI for decisions on continued treatment intensity considering the weak association with rASCVD observed in this post-MI cohort.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:1-7
Ohm J, Hjemdahl P, Skoglund PH, Discacciati A, ... Jernberg T, Svensson P
Int J Cardiol: 30 Nov 2019; 296:1-7 | PMID: 31303394
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Abstract

ACUTE HF score, a multiparametric prognostic tool for acute heart failure: A real-life study.

Cameli M, Pastore MC, De Carli G, Henein MY, ... Valente S, Mondillo S
Background
Acute heart failure (AHF) is the first cause of hospitalization for over-65 individuals, associated with high mortality and readmission rate. The aim of this study was to assess the prognostic value of a multiparametric score combining clinical, biochemical and echocardiographic indexes in AHF for clinical practice.
Methods
830 patients hospitalized for AHF were enrolled. Exclusion criteria were: active neoplasms; previous heart transplantation or left ventricular assist device implantation. Different variables were analyzed: etiology of AHF, clinical and biochemical data, lung congestion on chest-X ray, echocardiographic parameters and administered therapy. The endpoints were: all-cause mortality at 30 days, 6 months and 5 years and the duration of hospitalization.
Results
771 patients met eligibility criteria. Using the univariate and multivariate analysis the indexes with the best correlation with outcome were discretized and used to create the ACUTE HF score, computed as: 1.4*[serum creatinine>2 mg/dl] + 0.8*[ejection fraction<30] + 0.7*[age > 76] + 0.7*[prior hospitalization for AHF] + 0.9*[prior stroke/transient ischemic attack] + 0.5*[more than moderate mitral regurgitation] + 0.8*[use of non-invasive ventilation] and used to divide patients into 3 groups according to the risk of 6-months mortality. With the receiver operating curves and Kaplan-Meier analysis, this score proved to have a high predictive power for mortality at 30 days, 6 months and 5 years from hospitalization, and for event-free survival rates, providing a risk stratification capability superior to that of single variables.
Conclusions
The ACUTE HF score could be a complete and useful tool for assessing prognosis of AHF patients. It could represent a step in the long standardization pathway of prognostic protocols for AHF.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:103-108
Cameli M, Pastore MC, De Carli G, Henein MY, ... Valente S, Mondillo S
Int J Cardiol: 30 Nov 2019; 296:103-108 | PMID: 31324396
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Abstract

Managed Care after Acute Myocardial Infarction (MC-AMI) - a Poland\'s nationwide program of comprehensive post-MI care - improves prognosis in 12-month follow-up. Preliminary experience from a single high-volume center.

Wita K, Wilkosz K, Wita M, Kułach A, ... Turski M, Szydło K
Background
Despite progress in the treatment of acute myocardial infarction (AMI), long-term prognosis in MI survivors remains a challenge. The Managed Care in Acute Myocardial Infarction (MC-AMI, KOS-zawal) is the first program of a comprehensive, supervised care for patients with AMI to improve long-term prognosis. It includes acute intervention, complex revascularization, cardiac rehabilitation (CR), outpatient follow-up, and prevention of SCD. Our aim was to assess the relation between participation in MC-AMI and major adverse cardiovascular and cerebrovascular events (MACCE) in 12-month follow-up.
Methods and results
In this single-center, retrospective analysis we compared 719 patients participating in MC-AMI and compared them to 1130 subjects in the control group. After propensity score matching, two groups of 529 subjects each were compared. MC-AMI was related with MACCE reduction by 40% in a 12-month observation. Participants of MC-AMI had a higher adherence to cardiac rehabilitation (98 vs. 14%), higher rate of scheduled revascularisation (coronary artery bypass grafting: 9.8% vs. 4.9%, p ≪ 0.001; elective percutaneous coronary intervention: 3.0% vs 2.1%, p ≪ 0.05) and ICD implantation (2.8% vs. 0.6%, p ≪ 0.05) compared to control. Multivariable Cox regression analysis revealed MC-AMI to be inversely associated with the occurrence of MACCE (HR = 0.500, 95% Cl 0.349-0.718, p ≪ 0.001). Besides, older age, diabetes mellitus, hyperlipidemia, prior PAD, previous UA, and lower LVEF were significantly associated with the primary endpoint.
Conclusions
MC-AMI is the first program of comprehensive care for AMI patients. MC-AMI improves prognosis by increasing the rate of patients undergoing CR, complete revascularization and ICD implantation, thus reducing MACCE.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:8-14
Wita K, Wilkosz K, Wita M, Kułach A, ... Turski M, Szydło K
Int J Cardiol: 30 Nov 2019; 296:8-14 | PMID: 31256995
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Abstract

Exposure to second hand smoke and 10-year (2002-2012) incidence of cardiovascular disease in never smokers: The ATTICA cohort study.

Critselis E, Panagiotakos DB, Georgousopoulou EN, Katsaounou P, ... Pitsavos C,
Background
Despite WHO Framework Convention of Tobacco Control (FCTC) adoption, effective implementation of national smoking bans remains pending in several countries. This study quantified the association of second hand smoke (SHS) exposure and 10-year cardiovascular disease (CVD) among never smokers in such settings.
Methods
In 2001-2002, a sample of 1514 males and 1528 females (range: 18-89 years old) were randomly selected in Greece. Frequency and duration of SHS exposure (i.e. exposure extending >30 min/day) within the home and/or workplace were assessed by interview. Following a 10-year follow-up period (2002-2012), incidence of non-fatal and fatal CVD (ICD-10) was evaluated among n = 2020 participants. The analytic study sample consisted of all never smokers (n = 910).
Results
Despite national smoking ban implementation (2009), 44.6% (n = 406) of never smokers reported SHS exposure. While SHS exposed never smokers exhibited a more favorable profile of CVD-related risk factors at baseline, they subsequently developed similar 10-year CVD incidence rates, at a younger mean age (p = 0.001), than their non-exposed counterparts. Following adjustment for several lifestyle and clinical factors, SHS exposed never smokers exhibited a two-fold elevated 10-year CVD risk (adj. HR: 2.04, 95% CI: 1.43-2.92), particularly among women (adj. HR: 2.45, 95% CI: 1.45-4.06). SHS exposure accounted for 32% excess Population Attributable Risk (PAR) for 10-year CVD events in never smokers, with highest rates (PAR: 52%) being among those exposed in the workplace.
Conclusion
The prevention of SHS associated CVD and related healthcare costs mandates additional strategies for securing the effective implementation of comprehensive WHO FCTC based national smoking bans.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:29-35
Critselis E, Panagiotakos DB, Georgousopoulou EN, Katsaounou P, ... Pitsavos C,
Int J Cardiol: 14 Nov 2019; 295:29-35 | PMID: 31375335
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Abstract

Diagnosis of immune checkpoint inhibitor-associated myocarditis: A systematic review.

Pradhan R, Nautiyal A, Singh S
Background
Myocarditis is a rare but severe adverse event associated with immune checkpoint inhibitors, its diagnosis depending on a high index of suspicion and appropriate investigations. Our objective was to systematically review the diagnostic approaches to myocarditis associated with immune checkpoint inhibitors.
Methods
The systematic review was conducted according to the PRISMA guidelines (PROSPERO Registration: CRD42018097247). We searched Medline and Embase for case reports, case series, and observational studies published in journal articles or presented as conference abstracts that describe patients who developed myocarditis after immune checkpoint inhibitor therapy.
Results
After a review of 2326 citations, we included 88 cases (53 case reports/series published in journal articles and 35 cases in the observational study). Serum troponin was elevated in 98% of the case reports and 94% of participants in the observational study. ST changes including ST elevation were present in almost a third of case reports. Echocardiography revealed preserved left ventricular ejection fraction in 32% of case reports and 51% of cases in the observational study; however, preserved systolic function did not predict greater survival. Patients who suffered poorer prognosis tended to have major conduction defects or ventricular arrhythmias more frequently than patients who did not. Acute myocardial ischemia was ruled out in all cases (n = 31) when the diagnostic workup included coronary angiography.
Conclusions
Immune checkpoint inhibitor-associated myocarditis is characterized by elevation of cardiac troponin levels and non-specific electrocardiographic changes. Early coronary angiography may distinguish it from myocardial ischemia or myocardial infarction.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:113-121
Pradhan R, Nautiyal A, Singh S
Int J Cardiol: 30 Nov 2019; 296:113-121 | PMID: 31327516
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Impact:
Abstract

Cardiac troponin elevations in marathon runners. Role of coronary atherosclerosis and skeletal muscle injury. The MaraCat Study.

Paana T, Jaakkola S, Bamberg K, Saraste A, ... Pettersson K, Airaksinen KEJ
Background
Marathon running is associated with transient risk of sudden cardiac death and high cardiac troponin levels are common after race. There is limited data whether coronary atherosclerosis or skeletal muscle injury are related to troponin release caused by strenuous exercise. We aimed to assess whether coronary artery calcification (CAC), plaque vulnerability or skeletal muscle injury relate to cardiac troponin T (cTnT) elevations after marathon race.
Methods
In this observational study, 40 male runners participating in Paavo Nurmi 2018 Marathon were recruited with an open email invitation to evaluate the prevalence of post-race cTnT elevations and their predictors. In addition to baseline and post-race laboratory investigations, 28 runners aged >44 years underwent CAC measurement with computed tomography. Coronary plaque vulnerability was evaluated by free pregnancy-associated plasma protein A (fPAPP-A) concentration and skeletal muscle injury by skeletal troponin I (skTnI) measurement.
Results
The post-marathon cTnT concentrations rose above the normal reference limit in 38 (95%) participants. A 10-fold increase in skTnI concentrations was observed and elevated post-race values were seen in all participants. The correlation between the post-race cTnT and post-race skTnI (r = -0.26, p = 0.11) was non-significant. CAC was detected (Agatston score > 0) in 15 (53.6%) participants, with a median score of 2.0 (interquartile range [IQR] 80). There was no correlation between cTnT with CAC score or post-race fPAPP-A levels.
Conclusions
Asymptomatic cardiac troponin elevations are common after prolonged strenuous exercise, but are not related to markers of coronary atherosclerosis, plaque vulnerability or skeletal muscle injury.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:25-28
Paana T, Jaakkola S, Bamberg K, Saraste A, ... Pettersson K, Airaksinen KEJ
Int J Cardiol: 14 Nov 2019; 295:25-28 | PMID: 31420104
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Impact:
Abstract

Prognostic value of cardiac metaiodobenzylguanidine imaging and QRS duration in implantable cardioverter defibrillator patients with and without heart failure.

Kawasaki M, Yamada T, Morita T, Furukawa Y, ... Sakata Y, Fukunami M
Background
Cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with heart failure (HF). Recent studies showed that the highest rate of ventricular tachyarrhythmias (VTs) is seen in HF patients with an intermediate decrease in MIBG uptake, rather than in those with the lowest values. However, prolonged QRS duration (QRSd) has been shown to be associated with VTs in HF patients. This study assessed the prognostic value of the combination of an intermediate decrease in MIBG uptake and prolonged QRSd for predicting VTs in patients with implantable cardioverter defibrillators (ICDs) in relation to the presence of heart failure (HF).
Methods and results
A total of 196 outpatients with ICDs (age: 64 ± 14 years, male: 81%, left ventricular ejection fraction [LVEF]: 49% ± 16%) were prospectively enrolled; 135 had HF (NYHA class: 2.0 ± 0.6). At entry, cardiac MIBG imaging was performed, and QRSd was measured on standard 12‑lead electrocardiography. An intermediate decrease in the heart-to-mediastinum ratio on the delayed planar image (ID-H/M) was defined as 1.40-1.89. During the 3.3 ± 2.2-year follow-up, 59 patients had appropriate ICD discharges (ATx) for VTs. On multivariate Cox analysis, ID-H/M and prolonged QRSd (≥147 ms) were significantly and independently associated with ATx. In both patients with and without HF, ATx were significantly more frequent in patients with ID-H/M and/or prolonged QRSd than in those with neither (with HF: 40% vs. 14%, p = 0.020; without HF: 43% vs. 10%, p = 0.0028).
Conclusions
The combination of ID-H/M and prolonged QRSd provided more prognostic information for predicting VTs in ICD patients, with and without HF.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:164-171
Kawasaki M, Yamada T, Morita T, Furukawa Y, ... Sakata Y, Fukunami M
Int J Cardiol: 30 Nov 2019; 296:164-171 | PMID: 31371118
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Impact:
Abstract

Oral anticoagulation for subclinical atrial tachyarrhythmias detected by implantable cardiac devices: an international survey of the AF-SCREEN Group.

Boriani G, Healey JS, Schnabel RB, Lopes RD, ... Camm JA, Freedman B
Aims
At present, there is little evidence on how to treat subclinical atrial fibrillation (SCAF) or atrial high rate episodes (AHREs) detected by cardiac implantable electronic devices (CIEDs). Our aim was to assess current practice around oral anticoagulation (OAC) in such patients.
Methods
A web-based survey undertaken by 310 physicians: 59 AF-SCREEN International Collaboration members and 251 non-members.
Results
In patients with SCAF/AHRE and a CHADSVASc ≥ 2 in males or ≥ 3 in female the amount of SCAF/AHRE triggering use of OAC was variable but <2% of respondents considered that no AHRE would require OAC. Around one third (34%) considered SCAF/AHRE duration of >5-6 min as the basis for OAC prescription, while 16% and 18% required a burden of at least 5.5 h or 24 h, respectively. The propensity to prescribe OAC for a low burden of AHREs differed according to certain respondent characteristics (greater propensity to prescribe OAC for neurologists). When the clinical scenario included a prior stroke or a prior cardioembolic stroke, stated prescription of OAC was very high. More than 96% felt that any SCAF/AHRE should be treated with OAC.
Conclusions
There is substantial heterogeneity in the perception of the risk of stroke/systemic embolism associated with SCAF/AHRE of variable duration. The threshold of AHRE burden that would trigger initiation of OAC is highly variable, and differs according to the clinical scenario (lower threshold in case of previous stroke). Ongoing trials will clarify the real benefit and risk/benefit ratio of OAC in this specific clinical setting.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:65-70
Boriani G, Healey JS, Schnabel RB, Lopes RD, ... Camm JA, Freedman B
Int J Cardiol: 30 Nov 2019; 296:65-70 | PMID: 31327519
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Impact:
Abstract

Significance of the CAPRI risk score to predict heart failure hospitalization post-TAVI: The CAPRI-HF study.

Harbaoui B, Durand E, Dupré M, Rabilloud M, ... Eltchaninoff H, Lantelme P
Background
Predictors of heart failure (HF) hospitalization after transcatheter aortic valve implantation (TAVI) are not well defined. CAPRI is a score for predicting 1-year post-TAVI cardiovascular and all-cause mortality. The aim of the present study is to assess the prognostic significance of the CAPRI score for HF hospitalization 1 year after TAVI.
Methods and results
CAPRI-HF is an ancillary study of the C4CAPRI trial, analyzing 409 consecutive patients treated by TAVI. The primary outcome was hospitalization for HF during the first year post-intervention. The prognostic value of the CAPRI score was assessed by multivariable analysis adjusted for diabetes, atrial fibrillation, vascular route, pacemaker implantation, post-TAVI aortic regurgitation, transfusion and pulmonary artery systolic pressure. A subanalysis focused on patients with low-gradient aortic stenosis (LGAS). At 1 year, HF hospitalization occurred in 78 (19.9%) patients. Patients with HF were more prone to have diabetes, atrial fibrillation, renal dysfunction, lower mean aortic gradient, higher logistic EuroSCORE and higher CAPRI score (p < .05 for all associations). In the multivariable analysis, CAPRI score was the sole predictor of HF: hazard ratio (HR) for each 0.1 CAPRI score increase was 1.065, 95% confidence interval (CI) 1.021-1.110. This was confirmed when adjusted for EuroSCORE: HR 1.066, 95% CI 1.024-1.110. The predictive power of the CAPRI score increased for LGAS: HR 1.098, 95% CI 1.028-1.172.
Conclusions
CAPRI score helps predict HF post-TAVI. Including the score in the decision-making process may help selecting candidates for TAVI and identifying patients who need close monitoring post-procedure.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:98-102
Harbaoui B, Durand E, Dupré M, Rabilloud M, ... Eltchaninoff H, Lantelme P
Int J Cardiol: 30 Nov 2019; 296:98-102 | PMID: 31455517
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Impact:
Abstract

False-positive stress echocardiograms: Predictors and prognostic relevance.

Rachwan RJ, Mshelbwala FS, Dardari Z, Batal O
Background
Recent studies indicate that the pretest likelihood of significant coronary artery disease (CAD) (≥50% luminal stenosis) is over-estimated and that the frequency and severity of positive stress tests have been decreasing. This suggests an increased prevalence of false-positive (FP) stress tests. The aims of this retrospective study were to investigate the predictors of FP stress echocardiography (SE) and to compare the outcomes of patients with FP results to those with true-positive (TP) results.
Methods
Patients who underwent SE between 2013 and 2017 in a tertiary-care center were reviewed. Included were patients aged ≥40years who had cardiac catheterization (CC) within 1year of the index stress test. SE was considered FP if a new or worsening wall motion abnormality was present in the absence of significant corresponding CAD.
Results
Of the 5100 patients with SE, 1069 satisfied inclusion criteria. A total of 305 patients had positive SE results; of which 162 (53%) were FP. Logistic regression revealed that female gender (p=0.009), the absence of diabetes (p=0.03), the absence of a personal history of CAD (p=0.004), and lower stress WMSI (p=0.03) were independently associated with FP results. Patients with FP results on SE had similar all-cause mortality to those with TP results.
Conclusions
Accounting for predictors of FP findings on SE could improve the interpretation of SE results and limit the use of unnecessary CC. Furthermore, patients with FP results on SE could benefit from aggressive risk factor control and careful clinical follow-up.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:157-163
Rachwan RJ, Mshelbwala FS, Dardari Z, Batal O
Int J Cardiol: 30 Nov 2019; 296:157-163 | PMID: 31477317
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Impact:
Abstract

Loss of Rubicon ameliorates doxorubicin-induced cardiotoxicity through enhancement of mitochondrial quality.

Liu X, Zhang S, An L, Wu J, ... He L, Zhu H
Background
The therapeutic potential of doxorubicin (DOX) is limited by cardiotoxicity. Rubicon is an inhibitory interacting partner of autophagy protein UVRAG. Currently, the role of Rubicon in DOX-induced cardiotoxicity is unknown. In this study, we test the hypothesis that loss of Rubicon attenuates DOX-induced cardiotoxicity.
Methods
A mouse model of acute DOX-induced cardiotoxicity was established by a single intraperitoneal injection of DOX at a dose of 20 mg/kg. Rubicon expression was detected by Western blot. Cardiac damage was determined by measuring activities of lactate dehydrogenase and myocardial muscle creatine kinase in the serum, cytoplasmic vacuolization, collagen deposition, ROS levels, ATP content and mitochondrial damage in the heart. Cardiac morphometry and function were assessed by echocardiography. Markers for autophagy, mitophagy and mitochondrial dynamics were evaluated by Western blot and real time reverse transcription polymerase chain reaction.
Results
Rubicon expression was reduced in the heart 16 h after DOX treatment. DOX induced accumulation of cytoplasmic vacuolization and collagen, increased serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, enhanced ROS levels, reduced ATP content, pronounced mitochondrial damage and greater left ventricular wall thickness in wild type mice, which were mitigated by Rubicon deficiency. Mechanistically, loss of Rubicon improved DOX-induced impairment of autophagic flux, Parkin-mediated mitophagy and mitochondrial fission and fusion in the heart.
Conclusions
Loss of Rubicon ameliorates DOX-induced cardiotoxicity through enhancement of mitochondrial quality by improving autophagic flux, mitophagy and mitochondrial dynamics. Rubicon is a potential molecular target for prevention and therapy of DOX cardiotoxicity.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:129-135
Liu X, Zhang S, An L, Wu J, ... He L, Zhu H
Int J Cardiol: 30 Nov 2019; 296:129-135 | PMID: 31439425
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Impact:
Abstract

Gene therapy for atrial fibrillation - How close to clinical implementation?

Trivedi A, Hoffman J, Arora R

In this review we examine the current state of gene therapy for the treatment of cardiac arrhythmias. We describe advances and challenges in successfully creating and incorporating gene vectors into the myocardium. After summarizing the current scientific research in gene transfer technology we then focus on the most promising areas of gene therapy, the treatment of atrial fibrillation and ventricular tachyarrhythmias. We review the scientific literature to determine how gene therapy could potentially be used to treat patients with cardiac arrhythmias.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:177-183
Trivedi A, Hoffman J, Arora R
Int J Cardiol: 30 Nov 2019; 296:177-183 | PMID: 31439427
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Impact:
Abstract

Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction.

Vergaro G, Aimo A, Prontera C, Ghionzoli N, ... Passino C, Emdin M
Background
Evidence of sympathetic and renin-angiotensin-aldosterone system activation provided a rationale for neurohormonal antagonism in heart failure with reduced ejection fraction (HFrEF), while no data are available in patients with milder degree of systolic dysfunction. We aimed to investigate neurohormonal function in HF with preserved and mid-range EF (HFpEF/HFmrEF).
Methods
Three cohorts (n = 189/each) of stable HFpEF, HFmrEF and HFrEF patients were selected (median age 70, 67 and 67 years; male 56%, 73% and 74%, respectively). Patients received a baseline clinical assessment including plasma renin activity (PRA), aldosterone, catecholamines, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) assays, and were followed-up for all-cause death.
Results
Neuroendocrine profile was similar between HFpEF and HFmrEF, while all neurohormones except epinephrine were higher in HFrEF than in HFmrEF (NT-proBNP 2332 ng/L, IQR 995-5666 vs 575 ng/L, 205-1714; PRA 1.7 ng/mL/h, 0.4-5.6 vs 0.6 ng/mL/h, 0.2-2.6; aldosterone 153 ng/L, 85-246 vs 113 ng/L, 72-177; norepinephrine 517 ng/L, 343-844 vs 430 ng/L, 259-624; all p < 0.001, epinephrine 31 ng/L, 10-63 vs 25 ng/L, 10-44; p = 0.319). These findings were unrelated to treatment heterogeneity. Ten percent of HFpEF patients had elevated PRA, aldosterone and norepinephrine vs. 8% in HFmrEF and 21% in HFrEF. During a 5-year follow-up, survival decreased with the number of neurohormones elevated (HFpEF: log-rank 7.8, p = 0.048; HFmrEF: log-rank 11.8, p = 0.008; HFrEF: log-rank 8.1, p = 0.044).
Conclusions
Neurohormonal activation is present only in a subset of patients with HFpEF and HFmrEF, and may hold clinical significance. Neurohormonal antagonism may be useful in selected HFpEF/HFmrEF population.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:91-97
Vergaro G, Aimo A, Prontera C, Ghionzoli N, ... Passino C, Emdin M
Int J Cardiol: 30 Nov 2019; 296:91-97 | PMID: 31443984
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Abstract

Cardiovascular Disease and hospital admissions in African immigrants and former Soviet Union immigrants: A retrospective cohort study.

Reuven Y, Shvartzman P, Dreiher J
Background
Previous studies reported low prevalence of cardiovascular disease (CVD) despite an increasing prevalence of metabolic abnormalities in immigrants who moved from low CVD-risk regions to Western countries. Nevertheless, little is known about hospital admissions due to CVD in immigrants.
Methods
A retrospective cohort study of East Africa immigrants (EAI), Former Soviet Union immigrants (FSUI) and native-born Israelis (NBI) over 11-year period. Associations between ethnicity, age, sex, CVD, and hospital admission were assessed using logistic and Poisson regression models. Incidence density rates per person-years were calculated.
Results
The age-adjusted prevalence rates of ischemic heart disease in EAI, FSUI and NBI, respectively, were 1.8%, 8.2%, and 5.8%, respectively (p < 0.001). The corresponding rates for stroke were 2.6%, 3.5%, and 2.5%, respectively. Multivariate odds ratios for all CVD were found to be significantly lower in EAI for both sexes. Hospitalizations rate due to CVD were 9, 17, and 6 per 1000 person-years in EAI, FSUI and NBI, respectively (p < 0.001). EAI were more likely to be hospitalized due to hypertensive disease, cerebral vascular diseases and heart disease, in comparison to NBI and FSUI. However, when controlling for CVD risk factors profile, EAI had similar admission rates to NBI. EAI were more likely to be hospitalized in internal medicine, geriatrics, and neurology departments, and less likely to be admitted to intensive care units or surgical department.
Conclusions
EAI had low rates of all types of CVD, and low risk of hospitalization after controlling for CVD risk factors profile.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:172-176
Reuven Y, Shvartzman P, Dreiher J
Int J Cardiol: 30 Nov 2019; 296:172-176 | PMID: 31477314
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Impact:
Abstract

Usefulness of dual imaging stress echocardiography for the diagnosis of coronary allograft vasculopathy in heart transplant recipients.

Pichel IÁ, Fernández Cimadevilla OC, de la Hera Galarza JM, Pasanisi E, ... Sicari R, Fernández MM
Background
Coronary allograft vasculopathy (CAV) is the main factor limiting long-term survival after cardiac transplantation. Dual imaging stress echocardiography with wall motion and Doppler-derived coronary flow reserve (CRF) of the left anterior descending artery (LAD) is a state-of-the-art methodology during dipyridamole stress echocardiography (DiSE). This study involving 74 heart transplanted patients has the purpose to assess the diagnostic value of dipyridamole stress echocardiography with evaluation of wall motion (WM) and Doppler-derived coronary flow reserve for the diagnosis of coronary allograft vasculopathy.
Methods and results
All patients underwent DiSE and coronary angiography. Moderate-severe CAV was defined according to International Society of Heart and Lung Transplant (ISHLT) recommended nomenclature for CAV, and CFR < 2 was considered to be impaired. Moderate-severe CAV was present in 11 patients. WM analysis revealed four patients (5%) with rest WM abnormalities. CFR analysis revealed that 40 (54%) individuals had an abnormal result. The combined evaluation of WM analysis and CFR resulted in a sensitivity of 72.7% (95% CI: 39.3 to 92.6%), a specificity of 49.2% (95% CI: 36.5 to 61.9%), a positive predictive value of 20% (95% CI: 9.6 to 36.1%), and negative predictive value of 91.1% (95% CI: 75.1 to 97.6%) for the diagnosis of CAV.
Conclusions
Our results support the inclusion of DiSE performance in Heart transplant follow up protocol. The addition of CFR evaluation offers valuable information to the angiography findings in the detection of CAV and could be helpful in selected patients to adjust the time and indications of coronary angiography.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:109-112
Pichel IÁ, Fernández Cimadevilla OC, de la Hera Galarza JM, Pasanisi E, ... Sicari R, Fernández MM
Int J Cardiol: 30 Nov 2019; 296:109-112 | PMID: 31324395
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Impact:
Abstract

The age-related blood pressure trajectories from young-old adults to centenarians: A cohort study.

Wang R, Vetrano DL, Liang Y, Qiu C
Background
Blood pressure (BP) trajectories among older adults, especially among the oldest-old, are still poorly characterized.
Objective
To investigate the longitudinal trajectories of four BP components with age and their potential influential factors.
Methods
This population-based prospective cohort study included 3315 participants (age 60-105 years, 64.6% women) who were regularly examined from 2001 to 2004 through 2013-2016. The longitudinal trajectories of systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) with age were estimated using linear mixed-effects models.
Results
Overall, SBP and PP increased with age until ∼80 years and then declined, whereas DBP and MAP decreased constantly after 60 years of age. The age-related BP trajectories varied by survival time, birth cohort, use of antihypertensive drugs, and heart disease. Specifically, people who survived <2 years after the last visit showed higher levels of BP components before ∼80 years, followed by steeper declines in SBP and PP. At the same age, people who were born earlier showed higher BP than those who were born later. People who used antihypertensive drugs had higher BP than those who did not until ∼80-90 years old, thereafter BP showed no significant difference. After ∼80 years old, people with heart disease showed steeper declines in SBP and PP than those without.
Conclusions
The late-life longitudinal BP trajectories with age vary with demographics, clinical conditions, and contextual factors. These findings may help better understand the age-dependent relationship of BP with health outcomes as well as help achieve optimal BP control in older people.
Perspectives
Competency in medical knowledge: Understanding the age-related blood pressure trajectories and potential influential factors may help improve blood pressure management in older people. Translational outlook 1: Blood pressure trajectories with age in older adults vary by birth cohort, survival time, antihypertensive therapy, and heart disease. The age-related blood pressure trajectories by birth cohorts are featured with lower blood pressure levels at the same age in more recent birth cohorts, which may partially reflect the improvement of blood pressure control over time. Translational outlook 2: The age-related blood pressure trajectories in the oldest old (e.g., age ≥ 85 years) are characterized by steeper and faster blood pressure declines associated with heart disease and short survival (e.g., <2 years). This may have implications for the optimal management of blood pressure as well as for the interpretation of the relationships between blood pressure and health outcomes (e.g., death) among the oldest old.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:141-148
Wang R, Vetrano DL, Liang Y, Qiu C
Int J Cardiol: 30 Nov 2019; 296:141-148 | PMID: 31443986
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Impact:
Abstract

Circular RNA expression alterations in extracellular vesicles isolated from murine heart post ischemia/reperfusion injury.

Ge X, Meng Q, Zhuang R, Yuan D, ... Fan H, Zhou X
Background
Increasing studies indicated the involvement of extracellular vesicles (EVs) in cardiovascular diseases. However, the role of circular RNAs (circRNAs) in cardiac EVs (cEVs) during ischemia/reperfusion (I/R) injury remain unclear.
Methods
We isolated the cEVs from I/R injured hearts and performed RNA sequencing (RNA-seq) to identify the profile of circRNA in cEVs and investigated their potential roles in I/R pathological process.
Results
Cardiac I/R induced a significantly elevated release of EVs in heart within 24 h. RNA-seq of cEVs identified 185 significantly differentially expressed (DE) circRNAs including 119 down-regulated and 66 up-regulated circRNAs in I/R group compared with the sham. GO and pathway analysis showed that these DE-circRNAs were associated with protein binding and kinase activator activity and mainly involved in the metabolic process. The circRNA-miRNA analysis exhibited the broad potentials of the DE-circRNAs to regulate target genes by acting on the miRNAs.
Conclusions
These findings revealed for the first time the specific expression pattern of circRNAs in EVs derived from sham and I/R heart tissues and provided some potential targets and pathways involving in I/R injury which may provide important evidences for the role of both circRNA and EVs in the pathology of cardiac I/R.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:136-140
Ge X, Meng Q, Zhuang R, Yuan D, ... Fan H, Zhou X
Int J Cardiol: 30 Nov 2019; 296:136-140 | PMID: 31466885
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Impact:
Abstract

Late clinical outcomes of unselected patients with diabetic mellitus and multi-vessel coronary artery disease.

Ebrahim MEBM, Dignan R, Femia G, Kim S, ... Juergens CP, French JK
Background
The Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-Vessel Disease (FREEDOM) clinical trial randomized only a proportion of screened patients with diabetes mellitus (DM) and multi-vessel disease (MVD).
Methods and results
We determined late rates of death, non-fatal myocardial infarction (MI) and stroke in all 430 patients with DM who had MVD identified on angiographic screening for the FREEDOM Trial, which recruited from June 2006 -March 2010 at Liverpool Hospital, Sydney, Australia. Mortality at 6 years [median] was 23% among 192 FREEDOM-eligible patients and 26% among 238 FREEDOM-ineligible patients, of whom 139 [58%] had prior. CABG (mortality 31%). Overall, 196 (45%) had percutaneous coronary intervention (PCI), 127 (30%) underwent coronary artery bypass grafting (CABG) (who were 4 years younger; p = 0.003), and 107 (25%) had neither procedure of whom 80 were considered unsuitable for revascularization. Mortality was 26% post-PCI 16%, post-CABG and 33% among those who did not undergo revascularization (p = 0.01). On multivariable analyses, factors associated with late mortality were older age, hypertension and not undergoing CABG (all p < 0.05). Factors associated with late MI were presented with an acute coronary syndrome, whereas patients that underwent treatment with either PCI or CABG had less late MI (all p < 0.05).
Conclusion
Among consecutive diabetic patients with MVD, at a median of 6-years CABG was associated with better survival and fewer non-fatal MI outcomes compared to PCI.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:21-25
Ebrahim MEBM, Dignan R, Femia G, Kim S, ... Juergens CP, French JK
Int J Cardiol: 30 Nov 2019; 296:21-25 | PMID: 31451306
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Impact:
Abstract

Final-year medical students\' knowledge of cardiac arrest and CPR: We must do more!

Baldi E, Contri E, Bailoni A, Rendic K, ... Hertenberger N, Böttiger BW
Background
Students are an important part of the community response to an out-of-hospital cardiac arrest (OHCA). If even schoolchildren now know cardio-pulmonary resuscitation (CPR), even more the reason a young doctor should know how to treat an OHCA. The aim of our study was to assess medical students\' knowledge of CPR and OHCA throughout Europe.
Methods
An online survey was given to final-year students by the Medical Student Associations of different countries.
Results
1012 medical students from 99 different universities and 14 different countries completed the questionnaire. A total of 82.2% attended a BLS or BLS/AED course, provided by the University in only 69.7% of cases. In 84.3% it was a mandatory part of their degree. A total of 78.6% felt able to rescue a person in OHCA. Only 49.3% knew that \'unresponsiveness\' and \'absence of normal breathing\' are sufficient for lay people to identify an OHCA, and less than half of those interviewed knew the incidence of OHCA in Europe and the decrease in chance of survival if CPR is not performed. The correct compression:ventilation ratio was known by 90.2%, the correct compression depth by 69.7%, whilst only 57.8% knew the right compression rate. In total, 69.7% knew that an AED must be used immediately when available, and only 57.2% recognized the AED symbol.
Conclusions
Medical students\' knowledge of cardiac arrest and CPR needs to be improved throughout Europe and we believe that BLS/AED training should be mandatory in all European Universities.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:76-80
Baldi E, Contri E, Bailoni A, Rendic K, ... Hertenberger N, Böttiger BW
Int J Cardiol: 30 Nov 2019; 296:76-80 | PMID: 31375334
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Impact:
Abstract

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes.

Schüpke S, Neumann FJ, Menichelli M, Mayer K, ... Kastrati A,
Background
The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain.
Methods
In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding.
Results
A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P = 0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P = 0.46).
Conclusions
Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups. (Funded by the German Center for Cardiovascular Research and Deutsches Herzzentrum München; ISAR-REACT 5 ClinicalTrials.gov number, NCT01944800.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 16 Oct 2019; 381:1524-1534
Schüpke S, Neumann FJ, Menichelli M, Mayer K, ... Kastrati A,
N Engl J Med: 16 Oct 2019; 381:1524-1534 | PMID: 31475799
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Impact:
Abstract

20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia.

Luirink IK, Wiegman A, Kusters DM, Hof MH, ... Kastelein JJP, Hutten BA
Background
Familial hypercholesterolemia is characterized by severely elevated low-density lipoprotein (LDL) cholesterol levels and premature cardiovascular disease. The short-term efficacy of statin therapy in children is well established, but longer follow-up studies evaluating changes in the risk of cardiovascular disease are scarce.
Methods
We report a 20-year follow-up study of statin therapy in children. A total of 214 patients with familial hypercholesterolemia (genetically confirmed in 98% of the patients), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected siblings. Participants completed a questionnaire, provided blood samples, and underwent measurements of carotid intima-media thickness. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents.
Results
Of the original cohort, 184 of 214 patients with familial hypercholesterolemia (86%) and 77 of 95 siblings (81%) were seen in follow-up; among the 214 patients, data on cardiovascular events and on death from cardiovascular causes were available for 203 (95%) and 214 (100%), respectively. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter (from 6.13 to 4.16 mmol per liter) - a decrease of 32% from the baseline level; treatment goals (LDL cholesterol <100 mg per deciliter [2.59 mmol per liter]) were achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in siblings (mean difference adjusted for sex, -0.0001 mm per year; 95% confidence interval, -0.0010 to 0.0008). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs. 26% and 0% vs. 7%, respectively).
Conclusions
In this study, initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. (Funded by the AMC Foundation.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 16 Oct 2019; 381:1547-1556
Luirink IK, Wiegman A, Kusters DM, Hof MH, ... Kastelein JJP, Hutten BA
N Engl J Med: 16 Oct 2019; 381:1547-1556 | PMID: 31618540
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Impact:
Abstract

Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn.

Spechler SJ, Hunter JG, Jones KM, Lee R, ... Biswas K, Huang GD
Background
Heartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine).
Methods
Patients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance-pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)-Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year.
Results
A total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P = 0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, -5 to 38; P = 0.17).
Conclusions
Among patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 16 Oct 2019; 381:1513-1523
Spechler SJ, Hunter JG, Jones KM, Lee R, ... Biswas K, Huang GD
N Engl J Med: 16 Oct 2019; 381:1513-1523 | PMID: 31618539
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Impact:
Abstract

The prognostic value of biventricular long axis strain using standard cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

Yang F, Wang J, Li Y, Li W, ... Han Y, Chen Y
Background
Long axis strain (LAS) is a parameter derived from standard cardiovascular magnetic resonance imaging. However, the prognostic value of biventricular LAS in hypertrophic cardiomyopathy (HCM) is unknown.
Methods
Patients with HCM (n = 384) and healthy volunteers (n = 150) were included in the study. Left ventricular (LV)-LAS was defined as the percentage change in the length measured from the epicardial border of the LV apex to the midpoint of a line connecting the mitral annulus at end-systole and end-diastole. Right ventricular (RV)-LAS represented the percentage change of length between epicardial border of the LV apex to the midpoint of a line connecting the tricuspid annulus at end-systole and end-diastole. The primary endpoint was a combination of all-cause death and sudden cardiac death aborted by appropriate implantable cardioverter-defibrillator discharge and cardiopulmonary resuscitation after syncope. The secondary endpoint was a combination of the primary endpoint and hospitalization for congestive heart failure.
Results
Twenty-nine patients (7.6%) achieved the primary endpoint, and the secondary endpoint occurred in 66 (17.2%) patients. In multivariate Cox regression analysis, RV-LAS was an independent prognostic factor for the primary (hazard ratio (HR), 1.13) and secondary (HR, 1.11) endpoints. In the subgroup of patients with a normal RV ejection fraction (EF) (>45.0%, n = 345), impaired RV-LAS was associated with adverse outcomes and might add incremental prognostic value to RVEF and tricuspid annular plane systolic excursion (TAPSE) (p < 0.01).
Conclusions
RV-LAS is an independent predictor of adverse prognosis in HCM in addition to RVEF and TAPSE.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Oct 2019; 294:43-49
Yang F, Wang J, Li Y, Li W, ... Han Y, Chen Y
Int J Cardiol: 31 Oct 2019; 294:43-49 | PMID: 31405582
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Impact:
Abstract

Story telling of myocarditis.

Zanatta A, Carturan E, Rizzo S, Basso C, Thiene G

Myocarditis was discovered as heart disease at autopsy with the use of microscope. In 1900, with the name of acute interstitial myocarditis, Carl Ludwig Alfred Fiedler first reported the history of a sudden cardiac heart failure, in the absence of coronary, valve, pericardial disease or classical specific infections with multiorgan involvement. He postulated a peculiar isolated acute inflammation of the myocardium with poor prognosis due to invisible microorganisms, which years later would have been identified as viruses. Subsequent revision of Fiedler original histologic slides by Schmorl showed cases with either lymphocytic or giant cell infiltrates. The in vivo diagnosis became possible with the right heart catheterism and endomyocardial biopsy. Employment of immunohistochemistry and molecular techniques improved the diagnosis and etiology identification. The mechanism of myocyte injury by coxsackie virus was identified in protease 2A coded by the virus and disrupting the dystrophin in the cytoskeleton. Both RNA and DNA viruses may be cardiotropic, and coxsackie and adenovirus share a common receptor (CAR). Unfortunately, vaccination is not yet available. Cardiac Magnetic Resonance is a revolutionary diagnostic tool by detecting edema, of myocardial inflammation. However endomyocardial biopsy remains the gold standard for etiological and histotype diagnosis, with limited sensitivity due to sampling error. Viral lymphocytic fulminant myocarditis may not be fatal and the employment of mechanical assistant device - ECMO in acute phase for temporary support may be lifesaving with good prognosis.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Oct 2019; 294:61-64
Zanatta A, Carturan E, Rizzo S, Basso C, Thiene G
Int J Cardiol: 31 Oct 2019; 294:61-64 | PMID: 31378380
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Impact:
Abstract

Clinical and procedural predictors and short-term survival of the patients with no reflow phenomenon after primary percutaneous coronary intervention.

Ashraf T, Khan MN, Afaque SM, Aamir KF, ... Khan AA, Karim M
Objectives
In the present study, we analysed the incidence of no-reflow phenomenon, its clinical and procedural predictors, and associated in-hospital outcomes for the patients undergoing primary percutaneous coronary intervention (PCI).
Background
No-reflow phenomenon after primary PCI is a procedural complication associated with adverse post-procedure outcomes.
Methods
Data for this study were extracted from global registry, NCDR®, the site of National Institute of Cardiovascular Disease (NICVD), Karachi from July 2017 to March 2018. The demographic, clinical, and procedural characteristics, and in-hospital outcomes were analysed for the patients with and without no-reflow after primary PCI.
Results
Of total of 3255 patients, no-reflow phenomenon was found in 132 (4.1%) patients and it was associated with significantly higher in-hospitality mortality (6.8% vs. 2.9%; p = 0.01), cerebrovascular accident (1.5% vs. 0%; p < 0.001), post procedure bleeding (2.3% vs. 0.5%; p = 0.009), and cardiogenic shock (3.8% vs. 1.2%; p = 0.011). The multivariate analysis showed advanced age [odds ratio = 1.63, 95% confidence interval 1.09-2.44, p = 0.018], diabetes [1.66, 1.14-2.42, p = 0.009], prior history of CABG [8.70, 1.45-52.04, p = 0.018], low pre-procedure TIMI flow grade [2.04, 1.3-3.21, p = 0.002], longer length of target lesion [1.51, 1.06-2.16, p = 0.023], and 10 fold raised troponin I [1.55, 1.08-2.23, p = 0.018] were the independent predictors of no-reflow.
Conclusions
In this selected group of patients, the no-reflow phenomenon after primary percutaneous coronary intervention is not that uncommon. It is associated with an increased risk of adverse post-procedure hospital course including mortality. Pathophysiology of the no-reflow phenomenon is complex and opaque, however, it can be predicted based on certain clinical and procedural characteristics.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Oct 2019; 294:27-31
Ashraf T, Khan MN, Afaque SM, Aamir KF, ... Khan AA, Karim M
Int J Cardiol: 31 Oct 2019; 294:27-31 | PMID: 31387823
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Impact:
Abstract

Heart failure risk predictions in adult patients with congenital heart disease: a systematic review.

Wang F, Harel-Sterling L, Cohen S, Liu A, ... Paradis G, Marelli AJ

To summarise existing heart failure (HF) risk prediction models and describe the risk factors for HF-related adverse outcomes in adult patients with congenital heart disease (CHD). We performed a systematic search of MEDLINE, EMBASE and Cochrane databases from January 1996 to December 2018. Studies were eligible if they developed multivariable models for risk prediction of decompensated HF in adult patients with CHD (ACHD), death in patients with ACHD-HF or both, or if they reported corresponding predictors. A standardised form was used to extract information from selected studies. Twenty-five studies met the inclusion criteria and all studies were at moderate to high risk of bias. One study derived a model to predict the risk of a composite outcome (HF, death or arrhythmia) with a c-statistic of 0.85. Two studies applied an existing general HF model to patients with ACHD but did not report model performance. Twenty studies presented predictors of decompensated HF, and four examined patient characteristics associated with mortality (two reported predictors of both). A wide variation in population characteristics, outcome of interest and candidate risk factors was observed between studies. Although there were substantial inconsistencies regarding which patient characteristics were predictive of HF-related adverse outcomes, brain natriuretic peptide, New York Heart Association class and CHD lesion characteristics were shown to be important predictors. To date, evidence in the published literature is insufficient to accurately profile patients with ACHD. High-quality studies are required to develop a unique ACHD-HF prediction model and confirm the predictive roles of potential risk factors.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1661-1669
Wang F, Harel-Sterling L, Cohen S, Liu A, ... Paradis G, Marelli AJ
Heart: 30 Oct 2019; 105:1661-1669 | PMID: 31350277
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Impact:
Abstract

Unique cardiovascular risk factors in women.

Young L, Cho L

Despite an overall reduction in cardiovascular disease (CVD) mortality in the USA, the rate of coronary heart disease and CVD mortality is on the rise in younger women aged 35 to 54 years. This has been attributed to an increasing prevalence of CVD risk factors, which can portend disparate outcomes in women versus men. Women with diabetes and those who smoke have an excess relative risk of CVD when compared with their male counterparts. In addition to these discrepancies in traditional risk factors, a number of clinical conditions unique to women have been shown to increase CVD risks such as pre-eclampsia, gestational diabetes, polycystic ovary syndrome, early menopause and autoimmune diseases. The majority of these sex-specific risk factors can be identified at an early age, allowing for aggressive risk factor modification through lifestyle changes and, in certain patients, medications. The recently published 2018 American College of Cardiology and American Heart Association (ACC/AHA) hypercholesterolaemia and 2019 ACC/AHA primary prevention guidelines reflect this, citing pre-eclampsia, early menopause and autoimmune diseases as \'risk enhancers\' that if present may favour initiation of statin therapy in borderline or intermediate risk patients. This comprehensive review addresses both traditional and unique risk factors of CVD in women, as well as sex-specific risk stratification and management options.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1656-1660
Young L, Cho L
Heart: 30 Oct 2019; 105:1656-1660 | PMID: 31315936
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Impact:
Abstract

Individualizing Revascularization Strategy for Diabetic Patients With Multivessel Coronary Disease.

Qintar M, Humphries KH, Park JE, Arnold SV, ... Cohen DJ, Spertus JA
Background
In patients with diabetes and multivessel coronary artery disease (CAD), the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that, on average, coronary artery bypass grafting (CABG) was superior to percutaneous coronary intervention (PCI) for major acute cardiovascular events (MACE) and angina reduction. Nonetheless, multivessel PCI remains a common revascularization strategy in the real world.
Objectives
To translate the results of FREEDOM to individual patients in clinical practice, risk models of the heterogeneity of treatment benefit were built.
Methods
Using patient-level data from 1,900 FREEDOM patients, the authors developed models to predict 5-year MACE (all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke) and 1-year angina after CABG and PCI using baseline covariates and treatment interactions. Parsimonious models were created to support clinical use. The models were internally validated using bootstrap resampling, and the MACE model was externally validated in a large real-world registry.
Results
The 5-year MACE occurred in 346 (18.2%) patients, and 310 (16.3%) had angina at 1 year. The MACE model included 8 variables and treatment interactions with smoking status (c = 0.67). External validation in stable CAD (c = 0.65) and ACS (c = 0.68) demonstrated comparable performance. The 6-variable angina model included a treatment interaction with SYNTAX score (c = 0.67). PCI was never superior to CABG, and CABG was superior to PCI for MACE in 54.5% of patients and in 100% of patients with history of smoking.
Conclusions
To help disseminate the results of FREEDOM, the authors created a personalized risk prediction tool for patients with diabetes and multivessel CAD that could be used in shared decision-making for CABG versus PCI by estimating each patient\'s personal outcomes with both treatments.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Oct 2019; 74:2074-2084
Qintar M, Humphries KH, Park JE, Arnold SV, ... Cohen DJ, Spertus JA
J Am Coll Cardiol: 21 Oct 2019; 74:2074-2084 | PMID: 31623766
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Impact:
Abstract

Guiding Therapy by Coronary CT Angiography Improves Outcomes in Patients With Stable Chest Pain.

Adamson PD, Williams MC, Dweck MR, Mills NL, ... Berry C,
Background
Within the SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) trial of patients with stable chest pain, the use of coronary computed tomography angiography (CTA) reduced the rate of death from coronary heart disease or nonfatal myocardial infarction (primary endpoint).
Objectives
This study sought to assess the consistency and mechanisms of the 5-year reduction in this endpoint.
Methods
In this open-label trial, 4,146 participants were randomized to standard care alone or standard care plus coronary CTA. This study explored the primary endpoint by symptoms, diagnosis, coronary revascularizations, and preventative therapies.
Results
Event reductions were consistent across symptom and risk categories (p = NS for interactions). In patients who were not diagnosed with angina due to coronary heart disease, coronary CTA was associated with a lower primary endpoint incidence rate (0.23; 95% confidence interval [CI]: 0.13 to 0.35 vs. 0.59; 95% CI: 0.42 to 0.80 per 100 patient-years; p < 0.001). In those who had undergone coronary CTA, rates of coronary revascularization were higher in the first year (hazard ratio [HR]: 1.21; 95% CI: 1.01 to 1.46; p = 0.042) but lower beyond 1 year (HR: 0.59; 95% CI: 0.38 to 0.90; p = 0.015). Patients assigned to coronary CTA had higher rates of preventative therapies throughout follow-up (p < 0.001 for all), with rates highest in those with CT-defined coronary artery disease. Modeling studies demonstrated the plausibility of the observed effect size.
Conclusions
The beneficial effect of coronary CTA on outcomes is consistent across subgroups with plausible underlying mechanisms. Coronary CTA improves coronary heart disease outcomes by enabling better targeting of preventative treatments to those with coronary artery disease. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Oct 2019; 74:2058-2070
Adamson PD, Williams MC, Dweck MR, Mills NL, ... Berry C,
J Am Coll Cardiol: 21 Oct 2019; 74:2058-2070 | PMID: 31623764
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Impact:
Abstract

Sex-Specific Thresholds of High-Sensitivity Troponin in Patients With Suspected Acute Coronary Syndrome.

Lee KK, Ferry AV, Anand A, Strachan FE, ... Mills NL,
Background
Major disparities between women and men in the diagnosis, management, and outcomes of acute coronary syndrome are well recognized.
Objectives
The aim of this study was to evaluate the impact of implementing a high-sensitivity cardiac troponin I assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome.
Methods
Consecutive patients with suspected acute coronary syndrome were enrolled in a stepped-wedge, cluster-randomized controlled trial across 10 hospitals. Myocardial injury was defined as high-sensitivity cardiac troponin I concentration >99th centile of 16 ng/l in women and 34 ng/l in men. The primary outcome was recurrent myocardial infarction or cardiovascular death at 1 year.
Results
A total of 48,282 patients (47% women) were included. Use of the high-sensitivity cardiac troponin I assay with sex-specific thresholds increased myocardial injury in women by 42% and in men by 6%. Following implementation, women with myocardial injury remained less likely than men to undergo coronary revascularization (15% vs. 34%) and to receive dual antiplatelet (26% vs. 43%), statin (16% vs. 26%), or other preventive therapies (p < 0.001 for all). The primary outcome occurred in 18% (369 of 2,072) and 17% (488 of 2,919) of women with myocardial injury before and after implementation, respectively (adjusted hazard ratio: 1.11; 95% confidence interval: 0.92 to 1.33), compared with 18% (370 of 2,044) and 15% (513 of 3,325) of men (adjusted hazard ratio: 0.85; 95% confidence interval: 0.71 to 1.01).
Conclusions
Use of sex-specific thresholds identified 5 times more additional women than men with myocardial injury. Despite this increase, women received approximately one-half the number of treatments for coronary artery disease as men, and outcomes were not improved. (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]; NCT01852123).

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 21 Oct 2019; 74:2032-2043
Lee KK, Ferry AV, Anand A, Strachan FE, ... Mills NL,
J Am Coll Cardiol: 21 Oct 2019; 74:2032-2043 | PMID: 31623760
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Impact:
Abstract

Efficacy and Safety of Ticagrelor Monotherapy in Patients Undergoing Multivessel PCI.

Takahashi K, Serruys PW, Chichareon P, Chang CC, ... Carrie D, Windecker S
Background
Data on optimal antiplatelet treatment regimens in patients who undergo multivessel percutaneous coronary intervention (PCI) are sparse.
Objectives
This post hoc study investigated the impact of an experimental strategy (1-month dual antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) versus a reference regimen (12-month DAPT followed by 12-month aspirin monotherapy) according to multivessel PCI.
Methods
The GLOBAL LEADERS trial is a prospective, multicenter, open-label, randomized controlled trial, allocating all-comer patients in a 1:1 ratio to either the experimental strategy or the reference regimen. The primary endpoint was the composite of all-cause death or new Q-wave myocardial infarction at 2 years. The secondary safety endpoint was Bleeding Academic Research Consortium type 3 or 5 bleeding.
Results
Among the overall study population (n=15,845), 3,576 patients (22.4%) having multivessel PCI experienced a significantly higher risk of ischemic and bleeding events at 2 years, compared to those having single-vessel PCI. There was an interaction between the experimental strategy and multivessel PCI on the primary endpoint (hazard ratio: 0.62; 95% confidence interval: 0.44 to 0.88; p = 0.031). This difference was largely driven by a lower risk of all-cause mortality. In contrast, the risk of Bleeding Academic Research Consortium type 3 or 5 bleeding was statistically similar between the 2 regimens (hazard ratio: 0.92; 95% confidence interval: 0.61 to 1.39; p = 0.754).
Conclusions
Long-term ticagrelor monotherapy following 1-month DAPT can favorably balance ischemic and bleeding risks in patients with multivessel PCI. These findings should be interpreted as hypothesis-generating and need to be replicated in future dedicated randomized trials. (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation; NCT01813435).

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 21 Oct 2019; 74:2015-2027
Takahashi K, Serruys PW, Chichareon P, Chang CC, ... Carrie D, Windecker S
J Am Coll Cardiol: 21 Oct 2019; 74:2015-2027 | PMID: 31623758
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Impact:
Abstract

Implanted Monitor Alerting to Reduce Treatment Delay in Patients With Acute Coronary Syndrome Events.

Holmes DR, Krucoff MW, Mullin C, Mikdadi G, ... John MS, Gibson CM
Background
Increased pre-hospital delay during acute coronary syndrome (ACS) events contributes to worse outcome.
Objectives
The purpose of this study was to assess the effectiveness of an implanted cardiac monitor with real-time alarms for abnormal ST-segment shifts to reduce pre-hospital delay during ACS events.
Methods
In the ALERTS (AngeLmed Early Recognition and Treatment of STEMI) pivotal study, subjects at high risk for recurrent ACS events (n = 907) were randomized to control (Alarms OFF) or treatment groups for 6 months, after which alarms were activated in all subjects (Alarms ON). Emergency department (ED) visits with standard-of-care cardiac test results were independently adjudicated as true- or false-positive ACS events. Alarm-to-door (A2D) and symptom-to-door (S2D) times were calculated for true-positive ACS ED visits triggered by 3 possible prompts: alarm only, alarms + symptoms, or symptoms only.
Results
The Alarms ON group showed reduced delays, with 55% (95% confidence interval [CI]: 46% to 63%) of ED visits for ACS events <2 h compared with 10% (95% CI: 2% to 27%) in the Alarms OFF group (p < 0.0001). Results were similar when restricted to myocardial infarction (MI) events. Median pre-hospital delay for MI was 12.7 h for Alarms OFF and 1.6 h in Alarms ON subjects (p < 0.0089). Median A2D delay was 1.4 h for asymptomatic MI. Median S2D delay for symptoms-only MI (no alarm) in Alarms ON was 4.3 h.
Conclusions
Intracardiac monitoring with real-time alarms for ST-segment shift that exceeds a subject\'s self-normative ischemia threshold level significantly reduced the proportion of pre-hospital delays >2 h for ACS events, including asymptomatic MI, compared with symptoms-only ED visits in Alarms OFF. (AngeLmed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 21 Oct 2019; 74:2047-2055
Holmes DR, Krucoff MW, Mullin C, Mikdadi G, ... John MS, Gibson CM
J Am Coll Cardiol: 21 Oct 2019; 74:2047-2055 | PMID: 31623762
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Impact:
Abstract

Bedside mental status and outcome in elderly patients admitted for acute coronary syndromes.

Briet C, Blanchart K, Lemaître A, Roux I, ... Roule V, Beygui F
Objective
We investigated whether mental status assessed by simple bedside tests in elderly patients admitted for acute coronary syndromes (ACS) was associated with higher risk of mortality.
Methods
We used the data from a prospective, open, ongoing cohort of patients≥75 years old admitted for ACS to a tertiary centre. Cognitive impairment (CogI) was defined by delirium detected by the Confusion Assessment Method or an abnormal Mini Mental State Examination score. A Cox model adjusted on predefined correlates of mortality was used to assess the relationship between CogI and 1-year mortality.
Results
Six-hundred consecutive patients with mental status assessment within 48 hours after admission were included. CogI was identified in 172 (29%) patients among whom 153 (25.5%) had an abnormal Mini Mental State Evaluation and 19 (3.2%) delirium. Death occurred in 49 (28.6%) patients with and 43 (10.5%) patients without CogI at 1 year. There was a significant association between CogI and 1-year mortality (adjusted-HR 2.4, 95% CI 1.53 to 3.62), p<0.001) independent of other covariables. CogI was also independently associated with higher rates of in-hospital bleeding and mortality as well as 3-month rates of all-cause, cardiovascular-related and heart failure-related rehospitalisation.
Conclusions
CogI detected by simple bedside tests in patients≥75 admitted for ACS is associated with an increased risk of 1-year mortality and 3 month rehospitalisation independent of other correlates of poor outcome.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1635-1641
Briet C, Blanchart K, Lemaître A, Roux I, ... Roule V, Beygui F
Heart: 30 Oct 2019; 105:1635-1641 | PMID: 31142593
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Impact:
Abstract

Climate changes and ST-elevation myocardial infarction treated with primary percutaneous coronary angioplasty.

Versaci F, Biondi-Zoccai G, Giudici AD, Mariano E, ... Federici M, Romeo F
Background
The impact of seasonal changes on the incidence of acute myocardial infarction has been incompletely appraised, especially in the modern era of primary percutaneous coronary intervention (PPCI). We aimed to appraise the overall and season-specific impact of climate changes on the daily rate of PCCI.
Methods
Details on PPCI and climate changes were retrospectively collected in three high-volume Italian institutions with different geographical features. The association between rate of PPCI and temperature, atmospheric pressure (ATM), humidity and rainfall was appraised with Poisson models, with overall analyses and according to season of the year.
Results
Details on 6880 days with a total of 4132 PPCI were collected. Overall adjusted analysis showed that higher minimum atmospheric pressure 3 days before PPCI were associated with lower risk (regression coefficient = 0.999 [95% confidence interval 0.998-1.000], p = 0.030). Focusing on season, in Winter PPCI rates were increased by lower same day mean temperature (0.973 [0.956-0.990], p = 0.002) and lower rainfall (0.980 [0.960-1.000], p = 0.049). Conversely, in Spring greater changes in atmospheric pressure 3 days before PPCI were associated with increased risk (1.023 [1.002-1.045], p = 0.032), with similar effects in Summer for minimum temperature on the same day (1.022 [1.001-1.044], p = 0.040).
Conclusions
Climate has a significant impact on the risk of PPCI in the current era, with a complex interplay according to season. Higher risk risk is expected with lower minimum atmospheric pressure in the preceding days, lower rainfall in Winter, greater changes in atmospheric pressure in Spring, and higher temperatures in Summer. These findings have important implications for prevention strategies.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Oct 2019; 294:1-5
Versaci F, Biondi-Zoccai G, Giudici AD, Mariano E, ... Federici M, Romeo F
Int J Cardiol: 31 Oct 2019; 294:1-5 | PMID: 31301864
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Impact:
Abstract

Higher left ventricular mass-wall stress-heart rate product and outcome in aortic valve stenosis.

Gerdts E, Saeed S, Midtbø H, Rossebø A, ... Bahlmann E, Devereux R
Objective
Whether increased myocardial oxygen demand could help explain the association of left ventricular (LV) hypertrophy with higher adverse event rate in patients with aortic valve stenosis (AS) is unknown.
Methods
Data from 1522 patients with asymptomatic mostly moderate AS participating in the Simvastatin-Ezetimibe in AS study followed for a median of 4.3 years was used. High LV mass-wall stress-heart rate product was identified as >upper 95% CI limit in normal subjects. The association of higher LV mass-wall stress-heart rate product with major cardiovascular (CV) events, combined CV death and hospitalised heart failure and all-cause mortality was tested in Cox regression analyses, and reported as HR and 95% CI.
Results
High LV mass-wall stress-heart rate product was found in 19% at baseline, and associated with male sex, higher body mass index, hypertension, LV hypertrophy, more severe AS and lower LV ejection fraction (all p<0.01). Adjusting for these confounders in time-varying Cox regression analysis, 1 SD higher LV mass-wall stress-heart rate product was associated with higher HR of major CV events (HR 1.16(95% CI 1.06 to 1.29)), combined CV death and hospitalised heart failure (HR 1.29(95% CI 1.09 to 1.54)) and all-cause mortality (HR 1.34(95% CI 1.13 to 1.58), all p<0.01).
Conclusion
In patients with initially mild-moderate AS, higher LV mass-wall stress-heart rate product was associated with higher mortality and heart failure hospitalisation. Our results suggest that higher myocardial oxygen demand is contributing to the higher adverse event rate reported in AS patients with LV hypertrophy.
Trial registration number
NCT000092677;Post-results.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1629-1633
Gerdts E, Saeed S, Midtbø H, Rossebø A, ... Bahlmann E, Devereux R
Heart: 30 Oct 2019; 105:1629-1633 | PMID: 31154431
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Impact:
Abstract

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling.

Naruse G, Kanamori H, Yoshida A, Minatoguchi S, ... Nishigaki K, Minatoguchi S
Aims
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production.
Methods and results
Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out.
Conclusions
Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

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

Cardiovasc Res: 31 Oct 2019; 115:1873-1885
Naruse G, Kanamori H, Yoshida A, Minatoguchi S, ... Nishigaki K, Minatoguchi S
Cardiovasc Res: 31 Oct 2019; 115:1873-1885 | PMID: 30629149
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Abstract

Inhibition of heat shock protein 70 blocks the development of cardiac hypertrophy by modulating the phosphorylation of histone deacetylase 2.

Yoon S, Kim M, Min HK, Lee YU, ... Eom GH, Kook H
Aims
Previously, we reported that phosphorylation of histone deacetylase 2 (HDAC2) and the resulting activation causes cardiac hypertrophy. Through further study of the specific binding partners of phosphorylated HDAC2 and their mechanism of regulation, we can better understand how cardiac hypertrophy develops. Thus, in the present study, we aimed to elucidate the function of one such binding partner, heat shock protein 70 (HSP70).
Methods and results
Primary cultures of rat neonatal ventricular cardiomyocytes and H9c2 cardiomyoblasts were used for in vitro cellular experiments. HSP70 knockout (KO) mice and transgenic (Tg) mice that overexpress HSP70 in the heart were used for in vivo analysis. Peptide-precipitation and immunoprecipitation assay revealed that HSP70 preferentially binds to phosphorylated HDAC2 S394. Forced expression of HSP70 increased phosphorylation of HDAC2 S394 and its activation, but not that of S422/424, whereas knocking down of HSP70 reduced it. However, HSP70 failed to phosphorylate HDAC2 in the cell-free condition. Phosphorylation of HDAC2 S394 by casein kinase 2α1 enhanced the binding of HSP70 to HDAC2, whereas dephosphorylation induced by the catalytic subunit of protein phosphatase 2A (PP2CA) had the opposite effect. HSP70 prevented HDAC2 dephosphorylation by reducing the binding of HDAC2 to PP2CA. HSP70 KO mouse hearts failed to phosphorylate S394 HDAC2 in response to isoproterenol infusion, whereas Tg overexpression of HSP70 increased the phosphorylation and activation of HDAC2. 2-Phenylethynesulfonamide (PES), an HSP70 inhibitor, attenuated cardiac hypertrophy induced either by phenylephrine in neonatal ventricular cardiomyocytes or by aortic banding in mice. PES reduced HDAC2 S394 phosphorylation and its activation by interfering with the binding of HSP70 to HDAC2.
Conclusion
These results demonstrate that HSP70 specifically binds to S394-phosphorylated HDAC2 and maintains its phosphorylation status, which results in HDAC2 activation and the development of cardiac hypertrophy. Inhibition of HSP70 has possible application as a therapeutic.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Cardiovasc Res: 31 Oct 2019; 115:1850-1860
Yoon S, Kim M, Min HK, Lee YU, ... Eom GH, Kook H
Cardiovasc Res: 31 Oct 2019; 115:1850-1860 | PMID: 30596969
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Impact:
Abstract

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, ... Hodi FS, Wolchok JD
Background
Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.
Methods
We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.
Results
At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.
Conclusions
Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 16 Oct 2019; 381:1535-1546
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, ... Hodi FS, Wolchok JD
N Engl J Med: 16 Oct 2019; 381:1535-1546 | PMID: 31562797
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Impact:
Abstract

Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes.

Brown SA, Kovatchev BP, Raghinaru D, Lum JW, ... Beck RW,
Background
Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes.
Methods
In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring.
Results
A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group.
Conclusions
In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 15 Oct 2019; epub ahead of print
Brown SA, Kovatchev BP, Raghinaru D, Lum JW, ... Beck RW,
N Engl J Med: 15 Oct 2019; epub ahead of print | PMID: 31618560
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Abstract

A sequential interferon gamma directed chemotactic cellular immune response determines survival and cardiac function post-myocardial infarction.

Finger S, Knorr M, Molitor M, Schüler R, ... Karbach S, Wenzel P
Aims
Myelomonocytic cells are critical in injury and healing post-myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI.
Methods and results
MI was induced in 8- to 12-week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending (LAD) coronary artery. Lysozyme M (LysM)+ cell-depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1 day post-MI compared with infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumour necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28 days post-MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1, and Il12b mRNA were reduced 3 days after MI, as was the amount of CD11b+/Ly-6G-/Ly-6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post-MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post-MI.
Conclusion
IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post-MI.

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

Cardiovasc Res: 31 Oct 2019; 115:1907-1917
Finger S, Knorr M, Molitor M, Schüler R, ... Karbach S, Wenzel P
Cardiovasc Res: 31 Oct 2019; 115:1907-1917 | PMID: 30949687
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Impact:
Abstract

Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients.

Gast M, Rauch BH, Haghikia A, Nakagawa S, ... Zeller T, Poller W
Aims
Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model.
Methods and results
Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1-/- mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1-/- splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1-/- spleen displayed anomalous Treg and TH cell differentiation. NEAT1-/- bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1-/- BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1-/- bone marrow and blood. NEAT1-/- mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals.
Conclusion
The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1-/- mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.

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

Cardiovasc Res: 31 Oct 2019; 115:1886-1906
Gast M, Rauch BH, Haghikia A, Nakagawa S, ... Zeller T, Poller W
Cardiovasc Res: 31 Oct 2019; 115:1886-1906 | PMID: 30924864
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Impact:
Abstract

Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity.

Bonacina F, Moregola A, Porte R, Baragetti A, ... Garlanda C, Norata GD
Aims
Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity.
Methods and results
PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers.
Conclusion
Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.

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

Cardiovasc Res: 31 Oct 2019; 115:1861-1872
Bonacina F, Moregola A, Porte R, Baragetti A, ... Garlanda C, Norata GD
Cardiovasc Res: 31 Oct 2019; 115:1861-1872 | PMID: 30859179
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Impact:
Abstract

A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor.

Rimbert A, Dalila N, Wolters JC, Huijkman N, ... van de Sluis B, Kuivenhoven JA
Aims
Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR).
Methods and results
Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality. CCDC93 was furthermore studied in cells and mice. The lead variant of the INSIG2 locus (rs10490626) is not associated with changes in the expression of nearby genes but is a part of a genetic block, which excludes INSIG2. This block includes a coding variant in CCDC93 p.Pro228Leu, which is in strong linkage disequilibrium with rs10490626 (r2 > 0.96). In the general population, separately and combined, CCDC93 p.Pro228Leu is dose-dependently associated with lower LDL-c (P-trend 2.5 × 10-6 to 8.0 × 10-9), with lower risk of MI (P-trend 0.04-0.002) and lower risk of cardiovascular mortality (P-trend 0.005-0.004). These results were validated for LDL-c, risk of both coronary artery disease and MI in meta-analyses including from 194 000 to >700 000 participants. The variant is shown to increase CCDC93 protein stability, while overexpression of human CCDC93 decreases plasma LDL-c in mice. Conversely, CCDC93 ablation reduces LDL uptake as a result of reduced LDLR levels at the cell membrane.
Conclusion
This study provides evidence that a common variant in CCDC93, encoding a protein involved in recycling of the LDLR, is associated with lower LDL-c levels, lower risk of MI and cardiovascular mortality.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 18 Oct 2019; epub ahead of print
Rimbert A, Dalila N, Wolters JC, Huijkman N, ... van de Sluis B, Kuivenhoven JA
Eur Heart J: 18 Oct 2019; epub ahead of print | PMID: 31630160
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Impact:
Abstract

Neurodegenerative Disease Mortality among Former Professional Soccer Players.

Mackay DF, Russell ER, Stewart K, MacLean JA, Pell JP, Stewart W
Background
Neurodegenerative disorders have been reported in elite athletes who participated in contact sports. The incidence of neurodegenerative disease among former professional soccer players has not been well characterized.
Methods
We conducted a retrospective cohort study to compare mortality from neurodegenerative disease among 7676 former professional soccer players (identified from databases of Scottish players) with that among 23,028 controls from the general population who were matched to the players on the basis of sex, age, and degree of social deprivation. Causes of death were determined from death certificates. Data on medications dispensed for the treatment of dementia in the two cohorts were also compared. Prescription information was obtained from the national Prescribing Information System.
Results
Over a median of 18 years, 1180 former soccer players (15.4%) and 3807 controls (16.5%) died. All-cause mortality was lower among former players than among controls up to the age of 70 years and was higher thereafter. Mortality from ischemic heart disease was lower among former players than among controls (hazard ratio, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P = 0.02), as was mortality from lung cancer (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.001). Mortality with neurodegenerative disease listed as the primary cause was 1.7% among former soccer players and 0.5% among controls (subhazard ratio [the hazard ratio adjusted for competing risks of death from ischemic heart disease and death from any cancer], 3.45; 95% CI, 2.11 to 5.62; P<0.001). Among former players, mortality with neurodegenerative disease listed as the primary or a contributory cause on the death certificate varied according to disease subtype and was highest among those with Alzheimer\'s disease (hazard ratio [former players vs. controls], 5.07; 95% CI, 2.92 to 8.82; P<0.001) and lowest among those with Parkinson\'s disease (hazard ratio, 2.15; 95% CI, 1.17 to 3.96; P = 0.01). Dementia-related medications were prescribed more frequently to former players than to controls (odds ratio, 4.90; 95% CI, 3.81 to 6.31; P<0.001). Mortality with neurodegenerative disease listed as the primary or a contributory cause did not differ significantly between goalkeepers and outfield players (hazard ratio, 0.73; 95% CI, 0.43 to 1.24; P = 0.24), but dementia-related medications were prescribed less frequently to goalkeepers (odds ratio, 0.41; 95% CI, 0.19 to 0.89; P = 0.02).
Conclusions
In this retrospective epidemiologic analysis, mortality from neurodegenerative disease was higher and mortality from other common diseases lower among former Scottish professional soccer players than among matched controls. Dementia-related medications were prescribed more frequently to former players than to controls. These observations need to be confirmed in prospective matched-cohort studies. (Funded by the Football Association and Professional Footballers\' Association.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 20 Oct 2019; epub ahead of print
Mackay DF, Russell ER, Stewart K, MacLean JA, Pell JP, Stewart W
N Engl J Med: 20 Oct 2019; epub ahead of print | PMID: 31633894
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Impact:
Abstract

Conservative Oxygen Therapy during Mechanical Ventilation in the ICU.

, Mackle D, Bellomo R, Bailey M, ... Panwar R, Young P
Background
Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation).
Methods
We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo) was 90%. In the conservative-oxygen group, the upper limit of the Spo alarm was set to sound when the level reached 97%, and the Fio was decreased to 0.21 if the Spo was above the acceptable lower limit. In the usual-oxygen group, there were no specific measures limiting the Fio or the Spo. The primary outcome was the number of ventilator-free days from randomization until day 28.
Results
The number of ventilator-free days did not differ significantly between the conservative-oxygen group and the usual-oxygen group, with a median duration of 21.3 days (interquartile range, 0 to 26.3) and 22.1 days (interquartile range, 0 to 26.2), respectively, for an absolute difference of -0.3 days (95% confidence interval [CI], -2.1 to 1.6; P = 0.80). The conservative-oxygen group spent more time in the ICU with an Fio of 0.21 than the usual-oxygen group, with a median duration of 29 hours (interquartile range, 5 to 78) and 1 hour (interquartile range, 0 to 17), respectively (absolute difference, 28 hours; 95% CI, 22 to 34); the conservative-oxygen group spent less time with an Spo exceeding 96%, with a duration of 27 hours (interquartile range, 11 to 63.5) and 49 hours (interquartile range, 22 to 112), respectively (absolute difference, 22 hours; 95% CI, 14 to 30). At 180 days, mortality was 35.7% in the conservative-oxygen group and 34.5% in the usual-oxygen group, for an unadjusted odds ratio of 1.05 (95% CI, 0.81 to 1.37).
Conclusions
In adults undergoing mechanical ventilation in the ICU, the use of conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days. (Funded by the New Zealand Health Research Council; ICU-ROX Australian and New Zealand Clinical Trials Registry number, ACTRN12615000957594.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 13 Oct 2019; epub ahead of print
, Mackle D, Bellomo R, Bailey M, ... Panwar R, Young P
N Engl J Med: 13 Oct 2019; epub ahead of print | PMID: 31613432
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Impact:
Abstract

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

Kim J, Hu C, Moufawad El Achkar C, Black LE, ... Berde CB, Yu TW

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an \"N-of-1\" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila\'s Miracle Foundation and others.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 08 Oct 2019; epub ahead of print
Kim J, Hu C, Moufawad El Achkar C, Black LE, ... Berde CB, Yu TW
N Engl J Med: 08 Oct 2019; epub ahead of print | PMID: 31597037
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Impact:
Abstract

Ticagrelor in Patients with Stable Coronary Disease and Diabetes.

Steg PG, Bhatt DL, Simon T, Fox K, ... Leiter LA,
Background
Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear.
Methods
In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.
Results
A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).
Conclusions
In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 02 Oct 2019; 381:1309-1320
Steg PG, Bhatt DL, Simon T, Fox K, ... Leiter LA,
N Engl J Med: 02 Oct 2019; 381:1309-1320 | PMID: 31475798
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Impact:
Abstract

Metoprolol for the Prevention of Acute Exacerbations of COPD.

Dransfield MT, Voelker H, Bhatt SP, Brenner K, ... Connett JE,
Background
Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.
Methods
In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.
Results
A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.
Conclusions
Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 19 Oct 2019; epub ahead of print
Dransfield MT, Voelker H, Bhatt SP, Brenner K, ... Connett JE,
N Engl J Med: 19 Oct 2019; epub ahead of print | PMID: 31633896
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Impact:
Abstract

Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells.

Kavanagh DPJ, Lokman AB, Neag G, Colley A, Kalia N
Aims
Adequate microcirculatory perfusion, and not just opening of occluded arteries, is critical to salvage heart tissue following myocardial infarction. However, the degree of microvascular perfusion taking place is not known, limited primarily by an inability to directly image coronary microcirculation in a beating heart in vivo. Haematopoietic stem/progenitor cells (HSPCs) offer a potential therapy but little is known about their homing dynamics at a cellular level and whether they protect coronary microvessels. This study used intravital microscopy to image the anaesthetized mouse beating heart microcirculation following stabilization.
Methods and results
A 3D-printed stabilizer was attached to the ischaemia-reperfusion injured (IRI) beating heart. The kinetics of neutrophil, platelet and HSPC recruitment, as well as functional capillary density (FCD), was imaged post-reperfusion. Laser speckle contrast imaging (LSCI) was used for the first time to monitor ventricular blood flow in beating hearts. Sustained hyperaemic responses were measured throughout reperfusion, initially indicating adequate flow resumption. Intravital microscopy confirmed large vessel perfusion but demonstrated poor transmission of flow to downstream coronary microvessels. Significant neutrophil adhesion and microthrombus formation occurred within capillaries with the latter occluding them, resulting in patchy perfusion and reduced FCD. Interestingly, \'patrolling\' neutrophils were also observed in capillaries. Haematopoietic stem/progenitor cells readily trafficked through the heart but local retention was poor. Despite this, remarkable anti-thromboinflammatory effects were observed, consequently improving microvascular perfusion.
Conclusion
We present a novel approach for imaging multiple microcirculatory perturbations in the beating heart with LSCI assessment of blood flow. Despite deceptive hyperaemic responses, increased microcirculatory flow heterogeneity was seen, with non-perfused areas interspersed with perfused areas. Microthrombi, rather than neutrophils, appeared to be the major causative factor. We further applied this technique to demonstrate local stem cell presence is not a pre-requisite to confer vasculoprotection. This is the first detailed in vivo characterization of coronary microcirculatory responses post-reperfusion injury.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 31 Oct 2019; 115:1918-1932
Kavanagh DPJ, Lokman AB, Neag G, Colley A, Kalia N
Cardiovasc Res: 31 Oct 2019; 115:1918-1932 | PMID: 31062860
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Impact:
Abstract

Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease.

Stone GW, Kappetein AP, Sabik JF, Pocock SJ, ... Serruys PW,
Background
Long-term outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents, as compared with coronary-artery bypass grafting (CABG), in patients with left main coronary artery disease are not clearly established.
Methods
We randomly assigned 1905 patients with left main coronary artery disease of low or intermediate anatomical complexity (according to assessment at the participating centers) to undergo either PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). The primary outcome was a composite of death, stroke, or myocardial infarction.
Results
At 5 years, a primary outcome event had occurred in 22.0% of the patients in the PCI group and in 19.2% of the patients in the CABG group (difference, 2.8 percentage points; 95% confidence interval [CI], -0.9 to 6.5; P = 0.13). Death from any cause occurred more frequently in the PCI group than in the CABG group (in 13.0% vs. 9.9%; difference, 3.1 percentage points; 95% CI, 0.2 to 6.1). In the PCI and CABG groups, the incidences of definite cardiovascular death (5.0% and 4.5%, respectively; difference, 0.5 percentage points; 95% CI, -1.4 to 2.5) and myocardial infarction (10.6% and 9.1%; difference, 1.4 percentage points; 95% CI, -1.3 to 4.2) were not significantly different. All cerebrovascular events were less frequent after PCI than after CABG (3.3% vs. 5.2%; difference, -1.9 percentage points; 95% CI, -3.8 to 0), although the incidence of stroke was not significantly different between the two groups (2.9% and 3.7%; difference, -0.8 percentage points; 95% CI, -2.4 to 0.9). Ischemia-driven revascularization was more frequent after PCI than after CABG (16.9% vs. 10.0%; difference, 6.9 percentage points; 95% CI, 3.7 to 10.0).
Conclusions
In patients with left main coronary artery disease of low or intermediate anatomical complexity, there was no significant difference between PCI and CABG with respect to the rate of the composite outcome of death, stroke, or myocardial infarction at 5 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Sep 2019; epub ahead of print
Stone GW, Kappetein AP, Sabik JF, Pocock SJ, ... Serruys PW,
N Engl J Med: 27 Sep 2019; epub ahead of print | PMID: 31562798
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Impact:
Abstract

Ticagrelor with or without Aspirin in High-Risk Patients after PCI.

Mehran R, Baber U, Sharma SK, Cohen DJ, ... Pocock S, Gibson CM
Background
Monotherapy with a P2Y inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI).
Methods
In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an absolute margin of 1.6 percentage points.
Results
We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority).
Conclusions
Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded by AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 25 Sep 2019; epub ahead of print
Mehran R, Baber U, Sharma SK, Cohen DJ, ... Pocock S, Gibson CM
N Engl J Med: 25 Sep 2019; epub ahead of print | PMID: 31556978
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Impact:
Abstract

Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer.

de Wit R, de Bono J, Sternberg CN, Fizazi K, ... Castellano D,
Background
The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.
Methods
We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed.
Results
A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed.
Conclusions
Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 29 Sep 2019; epub ahead of print
de Wit R, de Bono J, Sternberg CN, Fizazi K, ... Castellano D,
N Engl J Med: 29 Sep 2019; epub ahead of print | PMID: 31566937
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Impact:
Abstract

Encorafenib, Binimetinib, and Cetuximab in V600E-Mutated Colorectal Cancer.

Kopetz S, Grothey A, Yaeger R, Van Cutsem E, ... Sandor V, Tabernero J
Background
Patients with metastatic colorectal cancer with theV600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
Methods
In this open-label, phase 3 trial, we enrolled 665 patients withV600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators\' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.
Results
The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
Conclusions
A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with theV600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 29 Sep 2019; epub ahead of print
Kopetz S, Grothey A, Yaeger R, Van Cutsem E, ... Sandor V, Tabernero J
N Engl J Med: 29 Sep 2019; epub ahead of print | PMID: 31566309
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Impact:
Abstract

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases.

Flaherty KR, Wells AU, Cottin V, Devaraj A, ... Brown KK,
Background
Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.
Methods
In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.
Results
A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.
Conclusions
In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 28 Sep 2019; epub ahead of print
Flaherty KR, Wells AU, Cottin V, Devaraj A, ... Brown KK,
N Engl J Med: 28 Sep 2019; epub ahead of print | PMID: 31566307
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Impact:
Abstract

Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm.

Lascarrou JB, Merdji H, Le Gouge A, Colin G, ... Reignier J,
Background
Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital cardiac arrest. However, the effectiveness of moderate therapeutic hypothermia in patients with nonshockable rhythms (asystole or pulseless electrical activity) is debated.
Methods
We performed an open-label, randomized, controlled trial comparing moderate therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit (ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the Cerebral Performance Category (CPC) scale (which ranges from 1 to 5, with higher scores indicating greater disability). We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome assessment was blinded. Mortality and safety were also assessed.
Results
From January 2014 through January 2018, a total of 584 patients from 25 ICUs underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P = 0.04). Mortality at 90 days did not differ significantly between the hypothermia group and the normothermia group (81.3% and 83.2%, respectively; difference, -1.9 percentage points; 95% CI, -8.0 to 4.3). The incidence of prespecified adverse events did not differ significantly between groups.
Conclusions
Among patients with coma who had been resuscitated from cardiac arrest with nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the French Ministry of Health and others; HYPERION ClinicalTrials.gov number, NCT01994772.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 01 Oct 2019; epub ahead of print
Lascarrou JB, Merdji H, Le Gouge A, Colin G, ... Reignier J,
N Engl J Med: 01 Oct 2019; epub ahead of print | PMID: 31577396
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Impact:
Abstract

Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture.

, Bhandari M, Einhorn TA, Guyatt G, ... Walter SD, Devereaux PJ
Background
Globally, hip fractures are among the top 10 causes of disability in adults. For displaced femoral neck fractures, there remains uncertainty regarding the effect of a total hip arthroplasty as compared with hemiarthroplasty.
Methods
We randomly assigned 1495 patients who were 50 years of age or older and had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. All enrolled patients had been able to ambulate without the assistance of another person before the fracture occurred. The trial was conducted in 80 centers in 10 countries. The primary end point was a secondary hip procedure within 24 months of follow-up. Secondary end points included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health end points.
Results
The primary end point occurred in 57 of 718 patients (7.9%) who were randomly assigned to total hip arthroplasty and 60 of 723 patients (8.3%) who were randomly assigned to hemiarthroplasty (hazard ratio, 0.95; 95% confidence interval [CI], 0.64 to 1.40; P = 0.79). Hip instability or dislocation occurred in 34 patients (4.7%) assigned to total hip arthroplasty and 17 patients (2.4%) assigned to hemiarthroplasty (hazard ratio, 2.00; 99% CI, 0.97 to 4.09). Function, as measured with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score, modestly favored total hip arthroplasty over hemiarthroplasty. Mortality was similar in the two treatment groups (14.3% among the patients assigned to total hip arthroplasty and 13.1% among those assigned to hemiarthroplasty, P = 0.48). Serious adverse events occurred in 300 patients (41.8%) assigned to total hip arthroplasty and in 265 patients (36.7%) assigned to hemiarthroplasty.
Conclusions
Among independently ambulating patients with displaced femoral neck fractures, the incidence of secondary procedures did not differ significantly between patients who were randomly assigned to undergo total hip arthroplasty and those who were assigned to undergo hemiarthroplasty, and total hip arthroplasty provided a clinically unimportant improvement over hemiarthroplasty in function and quality of life over 24 months. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00556842.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 25 Sep 2019; epub ahead of print
, Bhandari M, Einhorn TA, Guyatt G, ... Walter SD, Devereaux PJ
N Engl J Med: 25 Sep 2019; epub ahead of print | PMID: 31557429
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Impact:
Abstract

Discrimination, Abuse, Harassment, and Burnout in Surgical Residency Training.

Hu YY, Ellis RJ, Hewitt DB, Yang AD, ... Nasca TR, Bilimoria KY
Background
Physicians, particularly trainees and those in surgical subspecialties, are at risk for burnout. Mistreatment (i.e., discrimination, verbal or physical abuse, and sexual harassment) may contribute to burnout and suicidal thoughts.
Methods
A cross-sectional national survey of general surgery residents administered with the 2018 American Board of Surgery In-Training Examination assessed mistreatment, burnout (evaluated with the use of the modified Maslach Burnout Inventory), and suicidal thoughts during the past year. We used multivariable logistic-regression models to assess the association of mistreatment with burnout and suicidal thoughts. The survey asked residents to report their gender.
Results
Among 7409 residents (99.3% of the eligible residents) from all 262 surgical residency programs, 31.9% reported discrimination based on their self-identified gender, 16.6% reported racial discrimination, 30.3% reported verbal or physical abuse (or both), and 10.3% reported sexual harassment. Rates of all mistreatment measures were higher among women; 65.1% of the women reported gender discrimination and 19.9% reported sexual harassment. Patients and patients\' families were the most frequent sources of gender discrimination (as reported by 43.6% of residents) and racial discrimination (47.4%), whereas attending surgeons were the most frequent sources of sexual harassment (27.2%) and abuse (51.9%). Proportion of residents reporting mistreatment varied considerably among residency programs (e.g., ranging from 0 to 66.7% for verbal abuse). Weekly burnout symptoms were reported by 38.5% of residents, and 4.5% reported having had suicidal thoughts during the past year. Residents who reported exposure to discrimination, abuse, or harassment at least a few times per month were more likely than residents with no reported mistreatment exposures to have symptoms of burnout (odds ratio, 2.94; 95% confidence interval [CI], 2.58 to 3.36) and suicidal thoughts (odds ratio, 3.07; 95% CI, 2.25 to 4.19). Although models that were not adjusted for mistreatment showed that women were more likely than men to report burnout symptoms (42.4% vs. 35.9%; odds ratio, 1.33; 95% CI, 1.20 to 1.48), the difference was no longer evident after the models were adjusted for mistreatment (odds ratio, 0.90; 95% CI, 0.80 to 1.00).
Conclusions
Mistreatment occurs frequently among general surgery residents, especially women, and is associated with burnout and suicidal thoughts.

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Oct 2019; epub ahead of print
Hu YY, Ellis RJ, Hewitt DB, Yang AD, ... Nasca TR, Bilimoria KY
N Engl J Med: 27 Oct 2019; epub ahead of print | PMID: 31657887
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Impact:
Abstract

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.

McMurray JJV, Solomon SD, Inzucchi SE, Køber L, ... Langkilde AM,
Background
In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
Methods
In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
Results
Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.
Conclusions
Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 18 Sep 2019; epub ahead of print
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, ... Langkilde AM,
N Engl J Med: 18 Sep 2019; epub ahead of print | PMID: 31535829
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Abstract

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.

González-Martín A, Pothuri B, Vergote I, DePont Christensen R, ... Monk BJ,
Background
Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence ofmutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown.
Methods
In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival.
Results
Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred.
Conclusions
Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Sep 2019; epub ahead of print
González-Martín A, Pothuri B, Vergote I, DePont Christensen R, ... Monk BJ,
N Engl J Med: 27 Sep 2019; epub ahead of print | PMID: 31562799
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Impact:
Abstract

Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.

Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, ... Nathan FE, Ramalingam SS
Background
In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.
Methods
In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.
Results
Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.
Conclusions
First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Sep 2019; epub ahead of print
Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, ... Nathan FE, Ramalingam SS
N Engl J Med: 27 Sep 2019; epub ahead of print | PMID: 31562796
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Impact:
Abstract

Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer.

Coleman RL, Fleming GF, Brady MF, Swisher EM, ... Aghajanian C, Bookman MA
Background
Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.
Methods
In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the -mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the -mutation cohort), and the intention-to-treat population.
Results
A total of 1140 patients underwent randomization. In the -mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall.
Conclusions
Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Sep 2019; epub ahead of print
Coleman RL, Fleming GF, Brady MF, Swisher EM, ... Aghajanian C, Bookman MA
N Engl J Med: 27 Sep 2019; epub ahead of print | PMID: 31562800
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Abstract

A Genotype-Guided Strategy for Oral P2Y Inhibitors in Primary PCI.

Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, ... Deneer VHM, Ten Berg JM
Background
It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y inhibitors.
Methods
We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y inhibitor on the basis of earlygenetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of *2 or *3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome).
Results
For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04).
Conclusions
In patients undergoing primary PCI, agenotype-guided strategy for selection of oral P2Y inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 02 Sep 2019; epub ahead of print
Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, ... Deneer VHM, Ten Berg JM
N Engl J Med: 02 Sep 2019; epub ahead of print | PMID: 31479209
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Abstract

Gilteritinib or Chemotherapy for Relapsed or Refractory -Mutated AML.

Perl AE, Martinelli G, Cortes JE, Neubauer A, ... Bahceci E, Levis MJ
Background
Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene () infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory -mutated AML.
Methods
In a phase 3 trial, we randomly assigned adults with relapsed or refractory -mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission.
Results
Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).
Conclusions
Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory -mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 30 Oct 2019; 381:1728-1740
Perl AE, Martinelli G, Cortes JE, Neubauer A, ... Bahceci E, Levis MJ
N Engl J Med: 30 Oct 2019; 381:1728-1740 | PMID: 31665578
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Abstract

Final Analysis of a Trial of M72/AS01 Vaccine to Prevent Tuberculosis.

Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, ... Wilkinson RJ, Roman F
Background
Results of an earlier analysis of a trial of the M72/AS01 candidate vaccine againstshowed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity.
Methods
From August 2014 through November 2015, we enrolled adults 18 to 50 years of age withinfection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01 or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01 to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01 or placebo.
Results
A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01 or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01 group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01 group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.
Conclusions
Among adults infected with , vaccination with M72/AS01 elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 28 Oct 2019; epub ahead of print
Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, ... Wilkinson RJ, Roman F
N Engl J Med: 28 Oct 2019; epub ahead of print | PMID: 31661198
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Abstract

Drug-Resistant Bacteremia Transmitted by Fecal Microbiota Transplant.

DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, ... Chen YB, Hohmann EL

Fecal microbiota transplantation (FMT) is an emerging therapy for recurrent or refractoryinfection and is being actively investigated for other conditions. We describe two patients in whom extended-spectrum beta-lactamase (ESBL)-producingbacteremia occurred after they had undergone FMT in two independent clinical trials; both cases were linked to the same stool donor by means of genomic sequencing. One of the patients died. Enhanced donor screening to limit the transmission of microorganisms that could lead to adverse infectious events and continued vigilance to define the benefits and risks of FMT across different patient populations are warranted.

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 29 Oct 2019; epub ahead of print
DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, ... Chen YB, Hohmann EL
N Engl J Med: 29 Oct 2019; epub ahead of print | PMID: 31665575
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Abstract

Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Preliminary Report.

Layden JE, Ghinai I, Pray I, Kimball A, ... Mikosz CA, Meiman J
Background
E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosolized product to the user. Pulmonary illnesses related to e-cigarette use have been reported, but no large series has been described. In July 2019, the Wisconsin Department of Health Services and the Illinois Department of Public Health received reports of pulmonary disease associated with the use of e-cigarettes (also called vaping) and launched a coordinated public health investigation.
Methods
We defined case patients as persons who reported use of e-cigarette devices and related products in the 90 days before symptom onset and had pulmonary infiltrates on imaging and whose illnesses were not attributed to other causes. Medical record abstraction and case patient interviews were conducted with the use of standardized tools.
Results
There were 53 case patients, 83% of whom were male; the median age of the patients was 19 years. The majority of patients presented with respiratory symptoms (98%), gastrointestinal symptoms (81%), and constitutional symptoms (100%). All case patients had bilateral infiltrates on chest imaging (which was part of the case definition). A total of 94% of the patients were hospitalized, 32% underwent intubation and mechanical ventilation, and one death was reported. A total of 84% of the patients reported having used tetrahydrocannabinol products in e-cigarette devices, although a wide variety of products and devices was reported. Syndromic surveillance data from Illinois showed that the mean monthly rate of visits related to severe respiratory illness in June through August of 2019 was twice the rate that was observed in the same months in 2018.
Conclusions
Case patients presented with similar clinical characteristics. Although the features of e-cigarette use that were responsible for injury have not been identified, this cluster of illnesses represents an emerging clinical syndrome or syndromes. Additional work is needed to characterize the pathophysiology and to identify the definitive causes.

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 05 Sep 2019; epub ahead of print
Layden JE, Ghinai I, Pray I, Kimball A, ... Mikosz CA, Meiman J
N Engl J Med: 05 Sep 2019; epub ahead of print | PMID: 31491072
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Abstract

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.

Solomon SD, McMurray JJV, Anand IS, Ge J, ... Lefkowitz MP,
Background
The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear.
Methods
We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed.
Results
There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women.
Conclusions
Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 31 Aug 2019; epub ahead of print
Solomon SD, McMurray JJV, Anand IS, Ge J, ... Lefkowitz MP,
N Engl J Med: 31 Aug 2019; epub ahead of print | PMID: 31475794
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Impact:
Abstract

Preventive Cardiology as a Subspecialty of Cardiovascular Medicine: JACC Council Perspectives.

Shapiro MD, Maron DJ, Morris PB, Kosiborod M, ... Bhatt DL, Fazio S

Although significant progress has been made to reduce the global burden of cardiovascular disease, efforts have focused primarily on treatment of manifest disease rather than on prevention of events. An enormous opportunity exists to transition focus from intervention to providing equal attention to prevention of cardiovascular disease. The nascent specialty of \"preventive cardiology\" is emerging from the background of long-established services such as lipid, diabetes, hypertension, and general cardiology clinics. It is incumbent on the cardiology community to invest in cardiovascular prevention because past gains are threatened with the rising tide of obesity and diabetes. Now is the time to establish a dedicated preventive cardiology subspecialty to train the clinicians of the future. This American College of Cardiology Council Perspective aims to define the need for preventive cardiology as a unique subspecialty, broaches controversies, provides a structure for future training and education, and identifies possible paths forward to professional certification.

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 15 Oct 2019; 74:1926-1942
Shapiro MD, Maron DJ, Morris PB, Kosiborod M, ... Bhatt DL, Fazio S
J Am Coll Cardiol: 15 Oct 2019; 74:1926-1942 | PMID: 31601373
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Impact:
Abstract

Poor Long-Term Survival in Patients With Moderate Aortic Stenosis.

Strange G, Stewart S, Celermajer D, Prior D, ... Playford D,
Background
Historical data suggesting poor survival in patients with aortic stenosis (AS) who do not undergo treatment are largely confined to patients with severe AS.
Objectives
This study sought to determine the prognostic impact of all levels of native valvular AS.
Methods
Severity of AS was characterized by convention and by statistical distribution in 122,809 male patients (mean age 61 ± 17 years) and 118,494 female patients (mean age 62 ± 19 years), with measured aortic valve (AV) mean gradient, peak velocity, and/or area. The relationship between AS severity and survival was then examined during median 1,208 days (interquartile range: 598 to 2,177 days) of follow-up. Patients with previous aortic valve intervention were excluded.
Results
Overall, 16,129 (6.7%), 3,315 (1.4%), and 6,383 (2.6%) patients had mild, moderate, and severe AS, respectively. On an adjusted basis (vs. no AS; 5-year mortality 19%), patients with mild to severe AS had an increasing risk of long-term mortality (adjusted hazard ratio: 1.44 to 2.09; p < 0.001 for all comparisons). The 5-year mortality was 56% and 67%, respectively, in those with moderate AS (mean gradient 20.0 to 39.0 mm Hg/peak velocity 3.0 to 3.9 m/s) and severe AS (≥40.0 mm Hg, ≥4.0 m/s, or AV area <1.0 cm in low-flow, low-gradient severe AS). A markedly increased risk of death from all causes (5-year mortality >50%) and cardiovascular disease was evident from a mean AV gradient >20.0 mm Hg (moderate AS) after adjusting for age, sex, left ventricular systolic or diastolic dysfunction, and aortic regurgitation.
Conclusions
These data confirm that when left untreated, severe AS is associated with poor long-term survival. Moreover, they also suggest poor survival rates in patients with moderate AS. (National Echocardiographic Database of Australia [NEDA]; ACTRN12617001387314).

Copyright © 2019 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 15 Oct 2019; 74:1851-1863
Strange G, Stewart S, Celermajer D, Prior D, ... Playford D,
J Am Coll Cardiol: 15 Oct 2019; 74:1851-1863 | PMID: 31491546
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Impact:
Abstract

Long-Term Evolution of Premature Coronary Artery Disease.

Collet JP, Zeitouni M, Procopi N, Hulot JS, ... Montalescot G,
Background
The long-term evolution of premature coronary artery disease (CAD) is unknown.
Objectives
The objective of this study was to describe the evolution of coronary atherosclerosis in young patients and identify the risk factors of poor outcomes.
Methods
Participants age ≤45 years with acute or stable obstructive CAD were prospectively enrolled and followed. The primary endpoint was all-cause death, myocardial infarction (MI), refractory angina requiring coronary revascularization, and ischemic stroke.
Results
Eight hundred-eighty patients with premature CAD were included. They were age 40.1 ± 5.7 years, mainly men, smokers, with a family history of CAD or hypercholesterolemia. At baseline presentation, 91.2% underwent coronary revascularization, predominantly for acute MI (78.8%). Over a follow-up of 20 years, one-third (n = 264) of patients presented with a total of 399 ischemic events, and 36% had at least a second recurrent event. MI was the most frequent first recurrent event (n = 131 of 264), mostly related to new coronary lesions (17.3% vs. 7.8%; p = 0.01; hazard ratio [HR]:1.45; 95% confidence interval [CI]: 1.09 to 1.93 for new vs. initial culprit lesion). All-cause death (n = 55; 6.3%) occurred at 8.4 years (median time). Ethnic origin (sub-Saharan African vs. Caucasian, adjusted hazard ratio [adjHR]: 1.95; 95% CI: 1.13 to 3.35; p = 0.02), inflammatory disease (adjHR: 1.58; 95% CI: 1.05 to 2.36; p = 0.03), and persistent smoking (adjHR: 2.32; 95% CI: 1.63 to 3.28; p < 0.01) were the strongest correlates of a first recurrent event. When considering all recurrent events, the same factors and Asian ethnicity predicted poor outcome, but persistent smoking had the greatest impact on prognosis.
Conclusions
Premature CAD is an aggressive disease despite the currently recommended prevention measures, with high rates of recurrent events and mortality. Ethnicity and concomitant inflammatory disease are associated with poor prognoses, along with insufficient control of risk factors.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Oct 2019; 74:1868-1878
Collet JP, Zeitouni M, Procopi N, Hulot JS, ... Montalescot G,
J Am Coll Cardiol: 15 Oct 2019; 74:1868-1878 | PMID: 31601367
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Abstract

Secondary prevention medications after coronary artery bypass grafting and long-term survival: a population-based longitudinal study from the SWEDEHEART registry.

Björklund E, Nielsen SJ, Hansson EC, Karlsson M, ... Pivodic A, Jeppsson A
Aims
To evaluate the long-term use of secondary prevention medications [statins, β-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and platelet inhibitors] after coronary artery bypass grafting (CABG) and the association between medication use and mortality.
Methods and results
All patients who underwent isolated CABG in Sweden from 2006 to 2015 and survived at least 6 months after discharge were included (n = 28 812). Individual patient data from SWEDEHEART and other mandatory nationwide registries were merged. Multivariable Cox regression models using time-updated data on dispensed prescriptions were used to assess associations between medication use and long-term mortality. Statins were dispensed to 93.9% of the patients 6 months after discharge and to 77.3% 8 years later. Corresponding figures for β-blockers were 91.0% and 76.4%, for RAAS inhibitors 72.9% and 65.9%, and for platelet inhibitors 93.0% and 79.8%. All medications were dispensed less often to patients ≥75 years. Treatment with statins [hazard ratio (HR) 0.56, 95% confidence interval (95% CI) 0.52-0.60], RAAS inhibitors (HR 0.78, 95% CI 0.73-0.84), and platelet inhibitors (HR 0.74, 95% CI 0.69-0.81) were individually associated with lower mortality risk after adjustment for age, gender, comorbidities, and use of other secondary preventive drugs (all P < 0.001). There was no association between β-blockers and mortality risk (HR 0.97, 95% CI 0.90-1.06; P = 0.54).
Conclusion
The use of secondary prevention medications after CABG was high early after surgery but decreased significantly over time. The results of this observational study, with inherent risk of selection bias, suggest that treatment with statins, RAAS inhibitors, and platelet inhibitors is essential after CABG whereas the routine use of β-blockers may be questioned.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 21 Oct 2019; epub ahead of print
Björklund E, Nielsen SJ, Hansson EC, Karlsson M, ... Pivodic A, Jeppsson A
Eur Heart J: 21 Oct 2019; epub ahead of print | PMID: 31638654
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Abstract

Glucagon-like peptide 1 levels predict cardiovascular risk in patients with acute myocardial infarction.

Kahles F, Rückbeil MV, Mertens RW, Foldenauer AC, ... Marx N, Lehrke M
Aims
Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction.
Methods and results
In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan-Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67-14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63-45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients.
Conclusion
In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.

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

Eur Heart J: 15 Oct 2019; epub ahead of print
Kahles F, Rückbeil MV, Mertens RW, Foldenauer AC, ... Marx N, Lehrke M
Eur Heart J: 15 Oct 2019; epub ahead of print | PMID: 31620788
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Abstract

Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial.

Andrade JG, Champagne J, Dubuc M, Deyell MW, ... Khairy P,

Advanced generation ablation technologies have been developed to achieve more effective pulmonary vein isolation (PVI) and minimize arrhythmia recurrence following atrial fibrillation (AF) ablation.We randomly assigned 346 patients with drug-refractory paroxysmal AF to contactforce guided RF ablation (CF-RF ablation, 115), 4-minute cryoballoon ablation (CRYO-4, 115), or 2-minute cryoballoon ablation (CRYO-2, 116). Follow-up was 12 months. The primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) between days 91 and 365 post ablation, or a repeat ablation procedure at any time. Secondary endpoints included freedom from symptomatic arrhythmia, and AF burden. All patients received an implantable loop recorder.One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring, was 53.9%, 52.2%, and 51.7% with CF-RF, CRYO-4, and CRYO-2, respectively; P=0.87. One-year freedom from symptomatic atrial tachyarrhythmia defined by continuous rhythm monitoring, was 79.1%, 78.2%, and 73.3% with CF-RF, CRYO-4, and CRYO-2, respectively; P=0.26. Compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99.3% (IQR 67.8-100.0%) with CF-RF, 99.9% (IQR 65.3-100.0%) with CRYO4, and 98.4% (IQR 56.2-100.0%) with CRYO-2 (P=0.36). Serious adverse events occurred in 2 patients in CF-RF (2.6%), 6 patients in CRYO-4 (5.3%), and 7 patients in CRYO-2 (6.0%), with no significant difference between groups (P=0.24). The CF-RF group had a significantly longer procedure duration but significantly shorter fluoroscopy exposure (P<0.001 vs. cryoballoon groups).In this multicenter, randomized, single-blinded trial, contact-force RF ablation and two different regiments of cryoballoon ablation resulted in no difference in one-year efficacy, which was 53% by time to first recurrence but >98% burden reduction as assessed by continuous cardiac rhythm monitoring.



Circulation: 20 Oct 2019; epub ahead of print
Andrade JG, Champagne J, Dubuc M, Deyell MW, ... Khairy P,
Circulation: 20 Oct 2019; epub ahead of print | PMID: 31630538
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Abstract

Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development.

Aung N, Vargas JD, Yang C, Cabrera CP, ... Munroe PB, Petersen SE
Background
The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present.
Methods
The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events.
Results
The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent <1×10. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (, and ) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score).
Conclusions
We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.



Circulation: 14 Oct 2019; 140:1318-1330
Aung N, Vargas JD, Yang C, Cabrera CP, ... Munroe PB, Petersen SE
Circulation: 14 Oct 2019; 140:1318-1330 | PMID: 31554410
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Abstract

Management of Nonvariceal Upper Gastrointestinal Bleeding: Guideline Recommendations From the International Consensus Group.

Barkun AN, Almadi M, Kuipers EJ, Laine L, ... Marshall JK, Bardou M
Description
This update of the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding (UGIB) refines previous important statements and presents new clinically relevant recommendations.
Methods
An international multidisciplinary group of experts developed the recommendations. Data sources included evidence summarized in previous recommendations, as well as systematic reviews and trials identified from a series of literature searches of several electronic bibliographic databases from inception to April 2018. Using an iterative process, group members formulated key questions. Two methodologists prepared evidence profiles and assessed quality (certainty) of evidence relevant to the key questions according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Group members reviewed the evidence profiles and, using a consensus process, voted on recommendations and determined the strength of recommendations as strong or conditional.
Recommendations
Preendoscopic management: The group suggests using a Glasgow Blatchford score of 1 or less to identify patients at very low risk for rebleeding, who may not require hospitalization. In patients without cardiovascular disease, the suggested hemoglobin threshold for blood transfusion is less than 80 g/L, with a higher threshold for those with cardiovascular disease. Endoscopic management: The group suggests that patients with acute UGIB undergo endoscopy within 24 hours of presentation. Thermocoagulation and sclerosant injection are recommended, and clips are suggested, for endoscopic therapy in patients with high-risk stigmata. Use of TC-325 (hemostatic powder) was suggested as temporizing therapy, but not as sole treatment, in patients with actively bleeding ulcers. Pharmacologic management: The group recommends that patients with bleeding ulcers with high-risk stigmata who have had successful endoscopic therapy receive high-dose proton-pump inhibitor (PPI) therapy (intravenous loading dose followed by continuous infusion) for 3 days. For these high-risk patients, continued oral PPI therapy is suggested twice daily through 14 days, then once daily for a total duration that depends on the nature of the bleeding lesion. Secondary prophylaxis: The group suggests PPI therapy for patients with previous ulcer bleeding who require antiplatelet or anticoagulant therapy for cardiovascular prophylaxis.



Ann Intern Med: 21 Oct 2019; epub ahead of print
Barkun AN, Almadi M, Kuipers EJ, Laine L, ... Marshall JK, Bardou M
Ann Intern Med: 21 Oct 2019; epub ahead of print | PMID: 31634917
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Abstract

Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

Marston NA, Giugliano RP, Im K, Silverman MG, ... Ference BA, Sabatine MS
Background
Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events.
Methods
We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters.
Results
A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; <0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; <0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; =0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; <0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; =0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; <0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]).
Conclusions
In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.



Circulation: 14 Oct 2019; 140:1308-1317
Marston NA, Giugliano RP, Im K, Silverman MG, ... Ference BA, Sabatine MS
Circulation: 14 Oct 2019; 140:1308-1317 | PMID: 31530008
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Abstract

Risk of Mortality Following Catheter Ablation of Atrial Fibrillation.

Cheng EP, Liu CF, Yeo I, Markowitz SM, ... Lerman BB, Cheung JW
Background
Although procedure-related deaths during index admission following catheter ablation of AF have been reported to be low, adverse outcomes can occur after discharge. There are limited data on mortality early after AF ablation.
Objectives
This study aimed to identify rates, trends, and predictors of early mortality post-atrial fibrillation (AF) ablation.
Methods
Using the all-payer, nationally representative Nationwide Readmissions Database, we evaluated 60,203 admissions of patients 18 years of age or older for AF ablation between 2010 and 2015. Early mortality was defined as death during initial admission or 30-day readmission. Based on International Classification of Diseases-9th Revision, Clinical Modification codes, we identified comorbidities, procedural complications, and causes of readmission following AF ablation. Multivariable logistic regression was performed to assess predictors of early mortality.
Results
Early mortality following AF ablation occurred in 0.46% cases, with 54.3% of deaths occurring during readmission. From 2010 to 2015, quarterly rates of early mortality post-ablation increased from 0.25% to 1.35% (p < 0.001). Median time from ablation to death was 11.6 (interquartile range [IQR]: 4.2 to 22.7) days. After adjustment for age and comorbidities, procedural complications (adjusted odds ratio [aOR]: 4.06; p < 0.001), congestive heart failure (CHF) (aOR: 2.20; p = 0.011) and low AF ablation hospital volume (aOR: 2.35; p = 0.003) were associated with early mortality. Complications due to cardiac perforation (aOR: 2.98; p = 0.007), other cardiac (aOR: 12.8; p < 0.001), and neurologic etiologies (aOR: 8.72; p < 0.001) were also associated with early mortality.
Conclusions
In a nationally representative cohort, early mortality following AF ablation affected nearly 1 in 200 patients, with the majority of deaths occurring during 30-day readmission. Procedural complications, congestive heart failure, and low hospital AF ablation volume were predictors of early mortality. Prompt management of post-procedure complications and CHF may be critical for reducing mortality rates following AF ablation.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Nov 2019; 74:2254-2264
Cheng EP, Liu CF, Yeo I, Markowitz SM, ... Lerman BB, Cheung JW
J Am Coll Cardiol: 04 Nov 2019; 74:2254-2264 | PMID: 31672181
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Abstract

Advanced Heart Failure Therapies for Adults With Congenital Heart Disease: JACC State-of-the-Art Review.

Givertz MM, DeFilippis EM, Landzberg MJ, Pinney SP, Woods RK, Valente AM

In the contemporary era, nearly 85% of children with congenital heart disease will reach adulthood. Despite optimal medical and surgical treatment, many will experience a progressive decline in cardiopulmonary function leading to advanced heart failure. These patients present unique anatomic and physiological challenges to the care team, and unlike adults with acquired heart disease who progress to severe heart failure, advanced treatment options such as mechanical circulatory support and cardiac transplant may be limited. Severe ventricular dysfunction and/or pulmonary hypertension may not be amenable to corrective repair. Heart transplantation with or without mechanical circulatory support may be the only option for highly selected patients. The aim of this review is to describe advanced heart failure therapies for adults with congenital heart disease, including the general approach to evaluation and management, pre- and post-operative care, anticipated short- and long-term outcomes, and future directions for clinical care and research.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Nov 2019; 74:2295-2312
Givertz MM, DeFilippis EM, Landzberg MJ, Pinney SP, Woods RK, Valente AM
J Am Coll Cardiol: 04 Nov 2019; 74:2295-2312 | PMID: 31672187
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Abstract

Functional, Anatomical, and Prognostic Correlates of Coronary Flow Velocity Reserve During Stress Echocardiography.

Ciampi Q, Zagatina A, Cortigiani L, Gaibazzi N, ... Picano E,
Background
The assessment of coronary flow velocity reserve (CFVR) in left anterior descending coronary artery (LAD) expands the risk stratification potential of stress echocardiography (SE) based on stress-induced regional wall motion abnormalities (RWMA).
Objectives
The purpose of this study was to assess the feasibility and functional correlates of CFVR.
Methods
This prospective, observational, multicenter study initially screened 3,410 patients (2,061 [60%] male; age 63 ± 11 years; ejection fraction 61 ± 9%) with known or suspected coronary artery disease and/or heart failure. All patients underwent SE (exercise, n = 1,288; vasodilator, n = 1,860; dobutamine, n = 262) based on new or worsening RWMA in 20 accredited laboratories of 8 countries. CFVR was calculated as the stress/rest ratio of diastolic peak flow velocity pulsed-Doppler assessment of LAD flow. A subset of 1,867 patients was followed up.
Results
The success rate for CFVR on LAD was 3,002 of 3,410 (feasibility = 88%). Reduced (≤2.0) CFVR was found in 896 of 3,002 (30%) patients. At multivariable logistic regression analysis, inducible RWMA (odds ratio [OR]: 6.5; 95% confidence interval [CI]: 4.9 to 8.5; p < 0.01), abnormal left ventricular contractile reserve (OR: 3.4; 95% CI: 2.7 to 4.2; p < 0.01), and B-lines (OR: 1.5; 95% CI: 1.1 to 1.9; p = 0.01) were associated with reduced CFVR. During a median follow-up time of 16 months, 218 events occurred. RWMA (hazard ratio: 3.8; 95% CI: 2.3 to 6.3; p < 0.001) and reduced CFVR (hazard ratio: 1.5; 95% CI: 1.1 to 2.2; p = 0.009) were independently associated with adverse outcome.
Conclusions
CFVR is feasible with all SE protocols. Reduced CFVR is often accompanied by RWMA, abnormal LVCR, and pulmonary congestion during stress, and shows independent value over RWMA in predicting an adverse outcome.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Nov 2019; 74:2278-2291
Ciampi Q, Zagatina A, Cortigiani L, Gaibazzi N, ... Picano E,
J Am Coll Cardiol: 04 Nov 2019; 74:2278-2291 | PMID: 31672185
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Abstract

Outcomes of Second Arterial Conduits in Patients Undergoing Multivessel Coronary Artery Bypass Graft Surgery.

Chikwe J, Sun E, Hannan EL, Itagaki S, ... Adams DH, Egorova NN
Background
Benefits of multiarterial versus single-arterial coronary bypass grafting (CABG) are debated.
Objectives
This study sought to compare long-term survival, morbidity, and graft patency after multiarterial versus single-arterial CABG.
Methods
Mandatory clinical registries linked with discharge databases were used to identify baseline and operative characteristics and outcomes of 42,714 patients undergoing CABG from 2005 through 2012. Patients with single-vessel disease, without arterial conduits, or undergoing emergency, reoperative, or concomitant procedures were excluded. Survival, stroke, myocardial infarction, and repeat revascularization rates were compared using Cox modeling, and patients were matched by propensity score. Median follow-up was 7.8 years (interquartile range: 5 to 10 years); last follow-up was December 31, 2016.
Results
Of the 26,124 patients, 3,647 (14.0%) underwent multiarterial CABG. Single-arterial CABG patients were older (mean 68 vs. 61 years; p < 0.001), had more comorbidities, and received fewer bypass grafts (3.4 vs. 3.6; p < 0.001). After adjusting for baseline differences, multiarterial CABG was associated with lower 10-year mortality compared with single-arterial CABG in 3,588 propensity-matched pairs (15.1% vs. 17.3%; p = 0.01). Multiarterial CABG was associated with lower 10-year myocardial infarction (hazard ratio: 0.81; 95% confidence interval: 0.69 to 0.95) and lower 10-year reintervention rate (hazard ratio: 0.81; 95% confidence interval: 0.67 to 0.99).
Conclusions
In contemporary practice, single-arterial CABG is used in 85% of patients and is associated with increased long-term mortality, myocardial infarction, and reintervention compared with multiarterial CABG. Multiarterial CABG is underused in contemporary surgical revascularization, and targeted referral of younger patients for multiarterial revascularization may address this practice gap.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 04 Nov 2019; 74:2238-2248
Chikwe J, Sun E, Hannan EL, Itagaki S, ... Adams DH, Egorova NN
J Am Coll Cardiol: 04 Nov 2019; 74:2238-2248 | PMID: 31672179
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