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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

Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry.

Neubauer S, Kolm P, Ho CY, Kwong RY, ... Kramer CM,
Background
The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.
Objectives
The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.
Methods
Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.
Results
A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.
Conclusions
The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.

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

J Am Coll Cardiol: 11 Nov 2019; 74:2333-2345
Neubauer S, Kolm P, Ho CY, Kwong RY, ... Kramer CM,
J Am Coll Cardiol: 11 Nov 2019; 74:2333-2345 | PMID: 31699273
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Impact:
Abstract

Sex-Related Differences in Heart Failure After ST-Segment Elevation Myocardial Infarction.

Cenko E, van der Schaar M, Yoon J, Manfrini O, ... Badimon L, Bugiardini R
Background
ST-segment elevation myocardial infarction (STEMI) complicated by symptoms of acute de novo heart failure is associated with excess mortality. Whether development of heart failure and its outcomes differ by sex is unknown.
Objectives
This study sought to examine the relationships among sex, acute heart failure, and related outcomes after STEMI in patients with no prior history of heart failure recorded at baseline.
Methods
Patients were recruited from a network of hospitals in the ISACS-TC (International Survey of Acute Coronary Syndromes in Transitional Countries) registry (NCT01218776). Main outcome measures were incidence of Killip class ≥II at hospital presentation and risk-adjusted 30-day mortality rates were estimated using inverse probability of weighting and logistic regression models.
Results
This study included 10,443 patients (3,112 women). After covariate adjustment and matching for age, cardiovascular risk factors, comorbidities, disease severity, and delay to hospital presentation, the incidence of de novo heart failure at hospital presentation was significantly higher for women than for men (25.1% vs. 20.0%, odds ratio [OR]: 1.34; 95% confidence interval [CI]: 1.21 to 1.48). Women with de novo heart failure had higher 30-day mortality than did their male counterparts (25.1% vs. 20.6%; OR: 1.29; 95% CI: 1.05 to 1.58). The sex-related difference in mortality rates was still apparent in patients with de novo heart failure undergoing reperfusion therapy after hospital presentation (21.3% vs. 15.7%; OR: 1.45; 95% CI: 1.07 to 1.96).
Conclusions
Women are at higher risk to develop de novo heart failure after STEMI and women with de novo heart failure have worse survival than do their male counterparts. Therefore, de novo heart failure is a key feature to explain mortality gap after STEMI among women and men.

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

J Am Coll Cardiol: 11 Nov 2019; 74:2379-2389
Cenko E, van der Schaar M, Yoon J, Manfrini O, ... Badimon L, Bugiardini R
J Am Coll Cardiol: 11 Nov 2019; 74:2379-2389 | PMID: 31699278
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Impact:
Abstract

A Novel Algorithm for Treating Chronic Total Coronary Artery Occlusion.

Tanaka H, Tsuchikane E, Muramatsu T, Kishi K, ... Fujita T, Katoh O
Background
Guidewire manipulation time is rarely used in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) strategies.
Objectives
This study sought to develop an algorithm based on angiographic characteristics and guidewire manipulation time.
Methods
This study assessed 5,843 patients undergoing CTO PCI between January 2014 and December 2017 and enrolled in the Japanese CTO-PCI expert registry and analyzed their CTO-PCI strategies, procedural outcomes, and guidewire manipulation time.
Results
Primary retrograde approach was performed on 1,562 patients. The average Japanese CTO score of primary antegrade approach and primary retrograde approach were 1.7 ± 1.1 and 2.3 ± 1.1, respectively (p < 0.001). The overall guidewire and technical success rates were 92.8% and 90.6%, respectively. Median guidewire manipulation time of guidewire success and failure were 56 min (interquartile range [IQR]: 22 to 111 min) and 176 min (IQR: 130 to 229 min), respectively. Median successful guidewire crossing time of single wiring and parallel wiring in the antegrade alone were 23 min (IQR: 11 to 44 min) and 60 min (IQR: 36 to 97 min), and rescue retrograde approach and primary retrograde approach were 126 min (IQR: 87 to 174 min) and 107 min (IQR: 70 to 161 min), respectively (p < 0.001). Significant predictors for antegrade guidewire failure in primary antegrade approach, which were reattempt, CTO length of ≥20 mm, and no stump, did not predict guidewire failure after collateral channel crossing in primary retrograde approach.
Conclusions
Results from a large registry with information on guidewire manipulation time as well as CTO characteristics suggest a redefinition of the current strategy algorithms.

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

J Am Coll Cardiol: 11 Nov 2019; 74:2392-2404
Tanaka H, Tsuchikane E, Muramatsu T, Kishi K, ... Fujita T, Katoh O
J Am Coll Cardiol: 11 Nov 2019; 74:2392-2404 | PMID: 31699280
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Impact:
Abstract

Coronary Functional Abnormalities in Patients With Angina and Nonobstructive Coronary Artery Disease.

Suda A, Takahashi J, Hao K, Kikuchi Y, ... Sakata Y, Shimokawa H
Background
Approximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary stenosis, in whom coronary functional abnormalities could be involved.
Objectives
This study examined the significance of coronary functional abnormalities in a comprehensive manner for both epicardial and microvascular coronary arteries in patients with angina and nonobstructive coronary artery disease (CAD).
Methods
This study prospectively enrolled 187 consecutive patients (male/female 113/74, 63.2 ± 12.3 years), who underwent acetylcholine provocation test for coronary spasm and measurement of index of microcirculatory resistance (IMR) to evaluate coronary microvascular function, and followed them for a median of 893 days.
Results
Of all subjects, acetylcholine test identified 128 patients with vasospastic angina (VSA) (68%), and cardiac events occurred in 10 patients (5.3%) during the follow-up. Multivariable analysis revealed that IMR correlated with the incidence of cardiac events (hazard ratio: 1.05; 95% confidence interval: 1.02 to 1.09; p = 0.002) and receiver-operating characteristics (ROC) curve analysis identified IMR of 18.0 as the optimal cut-off value. Among the 4 groups based on the cut-off value of IMR and the presence of VSA, the Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with high IMR (≥18.0) and VSA compared with other groups (log rank, p = 0.002). Importantly, intracoronary administration of fasudil, a Rho-kinase inhibitor, significantly ameliorated IMR in the VSA patients with increased IMR (p < 0.0001).
Conclusions
These results indicate that in patients with angina and nonobstructive CAD, coexistence of epicardial coronary spasm and increased microvascular resistance is associated with worse prognosis, for which Rho-kinase activation may be involved.

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

J Am Coll Cardiol: 11 Nov 2019; 74:2350-2360
Suda A, Takahashi J, Hao K, Kikuchi Y, ... Sakata Y, Shimokawa H
J Am Coll Cardiol: 11 Nov 2019; 74:2350-2360 | PMID: 31699275
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Impact:
Abstract

SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for endothelial to mesenchymal transition.

Qin W, Zhang L, Li Z, Xiao D, ... Yang B, Zhang Y
Background
Vascular aging has profound effects on cardiovascular diseases. Endothelial to mesenchymal transition (EndMT) is defined as the acquisition of mesenchymal characteristics by endothelial cells (ECs) and has been found induced in a model of ECs aging. However, whether EndMT occurs during aging in vivo, the functional significance of EndMT on vascular biology and the underlying mechanisms remain unknown.
Methods and results
In this study, we examined the vascular ECs from young (2 months old) and old (18 months old) mice, and demonstrated that aged ECs underwent EndMT. Moreover, the transwell assay showed that EndMT process was accompanied by increased endothelial permeability. It was found that sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, was down-regulated during ECs aging. Knockdown of SIRT6 in young ECs could induce EndMT. Next, we identified five long non-coding RNAs that are enriched in ECs for downstream effector of SIRT6; only metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was significantly up-regulated in aged ECs. Knockdown of SIRT6 could increase MALAT1 levels. Furthermore, the ChIP assay and luciferase reporter gene assay confirmed that SIRT6 bound directly to the promoter region of MALAT1 and suppressed MALAT1 expression. Finally, we demonstrated that MALAT1 mediated aging-induced EndMT through increasing Snail expression.
Conclusion
Our study provides in vivo evidence that ECs undergo EndMT during vascular aging, which increases endothelial permeability. SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for EndMT. Manipulating EndMT may be considered as a new therapeutic strategy for retarding aging-associated vascular diseases.

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

Int J Cardiol: 14 Nov 2019; 295:7-13
Qin W, Zhang L, Li Z, Xiao D, ... Yang B, Zhang Y
Int J Cardiol: 14 Nov 2019; 295:7-13 | PMID: 31399301
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Impact:
Abstract

Treadmill Stress Test in a 56-Year-Old Man.

Kawji MM, Glancy DL

Several findings on an exercise electrocardiogram predicted left main and/or 3-vessel coronary arterial disease, which was confirmed by coronary arteriography, and the 56-year-old man underwent a multivessel coronary arterial bypass operation the following day.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Nov 2019; 124:1647-1648
Kawji MM, Glancy DL
Am J Cardiol: 14 Nov 2019; 124:1647-1648 | PMID: 31514967
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Impact:
Abstract

Relation Between Mitral Valve Prolapse and Erectile Dysfunction (from a Nationwide Case-Control Study).

Chung SD, Liu JC, Lou TN, Shia BC, Lin HC, Kao LT

Some previous literature indicated an association between cardiovascular diseases and erectile dysfunction (ED). This case-control study purposed to evaluate the association between prior mitral valve prolapse (MVP) and ED using data from the Taiwan National Health Insurance Research Dataset. In this study, 48,755 patients with ED were identified as cases, and 195,020 propensity score-matched patients without ED were selected as controls. Conditional logistic regressions were conducted to evaluate the odds ratios (ORs) for previous MVP between cases and the matched controls. In all sampled patients, 4,565 (1.87%) patients had MVP before the index date. MVP was found in 1,304 (2.67%) cases and in 3,261 (1.67%) matched controls. Patients with ED had a significantly higher occurrence of MVP than the controls. In addition, after propensity score matching, a conditional logistic regression analysis showed that the OR of previous MVP for patients with ED was 1.63 (95% confidence interval [CI] 1.52 to 1.74) compared to the matched controls. The ORs of previous MVP for patients with ED aged ≤65 years and those >65 years were 1.68 (95% CI 1.56 to 1.81) and 1.49 (95% CI 1.30 to 1.70), respectively, compared with the matched controls. We found that patients with erectile dysfunction had significantly higher odds of previous MVP compared with matched control subjects without ED regardless of the age group.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Nov 2019; 124:1590-1593
Chung SD, Liu JC, Lou TN, Shia BC, Lin HC, Kao LT
Am J Cardiol: 14 Nov 2019; 124:1590-1593 | PMID: 31514966
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Impact:
Abstract

Living myocardial slices: a novel multicellular model for cardiac translational research.

Perbellini F, Thum T

Heart function relies on the interplay of several specialized cell types and a precisely regulated network of chemical and mechanical stimuli. Over the last few decades, this complexity has often been undervalued and progress in translational cardiovascular research has been significantly hindered by the lack of appropriate research models. The data collected are often oversimplified and these make the translation of results from the laboratory to clinical trials challenging and occasionally misleading. Living myocardial slices are ultrathin (100-400μm) sections of living cardiac tissue that maintain the native multicellularity, architecture, and structure of the heart and can provide information at a cellular/subcellular level. They overcome most of the limitations that affect other in vitro models and they can be prepared from human specimens, proving a clinically relevant multicellular human model for translational cardiovascular research. The publication of a reproducible protocol, and the rapid progress in methodological and technological discoveries which prevent significant structural and functional changes associated with chronic in vitro culture, has overcome the last barrier for the in vitro use of this human multicellular preparations. This technology can bridge the gap between in vitro and in vivo human studies and has the potential to revolutionize translational research approaches.

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

Eur Heart J: 10 Nov 2019; epub ahead of print
Perbellini F, Thum T
Eur Heart J: 10 Nov 2019; epub ahead of print | PMID: 31711161
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Impact:
Abstract

Impact of renin-angiotensin system inhibitors on clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: an analysis of from the PARTNER 2 trial and registries.

Chen S, Redfors B, Nazif T, Kirtane A, ... Kodali SK, Leon MB
Aims
Left ventricular pressure overload is associated with activation of the cardiac renin-angiotensin system, which may contribute to myocardial fibrosis and worse clinical outcomes. We sought to assess the association between treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) at baseline and clinical outcomes in patients with symptomatic, severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) in the PARTNER 2 trial and registries.
Methods and results
A total of 3979 intermediate, high, or prohibitive risk patients who underwent TAVR in the PARTNER 2 trial and registries (excluding the valve in valve registry) were included in the study. Clinical outcomes at 2 years were compared according to baseline ACEI/ARB treatment status using Kaplan-Meier event rates and study-stratified multivariable Cox proportional hazards regression models. Sensitivity analysis was conducted using propensity score matching. Of 3979 patients who were included in the current analysis, 1736 (43.6%) were treated and 2243 (56.4%) were not treated with ACEI/ARB at baseline. Treatment with ACEI/ARB was associated with lower 2-year all-cause mortality (18.6% vs. 27.5%, P < 0.0001), cardiovascular mortality (12.3% vs. 17.9%, P < 0.0001), and non-cardiovascular mortality (7.2% vs. 11.7%, P < 0.0001). Angiotensin-converting enzyme inhibitor/ARB treatment at baseline remained independently associated with a lower hazard of 2-year all-cause and cardiovascular mortality after multivariable adjustment, and propensity score matching.
Conclusion
In a large cohort of patients with severe symptomatic AS from the PARTNER 2 trial and registries, ACEI/ARB treatment at baseline was independently associated with a lower risk of 2-year all-cause and cardiovascular mortality.

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: 10 Nov 2019; epub ahead of print
Chen S, Redfors B, Nazif T, Kirtane A, ... Kodali SK, Leon MB
Eur Heart J: 10 Nov 2019; epub ahead of print | PMID: 31711153
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Impact:
Abstract

ACC/AHA/HRS Versus ESC Guidelines for the Diagnosis and Management of Syncope: JACC Guideline Comparison.

Goldberger ZD, Petek BJ, Brignole M, Shen WK, ... Moya A, Hamdan MH

Syncope is a commonly encountered and challenging problem in medical practice. Presentations are variable, and the causal mechanism often remains elusive even after extensive (and often expensive) evaluation. Clinical practice guidelines have been developed to help guide the multidisciplinary approach necessary to diagnose and manage the broad spectrum of patients presenting with syncope. The American College of Cardiology/American Heart Association, in collaboration with the Heart Rhythm Society, published its first syncope guidelines in 2017. The European Society of Cardiology released the fourth iteration of its syncope guidelines in 2018. This review highlights the differences and congruencies between the 2 sets of recommendations, their implications for clinical practice, the remaining gaps in understanding, and areas of future research.

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

J Am Coll Cardiol: 11 Nov 2019; 74:2410-2423
Goldberger ZD, Petek BJ, Brignole M, Shen WK, ... Moya A, Hamdan MH
J Am Coll Cardiol: 11 Nov 2019; 74:2410-2423 | PMID: 31699282
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Impact:
Abstract

Cardiorespiratory fitness, muscular strength, and obesity in adolescence and later chronic disability due to cardiovascular disease: a cohort study of 1 million men.

Henriksson H, Henriksson P, Tynelius P, Ekstedt M, ... Lavie CJ, Ortega FB
Aims
Cardiorespiratory fitness, muscular strength, and obesity in adulthood are risk factors for cardiovascular disease (CVD). However, little is known regarding the associations of these risk factors, already in adolescence, with later disability due to chronic CVD. Hence, we investigated associations of cardiorespiratory fitness, muscular strength, and body mass index (BMI) in adolescence with later chronic disability due to specific causes of CVD disability (i.e. cerebrovascular disease, ischaemic heart disease and heart failure).
Methods and results
This population-based cohort study included 1 078 685 male adolescents (16-19 years) from the Swedish military conscription register from 1972 to 1994. Cardiorespiratory fitness (bicycle ergometer test), muscular strength (knee extension strength), and BMI were measured during the conscription examination. Information about disability pension due to CVD was retrieved from the Social Insurance Agency during a mean follow-up of 28.4 years. Cardiorespiratory fitness was strongly and inversely associated with later risk of chronic CVD disability for all investigated causes. The association was particularly strong for ischaemic heart diseases (hazard ratio 0.11, 95% confidence interval 0.05-0.29 for highest vs. lowest fitness-quintiles). Furthermore, overweight/obesity were associated with CVD disability for all investigated causes. Conversely, associations of muscular strength with CVD disability were generally weak.
Conclusions
This study provides evidence for associations between low levels of cardiorespiratory fitness and obesity with later risk of chronic disability due to CVD. Preventive actions may begin at young ages and include promotion of cardiorespiratory fitness and healthy body weight.

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

Eur Heart J: 08 Nov 2019; epub ahead of print
Henriksson H, Henriksson P, Tynelius P, Ekstedt M, ... Lavie CJ, Ortega FB
Eur Heart J: 08 Nov 2019; epub ahead of print | PMID: 31710669
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Impact:
Abstract

Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2).

Kuntic M, Oelze M, Steven S, Kröller-Schön S, ... Daiber A, Münzel T
Aims
Electronic (e)-cigarettes have been marketed as a \'healthy\' alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms.
Methods and results
Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation.
Conclusions
E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.

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

Eur Heart J: 12 Nov 2019; epub ahead of print
Kuntic M, Oelze M, Steven S, Kröller-Schön S, ... Daiber A, Münzel T
Eur Heart J: 12 Nov 2019; epub ahead of print | PMID: 31715629
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Impact:
Abstract

The role of implantable cardioverter-defibrillators and sudden cardiac death prevention: indications, device selection, and outcome.

Goldenberg I, Huang DT, Nielsen JC

Multiple randomized multicentre clinical trials have established the role of the implantable cardioverter-defibrillator (ICD) as the mainstay in the treatment of ventricular tachyarrhythmias and sudden cardiac death (SCD) prevention. These trials have focused mainly on heart failure patients with advanced left ventricular dysfunction and were mostly conducted two decades ago, whereas a more recent trial has provided conflicting results. Therefore, much remains to be determined on how best to balance the identification of patients at high risk of SCD together with who would benefit most from ICD implantation in a contemporary setting. Implantable cardioverter-defibrillators have also evolved from the simple, defibrillation-only devices implanted surgically to more advanced technologies of multi-chamber devices, with physiologic bradycardic pacing, including cardiac resynchronization therapy, atrial and ventricular therapeutic pacing algorithms, and subcutaneous ICDs. These multiple options necessitate individualized approach to device selection and programming. This review will focus on the current knowledge on selection of patients for ICD treatment, device selection and programming, and future directions of implantable device therapy for SCD prevention.

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: 11 Nov 2019; epub ahead of print
Goldenberg I, Huang DT, Nielsen JC
Eur Heart J: 11 Nov 2019; epub ahead of print | PMID: 31713598
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Impact:
Abstract

Atrial fibrillation and cardiac fibrosis.

Sohns C, Marrouche NF

The understanding of atrial fibrillation (AF) evolved from a sole rhythm disturbance towards the complex concept of a cardiomyopathy based on arrhythmia substrates. There is evidence that atrial fibrosis can be visualized using late gadolinium enhancement cardiac magnetic resonance imaging and that it is a powerful predictor for the outcome of AF interventions. However, a strategy of an individual and fibrosis guided management of AF looks promising but results from prospective multicentre trials are pending. This review gives an overview about the relationship between cardiac fibrosis and AF focusing on translational aspects, clinical observations, and fibrosis imaging to emphasize the concept of personalized paths in AF management taking into account the individual amount and distribution of fibrosis.

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

Eur Heart J: 11 Nov 2019; epub ahead of print
Sohns C, Marrouche NF
Eur Heart J: 11 Nov 2019; epub ahead of print | PMID: 31713590
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Impact:
Abstract

Gender in cardiovascular medicine: chest pain and coronary artery disease.

Mehta PK, Bess C, Elias-Smale S, Vaccarino V, ... Pepine CJ, Bairey Merz CN

Ischaemic heart disease (IHD) remains the leading cause of morbidity and mortality among women and men yet women are more often underdiagnosed, have a delay in diagnosis, and/or receive suboptimal treatment. An implicit gender-bias with regard to lack of recognition of sex-related differences in presentation of IHD may, in part, explain these differences in women compared with men. Indeed, existing knowledge demonstrates that angina does not commonly relate to obstructive coronary artery disease (CAD). Emerging knowledge supports an inclusive approach to chest pain symptoms in women, as well as a more thoughtful consideration of percutaneous coronary intervention for angina in stable obstructive CAD, to avoid chasing our tails. Emerging knowledge regarding the cardiac autonomic nervous system and visceral pain pathways in patients with and without obstructive CAD offers explanatory mechanisms for angina. Interdisciplinary investigation approaches that involve cardiologists, biobehavioural specialists, and anaesthesia/pain specialists to improve angina treatment should be pursued.

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: 11 Nov 2019; epub ahead of print
Mehta PK, Bess C, Elias-Smale S, Vaccarino V, ... Pepine CJ, Bairey Merz CN
Eur Heart J: 11 Nov 2019; epub ahead of print | PMID: 31713592
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Impact:
Abstract

Molecular signature of cardiogenic shock.

Iborra-Egea O, Rueda F, García-García C, Borràs E, Sabidó E, Bayes-Genis A

The incidence of cardiogenic shock (CS) has increased remarkably over the past decade and remains a challenging condition with mortality rates of ∼50%. Cardiogenic shock encompasses cardiac contractile dysfunction; however, it is also a multiorgan dysfunction syndrome, often complicated by a systemic inflammatory response with severe cellular and metabolic dysregulations. Here, we review the evidence on the biochemical manifestations of CS, elaborating on current gold standard biomarkers and novel candidates from molecular signatures of CS. Glucose and lactate, both identified over a century ago, remain the only clinically used biomarkers in current predictive risk scores. Novel genomic, transcriptomic, and proteomic data are discussed, and a recently reported molecular score derived from unbiased proteomic discovery, the CS4P, which includes liver fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1 is comprehensively described. Recent advances in -omics technologies provide new insight into a more holistic molecular signature of CS. Thus, we need to open new diagnostic and therapeutic avenues if we aim to improve outcomes.

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

Eur Heart J: 12 Nov 2019; epub ahead of print
Iborra-Egea O, Rueda F, García-García C, Borràs E, Sabidó E, Bayes-Genis A
Eur Heart J: 12 Nov 2019; epub ahead of print | PMID: 31722370
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Impact:
Abstract

Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY).

White WB, Wakefield DB, Moscufo N, Guttmann CRG, ... Hall CB, Wolfson L
Background
Subcortical microvascular disease represented by brain white matter hyperintensity on magnetic resonance imaging is associated with functional decline in older people with hypertension. The effects of 2 levels of 24-hour average systolic blood pressure (BP) on mobility, white matter disease progression, and cognitive function over 3 years were studied.
Methods
This trial was a prospective, randomized, blinded end-points study in patients ≥75 years of age with systolic hypertension and magnetic resonance imaging evidence of white matter hyperintensity lesions. Patients were randomized to a 24-hour mean systolic BP of ≤130 mm Hg (intensive treatment) versus ≤145 mm Hg (standard treatment) with antihypertensive therapies. Primary study outcomes were changes in mobility (gait speed) and accrual of white matter hyperintensity volume after 3 years. Changes in cognitive function (executive processing) and adverse events were also evaluated.
Results
In 199 randomized patients, the mean age of the cohort was 80.5 years, and 54% were women; the average 24-hour systolic BP was 149 mm Hg. Goal BPs were achieved after a median treatment period of 3 to 4 months; at that time, the mean 24-hour systolic BP was 127.7 mm Hg in the intensive treatment group and 144.0 mm Hg in the standard treatment group for an average difference of 16.3 mm Hg. Changes in gait speed were not different between treatment groups (0.40±2.0 versus 0.42±2.7 s in the intensive treatment and standard treatment groups, respectively; =0.91), whereas changes from baseline in white matter hyperintensity volumes were smaller (0.29%) in the intensive treatment group compared with the standard treatment group (0.48%; =0.03). Cognitive outcomes also were not different between the treatment groups. Major adverse cardiovascular events were higher in the standard treatment group compared with the intensive treatment group (17 versus 4 patients; =0.01). Falls, with or without injury, and syncope were comparable in the treatment groups.
Conclusions
Intensive lowering of ambulatory BP reduction in older patients with hypertension did not result in differences in mobility outcomes but was associated with a reduction in accrual of subcortical white matter disease. Over periods >3 years, a reduction in the accumulation of white matter disease may be a factor in conserving function.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01650402.



Circulation: 11 Nov 2019; 140:1626-1635
White WB, Wakefield DB, Moscufo N, Guttmann CRG, ... Hall CB, Wolfson L
Circulation: 11 Nov 2019; 140:1626-1635 | PMID: 31607143
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Impact:
Abstract

Usefulness of ventilatory gas analysis for the non-invasive evaluation of the severity of chronic thromboembolic pulmonary hypertension.

Akizuki M, Sugimura K, Aoki T, Kakihana T, ... Shimokawa H, Kohzuki M
Background
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organic thrombotic obstructions in the pulmonary arteries with reduced pulmonary vascular reserve. This study aimed to examine whether postural changes in ventilatory gas analysis parameters are useful for assessing pulmonary hemodynamics in patients with CTEPH.
Methods
A total of 44 patients with newly diagnosed CTEPH (CTEPH group), 33 patients with improved CTEPH (mean pulmonary arterial pressure [mPAP] <25 mm Hg), and 25 controls were enrolled. Patients with improved CTEPH referred to patients without residual PH who were previously diagnosed with CTEPH and already received optimal therapies. Various pulmonary function parameters were examined in supine and sitting positions, and postural changes were calculated (Δ[supine - sitting]). In 32 patients with CTEPH, we examined hemodynamic and ventilatory gas analysis parameters before the first balloon pulmonary angioplasty (BPA) and during follow-up.
Results
Patients with CTEPH had significantly lower supine end-tidal carbon dioxide pressure (PCO) and ΔPCO than controls (both P < 0.001), and these parameters were significantly correlated with mPAP (R = 0.507, P < 0.0001 and R = 0.470, P < 0.001, respectively). Supine PCO and ΔPCO were significantly lower in patients with improved CTEPH than in controls (both P < 0.001). Hemodynamic and echocardiographic parameters were comparable in both groups. Furthermore, significant correlation between the change in mPAP and change in supine PCO by BPA was noted (R = 0.478, P < 0.001).
Conclusion
These results indicate that postural changes in ventilatory gas analysis parameters are useful and non-invasive method for the evaluation of mPAP, which is one of the hemodynamic parameters of CTEPH severity.

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

Int J Cardiol: 30 Nov 2019; 296:149-154
Akizuki M, Sugimura K, Aoki T, Kakihana T, ... Shimokawa H, Kohzuki M
Int J Cardiol: 30 Nov 2019; 296:149-154 | PMID: 31350036
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Impact:
Abstract

Association between reduced left ventricular ejection fraction following non-ST-segment elevation myocardial infarction and long-term mortality in patients of advanced age.

Siddiqui AJ, Holzmann MJ
Objectives
We sought to investigate the association between LVEF and clinical outcomes after NSTEMI, and the benefit of guideline-recommended pharmacotherapy in elderly patients.
Background
New-onset reduction in LVEF is common after NSTEMI in patients of advanced age. There is little information about outcomes in relation to LVEF, and the benefit of guideline-recommended pharmacotherapy in elderly patients.
Materials and methods
The SWEDEHEART registry was used to identify all patients in Sweden >80 years with NSTEMI from 2011 to 2014. A normal LVEF was defined as >50%; mildly reduced, 40%-49%; moderately reduced, 30%-39%; and severely reduced, <30%. Cox regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between a reduced LVEF compared with a normal LVEF and all-cause mortality. Similarly, the presence versus absence of treatment with guideline-recommended medications at discharge and mortality was evaluated.
Results
6287 patients were included where 59%, 20%, 13%, and 6% had a normal, mildly reduced, moderately reduced, and severely reduced LVEF, respectively. During a median follow-up of 2.4 years, 2211 (35%) patients died. All three categories of impaired LVEF were associated with higher mortality: mildly reduced (1.44, 1.25-1.65), moderately reduced (1.93, 1.67-2.23), and severely reduced (3.24, 2.74-3.85). Patients who were treated with beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, or statins at discharge had lower mortality.
Conclusions
New-onset reduction of the LVEF is common in advanced-age patients with NSTEMI and is associated with higher mortality. Treatment with guideline-recommended medications is associated with a better prognosis.

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

Int J Cardiol: 30 Nov 2019; 296:15-20
Siddiqui AJ, Holzmann MJ
Int J Cardiol: 30 Nov 2019; 296:15-20 | PMID: 31327520
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Impact:
Abstract

Peri-procedural thrombocytopenia after aortic bioprosthesis implant: A systematic review and meta-analysis comparison among conventional, stentless, rapid-deployment, and transcatheter valves.

Jiritano F, Santarpino G, Serraino GF, Ten Cate H, ... Mastroroberto P, Lorusso R
Background
Thrombocytopenia has been shown to occur soon after surgical biological aortic valve replacement (AVR), and recently reported also after transcatheter valve implantation (TAVI). The mechanism underlying this phenomenon is still unknown, and its clinical impact on the peri-operative outcome has been poorly investigated.
Methods
A systematic review and a meta-analysis of all available studies reporting data about peri-procedural thrombocytopenia on isolated bio-AVR, comparing rapid-deployment (RDV), stentless (stentless-AVR), and TAVI vs. stented (stented-AVR) valves, have been performed.
Results
Fifteen trials (2.163 patients) were included in the meta-analysis. Perioperative platelet reduction ranged from 35% to 55% in stented-AVR, from 60% to 77% in stentless-AVR, from 53% to 60% in RDV, and from to 21% to 72% in TAVI (apparently, balloon-expandable valves more frequently associated to thrombocytopenia). Stented-AVR required more red blood cells transfusion than stentless-AVR (P < 0.0001), whereas no difference has been found between RDV and stented-AVR. Platelet transfusion rate was very low in all surgical groups. No difference has been found in RDV and stentless-AVR vs. stented-AVR, in terms of reoperation for bleeding, and length-of-intensive care unit or hospital stay.
Conclusions
Thrombocytopenia-related major adverse events were mainly reported in TAVI patients, whereas clinically meaningless in surgical patients. Transient peri-procedural thrombocytopenia is common after bio-AVR, regardless of prosthesis\'s type or implant modality. It should receive appropriate monitoring and focused investigations.

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

Int J Cardiol: 30 Nov 2019; 296:43-50
Jiritano F, Santarpino G, Serraino GF, Ten Cate H, ... Mastroroberto P, Lorusso R
Int J Cardiol: 30 Nov 2019; 296:43-50 | PMID: 31351790
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Impact:
Abstract

Modified Bentall procedure: Mechanical vs biological valved conduits in patients older than 65 years.

Lechiancole A, Celiento M, Isola M, Gatti G, ... Bortolotti U, Livi U
Background
The modified Bentall procedure is still the treatment of choice for patients requiring combined replacement of the ascending aorta and aortic valve. We compared the long-term outcome of patients >65 years of age undergoing Bentall procedure with biological vs mechanical valved conduits in a multi institutional study.
Methods
A total of 282 patients, undergoing a Bentall operation (January 1994-May 2015), with a biological (Group 1, 173 patients) or a mechanical (Group 2, 109 patients) conduit were reviewed, the primary outcome being analysis of late survival and freedom from major adverse events.
Results
Hospital mortality was 5% (9 patients) and 2% (2 patients) for Group 1 and Group 2 (p = 0.2). Median follow-up was 77 months (range Q1-Q3: 49-111) for Group 1 vs 107 months (range Q1-Q3: 63-145) for Group 2 (p < 0.001). A not statistically significant advantage in late survival was found in patients receiving mechanical valved conduits (36% for Group 1 vs 58% for Group 2 at 12 years; p = 0.09), although freedom from major adverse events was similar between the 2 groups (33% in Group 1 vs 50% in Group 2 at 12 years; p = 0.3).
Conclusions
In conclusion, mechanical-valved conduits employed for the modified Bentall procedure show a trend towards an improved late survival in patients ≥65 years of age and particularly in those between 65 and 75 years, despite a higher incidence of major adverse events. Our results indicate the need for specific guidelines to better define the ideal age limit for each type of valved conduit.

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

Int J Cardiol: 30 Nov 2019; 296:38-42
Lechiancole A, Celiento M, Isola M, Gatti G, ... Bortolotti U, Livi U
Int J Cardiol: 30 Nov 2019; 296:38-42 | PMID: 31351789
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Impact:
Abstract

Risk and predictors of subsequent cancers of patients with newly-diagnosed atrial fibrillation - A nationwide population-based study.

Hung YP, Hu YW, Liu CJ, Lin YJ, ... Albert CM, Chao TF
Aims
Patients with atrial fibrillation (AF) may be at higher risk for cancer, possibly due to the presence of coexisting risk factors. In this study, we investigate the magnitude and predictors of this potential risk within a population-based study.
Methods and results
The study cohort included 332,555 AF patients aged ≥20 years without past history of cancer. Standardized incidence ratio (SIR) was used as a measure of relative risk, comparing observed cancer incidence among patients with AF with that expected based on cancer incidence in the Taiwanese population. During the observation period, 22,911 incident cancers occurred with an incidence of 1.65%/year. Compared with the general population, AF patients had a significantly higher cancer risk with a SIR of 1.37 (95%CI = 1.36-1.39). Patients with new-onset AF had an elevated cancer risk which was highest within 1 year (SIR = 2.30; 95%CI, 2.25-2.36) and persisted beyond 10 years after AF was diagnosed (SIR = 1.18; 95%CI, 1.11-1.25). Age ≥ 65 years, male gender, hypertension, diabetes, chronic obstructive pulmonary disease (COPD) and liver cirrhosis were significantly associated with development of cancers among AF patients. The hazard ratio of cancers increased from 1.40 (95%CI = 1.28-1.53) for patients having 1 risk factor to 5.14 (95%CI = 4.03-6.06) for patients with 6 risk factors, in comparison to those without any risk factors.
Conclusion
In the nationwide cohort study, we show that AF patients had a higher risk of cancer. Age, male gender, hypertension, diabetes, COPD and liver cirrhosis are important risk factors of cancer among AF patients. Prompt and detailed examinations may be considered for incident AF patients with multiple risk factors to early detect the occult malignancy.

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

Int J Cardiol: 30 Nov 2019; 296:81-86
Hung YP, Hu YW, Liu CJ, Lin YJ, ... Albert CM, Chao TF
Int J Cardiol: 30 Nov 2019; 296:81-86 | PMID: 31466884
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Impact:
Abstract

Stent Thrombosis in Patients with Atrial Fibrillation Undergoing Coronary Stenting in the AUGUSTUS Trial.

Lopes RD, Leonardi S, Wojdyla DM, Vora AN, ... Mehran R, Alexander JH

We describe the incidence, timing, and characteristics of stent thrombosis and its consequences in patients with atrial fibrillation (AF) in the AUGUSTUS trial who received a coronary stent during their qualifying admission (acute coronary syndrome [ACS] or elective percutaneous coronary intervention [PCI]) and the randomized treatment effects of low-dose aspirin (compared with placebo) and apixaban (compared with vitamin K antagonist [VKA]) on the risk of stent thrombosis. We included patients who received a stent during their qualifying admission. We excluded patients with medically-managed ACS (n=1097) or an unknown qualifying index event (n=19). The protocol was approved by appropriate ethics committees; patients provided written informed consent prior to participation.



Circulation: 10 Nov 2019; epub ahead of print
Lopes RD, Leonardi S, Wojdyla DM, Vora AN, ... Mehran R, Alexander JH
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707833
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Impact:
Abstract

Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis.

Bick AG, Pirruccello JP, Griffin GK, Gupta N, ... Kathiresan S, Natarajan P

Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells due to acquired leukemic mutations in genes such asor . In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk.We analyzed exome sequences from 35,416 individuals in the UK Biobank without prevalent CVD, to identify participants withorCHIP. We used thep.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified byp.Asp358Ala.We identified 1,079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (HR=1.27, 95% CI: 1.04-1.56, p=0.019), with greater risk from large CHIP clones (HR=1.59, 95% CI: 1.21-2.09, p<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (HR=0.46, 95% CI: 0.29-0.73, p<0.001) but not in individuals without CHIP (HR=0.95, 95% CI: 0.89-1.06, p=0.08) (p=0.003). In 9,951 independent participants, the association of CHIP status with myocardial infarction similarly varied byp.Asp358Ala (pinteraction=0.036).CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.



Circulation: 10 Nov 2019; epub ahead of print
Bick AG, Pirruccello JP, Griffin GK, Gupta N, ... Kathiresan S, Natarajan P
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707836
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Impact:
Abstract

Slowing Progression of Cardiovascular Calcification with SNF472 in Patients on Hemodialysis: Results of a Randomized, Phase 2b Study.

Raggi P, Bellasi A, Bushinsky D, Bover J, ... Perelló J, Chertow GM

The high cardiovascular morbidity and mortality in patients with end-stage kidney disease (ESKD) could be partially due to extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits formation and growth of hydroxyapatite.This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium (CAC) volume score and other measurements of cardiovascular calcification by CT scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with ESKD receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log CAC volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least one dose of SNF472 or placebo and had an evaluable CT scan post-randomization.The mean change in CAC volume score was 11% (95% CI, 7%-15%) for the combined SNF472 dose group and 20% (95% CI, 14%-26%) for placebo (=0.016). SNF472 compared to placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5%-24%] vs 98% [95% CI, 77%-123%], <0.001), but not in the thoracic aorta (23% [95% CI, 16%-30%] vs 28% [95% CI, 19%-38%], P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least one treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively.Compared with placebo, SNF472 significantly attenuated progression of CAC and aortic valve calcification in patients with ESKD receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events.URL: https://www.clinicaltrials.gov Unique identifier: NCT02966028.



Circulation: 10 Nov 2019; epub ahead of print
Raggi P, Bellasi A, Bushinsky D, Bover J, ... Perelló J, Chertow GM
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707860
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Impact:
Abstract

Patients with High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit from Alirocumab Treatment in the Odyssey Outcomes Trial.

Damask A, Steg PG, Schwartz GG, Szarek M, ... Paulding C,

Alirocumab, an antibody that blocks proprotein convertase subtilisin/kexin type 9 (PCSK9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial. In this study, higher baseline LDL cholesterol (LDL-C) levels predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. Herein we performanalyses to determine whether high PRS for CAD identifies higher-risk individuals, independently from baseline LDLC and other known risk factors, who might derive greater benefit from alirocumab treatment.ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death from CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6,579,025 genetic variants was evaluated in 11,953 patients with available DNA samples. Analysis of MACE risk was performed in placebo treated patients while treatment benefit analysis was performed in all patients.The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile) (p<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.46-0.86; p = 0.004) versus 13% reduction in the low PRS group (HR 0.87; 95% CI 0.78-0.98; p=0.022; interaction p = 0.04).A high PRS for CAD is associated with elevated risk for recurrent MACE after ACS, and larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.



Circulation: 10 Nov 2019; epub ahead of print
Damask A, Steg PG, Schwartz GG, Szarek M, ... Paulding C,
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707832
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Impact:
Abstract

Inhibition of mTOR Signaling Enhances Maturation of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells via p53-Induced Quiescence.

Garbern JC, Helman A, Sereda R, Sarikhani M, ... Melton DA, Lee RT

Current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells (iPSCs) are capable of generating highly pure cardiomyocyte populations as determined by expression of cardiac troponin T. However, these cardiomyocytes remain immature, more closely resembling the fetal state, with a lower maximum contractile force, slower upstroke velocity, and immature mitochondrial function compared with adult cardiomyocytes. Immaturity of iPSC-derived cardiomyocytes may be a significant barrier to clinical translation of cardiomyocyte cell therapies for heart disease. During development, cardiomyocytes undergo a shift from a proliferative state in the fetus to a more mature but quiescent state after birth. The mechanistic target of rapamycin (mTOR) signaling pathway plays a key role in nutrient sensing and growth. We hypothesized that transient inhibition of the mTOR signaling pathway could lead cardiomyocytes to a quiescent state and enhance cardiomyocyte maturation.Cardiomyocytes were differentiated from three human iPSC lines using small molecules to modulate the Wnt pathway. Torin1 (0-200 nM) was used to inhibit the mTOR pathway at various time points. We quantified contractile, metabolic, and electrophysiological properties of matured iPSC-derived cardiomyocytes. We utilized the small molecule inhibitor, pifithrin-α, to inhibit p53 signaling, and nutlin-3a, a small molecule inhibitor of MDM2 to upregulate and increase activation of p53.Torin1 (200 nM) increased the percentage of quiescent cells (G phase) from 24% to 48% compared to vehicle control (p<0.05). Torin1 significantly increased expression of selected sarcomere proteins (including TNNI3) and ion channels (including Kir2.1) in a dose-dependent manner when Torin1 was initiated after onset of cardiomyocyte beating. Torin1-treated cells had an increased relative maximum force of contraction, increased maximum oxygen consumption rate, decreased peak rise time, and increased downstroke velocity. Torin1 treatment increased protein expression of p53, and these effects were inhibited by pifithrin-α. In contrast, nutlin-3a independently upregulated p53, led to an increase in TNNI3 expression and worked synergistically with Torin1 to further increase expression of both p53 and TNNI3. Transient treatment of human iPSC-derived cardiomyocytes with Torin1 shifts cells to a quiescent state and enhances cardiomyocyte maturity.



Circulation: 10 Nov 2019; epub ahead of print
Garbern JC, Helman A, Sereda R, Sarikhani M, ... Melton DA, Lee RT
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707831
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Impact:
Abstract

Effect of Empagliflozin on Erythropoietin Levels, Iron Stores and Red Blood Cell Morphology in Patients with Type 2 Diabetes and Coronary Artery Disease.

Mazer CD, Hare GMT, Connelly PW, Gilbert RE, ... Connelly KA, Verma S

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes including hospitalization for heart failure and mortality in people with and without diabetes. The mechanism(s) underlying this benefit remain unclear. While several hypotheses have been suggested (including SGLT2 inhibitor mediated diuresis and natriuresis, reduction in blood pressure and afterload, direct effects on myocardial sodium and calcium handling, alterations in myocardial energetics, reduction in left ventricular mass and improved progenitor cell response), a mediation analysis from the EMPA-REG OUTCOME trial suggests that an increase in hematocrit may account for over half of the mortality benefit observed. The consistent observation of an increase in hematocrit, even in those without diabetes, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin (EPO) secretion by the kidney. This SGLT2 inhibitor mediated increase in EPO production (and resultant rise in hematocrit) could lead to systemic organ protection by virtue of its capacity as a circulating pleiotropic cytokine, known to favorably influence cardiomyocyte mitochondrial function, angiogenesis, cell proliferation and inflammation. In addition, an increase in EPO-induced hematocrit may also improve myocardial function by directly enhancing myocardial and systemic tissue oxygen delivery.



Circulation: 10 Nov 2019; epub ahead of print
Mazer CD, Hare GMT, Connelly PW, Gilbert RE, ... Connelly KA, Verma S
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707794
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Impact:
Abstract

Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Chronic Kidney Disease According to Baseline HbA1c, Including Those with HbA1c <7%: Results From the CREDENCE Trial.

Cannon CP, Perkovic V, Agarwal R, Baldassarre J, ... Zinman B, Mahaffey KW

Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents. Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD). Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%. We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.



Circulation: 10 Nov 2019; epub ahead of print
Cannon CP, Perkovic V, Agarwal R, Baldassarre J, ... Zinman B, Mahaffey KW
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707795
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Impact:
Abstract

REDUCE-IT USA: Results from the 3,146 Patients Randomized in the United States.

Bhatt DL, Miller M, Brinton EA, Jacobson TA, ... Ballantyne CM,

Some trials have found patients from the United States of America (USA) derive less benefit than patients enrolled outside the USA. This prespecified subgroup analysis of Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial (REDUCE-IT) was conducted to determine the degree of benefit of icosapent ethyl in the USA.REDUCE-IT randomized 8,179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein (LDL)-cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes to icosapent ethyl 4 grams/day or placebo. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. A prespecified hierarchy examined individual and composite endpoints.A total of 3,146 USA patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women, 9.7% Hispanic. The primary endpoint occurred in 24.7% of placebo versus 18.2% of icosapent ethyl patients [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.59-0.80, p=0.000001]; the key secondary endpoint occurred in 16.6% versus 12.1% (HR 0.69, 95% CI 0.57-0.83, p=0.00008). All prespecified hierarchy endpoints were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%, HR 0.66, 95% CI 0.49-0.90, p=0.007), myocardial infarction (8.8% to 6.7%, HR 0.72, 95% CI 0.56-0.93, p=0.01), stroke (4.1% to 2.6%, HR 0.63, 95% CI 0.43-0.93, p=0.02), and all-cause mortality (9.8% to 7.2%, HR 0.70, 95% CI 0.55-0.90, p=0.004); for all-cause mortality for the USA versus non-USA patients, p=0.02. Safety and tolerability findings were consistent with the full study cohort.While the non-USA subgroup showed significant reductions in the primary and key secondary endpoints, the USA subgroup demonstrated particularly robust risk reductions across a variety of composite and individual endpoints, including all-cause mortality.URL: https://clinicaltrials.gov Unique Identifier: NCT01492361.



Circulation: 10 Nov 2019; epub ahead of print
Bhatt DL, Miller M, Brinton EA, Jacobson TA, ... Ballantyne CM,
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707829
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Impact:
Abstract

Supplementation with Vitamin D and/or Omega-3 Fatty Acids and Incidence of Heart Failure Hospitalization: VITAL-Heart Failure.

Djoussé L, Cook NR, Kim E, Bodar V, ... Manson JE,

Among older adults, heart failure (HF) is the leading cause of hospitalization in the US and is associated with high costs and mortality. Vitamin D and marine omega-3 (n-3) fatty acids have each been associated with reduced risks of HF in observational studies, but randomized trial evidence is limited. The current ancillary study sought to investigate the effects of vitamin D and n-3 supplements on the incidence of HF hospitalization in a large multi-ethnic cohort. VITAL-HF is an ancillary study of the parent VITAL trial, which is a completed randomized trial with a two-by-two factorial design to examine the efficacy of vitamin D (2000 IU/d) and n-3 fatty acids (1 gram per day, including eicosapentaenoic acid [EPA, 460 mg] + docosahexaenoic acid [DHA, 380 mg]) for the prevention of cardiovascular disease and cancer in 25, 871 adults from 2011 to 2017. Detailed description of the VITAL design and main results has been published. We excluded 36 participants with prevalent HF for current analyses. Each participant signed informed consent and the study protocol was approved by the Institutional Review Board of Brigham and Women\'s Hospital.



Circulation: 10 Nov 2019; epub ahead of print
Djoussé L, Cook NR, Kim E, Bodar V, ... Manson JE,
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31709816
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Impact:
Abstract

HIV Infection is Associated with Variability in Ventricular Repolarization: The Multicenter AIDS Cohort Study (MACS).

Heravi AS, Etzkorn L, Urbanek J, Crainiceanu C, ... Wu KC, Post WS

People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV-) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability using QT variability index (QTVI), defined as a log measure of QT interval variance indexed to heart rate (HR) variance.We studied 1123 men (589 HIV+ and 534 HIV-) from the Multicenter AIDS Cohort Study (MACS), using the Zio ambulatory electrocardiography (ECG) patch. Beat-to-beat analysis of up to 4 full days of ECG data per participant were performed using an automated algorithm [median analyzed duration (Q1-Q3): 78.3 (66.3-83.0) hours/person]. QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.Mean (SD) age was 60.1 (11.9) years among HIV- and 54.2 (11.2) years among HIV+ participants (p<0.001), 83% of whom had undetectable (<20 copies/mL) HIV-1 viral load (VL). Compared to HIV- men, HIV+ men had higher QTVI [adjusted difference of +0.077 (95% CI: +0.032 to +0.123)]. Magnitude of this association depended on the degree of viremia such that in HIV+ men with undetectable VL, adjusted QTVI was +0.064 (95% CI: +0.017 to +0.111) higher compared to HIV- men, while in HIV+ men with detectable VL adjusted QTVI was higher by +0.150 (95% CI: 0.072-0.228) compared to HIV- referents. Analysis of QTVI subcomponents showed HIV+ men had: (1) lower HR variability irrespective of VL status, and (2) higher QT variability if they had detectable-but not with undetectable-VL, when compared to HIV- men. Higher levels of C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule (ICAM)-1, soluble tumor necrosis factor (TNF)-receptor 2, and soluble cluster of differentiation (CD)-163 (borderline), were associated with higher QTVI and partially attenuated the association with HIV serostatus.HIV+ men have greater beat-to-beat variability in QT interval (QTVI) compared to HIV- men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability which can increase susceptibility to arrhythmias, while lower HR variability signals a component of autonomic dysfunction.



Circulation: 10 Nov 2019; epub ahead of print
Heravi AS, Etzkorn L, Urbanek J, Crainiceanu C, ... Wu KC, Post WS
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707799
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Impact:
Abstract

Population Impact of Generic Valsartan Recall.

Jackevicius CA, Krumholz HM, Chong A, Koh M, ... Udell JA, Ko DT

On July 9, 2018, Health Canada announced a voluntary recall of 6 generic valsartan products due to the detection of a known carcinogen nitrosodimethylamine (NDMA). In total, more than 22 countries, including the United States, initiated recalls. Despite an increase in drug recalls, few studies have evaluated their impact. The valsartan recall, of a frequently used oral medication for high prevalence chronic conditions, such as, hypertension, provides an opportunity to examine the consequences of a drug recall by patients and health care systems. We used a segmented regression analysis using multiple linked healthcare databases in Ontario, Canada, including the Ontario Drug Benefit (ODB) prescription claims database to identify our cohort of recalled valsartan users and to ascertain non-valsartan medication use, the Ontario Registered Persons database for vital status, Canadian Institute for Health Information for discharge diagnoses for hospital admissions, baseline comorbidities, and clinical outcomes, National Ambulatory Care Reporting System database for emergency department (ED) visits, and Statistics Canada census database for income datasets. These datasets were linked using unique encoded identifiers and analyzed at ICES. We included patients ≥65 years old who had been dispensed a supply of at least one recalled valsartan product that would cover the period up to and including the date of 7/9/2018, and were alive on this date.



Circulation: 10 Nov 2019; epub ahead of print
Jackevicius CA, Krumholz HM, Chong A, Koh M, ... Udell JA, Ko DT
Circulation: 10 Nov 2019; epub ahead of print | PMID: 31707798
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Impact:
Abstract

2019 American Heart Association Focused Update on Advanced Cardiovascular Life Support: Use of Advanced Airways, Vasopressors, and Extracorporeal Cardiopulmonary Resuscitation During Cardiac Arrest: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Panchal AR, Berg KM, Hirsch KG, Kudenchuk PJ, ... Hazinski MF, Donnino MW

The fundamentals of cardiac resuscitation include the immediate provision of high-quality cardiopulmonary resuscitation combined with rapid defibrillation (as appropriate). These mainstays of therapy set the groundwork for other possible interventions such as medications, advanced airways, extracorporeal cardiopulmonary resuscitation, and post-cardiac arrest care, including targeted temperature management, cardiorespiratory support, and percutaneous coronary intervention. Since 2015, an increased number of studies have been published evaluating some of these interventions, requiring a reassessment of their use and impact on survival from cardiac arrest. This 2019 focused update to the American Heart Association advanced cardiovascular life support guidelines summarizes the most recent published evidence for and recommendations on the use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest. It includes revised recommendations for all 3 areas, including the choice of advanced airway devices and strategies during cardiac arrest (eg, bag-mask ventilation, supraglottic airway, or endotracheal intubation), the training and retraining required, the administration of standard-dose epinephrine, and the decisions involved in the application of extracorporeal cardiopulmonary resuscitation and its potential impact on cardiac arrest survival.



Circulation: 13 Nov 2019:CIR0000000000000732; epub ahead of print
Panchal AR, Berg KM, Hirsch KG, Kudenchuk PJ, ... Hazinski MF, Donnino MW
Circulation: 13 Nov 2019:CIR0000000000000732; epub ahead of print | PMID: 31722552
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Impact:
Abstract

2019 American Heart Association Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Escobedo MB, Aziz K, Kapadia VS, Lee HC, ... Yamada NK, Zaichkin JG

This 2019 focused update to the American Heart Association neonatal resuscitation guidelines is based on 2 evidence reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. The International Liaison Committee on Resuscitation Expert Systematic Reviewer and content experts performed comprehensive reviews of the scientific literature on the appropriate initial oxygen concentration for use during neonatal resuscitation in 2 groups: term and late-preterm newborns (≥35 weeks of gestation) and preterm newborns (<35 weeks of gestation). This article summarizes those evidence reviews and presents recommendations. The recommendations for neonatal resuscitation are as follows: In term and late-preterm newborns (≥35 weeks of gestation) receiving respiratory support at birth, the initial use of 21% oxygen is reasonable. One hundred percent oxygen should not be used to initiate resuscitation because it is associated with excess mortality. In preterm newborns (<35 weeks of gestation) receiving respiratory support at birth, it may be reasonable to begin with 21% to 30% oxygen and to base subsequent oxygen titration on oxygen saturation targets. These guidelines require no change in the Neonatal Resuscitation Algorithm-2015 Update.



Circulation: 13 Nov 2019:CIR0000000000000729; epub ahead of print
Escobedo MB, Aziz K, Kapadia VS, Lee HC, ... Yamada NK, Zaichkin JG
Circulation: 13 Nov 2019:CIR0000000000000729; epub ahead of print | PMID: 31724451
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Impact:
Abstract

2019 American Heart Association Focused Update on Systems of Care: Dispatcher-Assisted Cardiopulmonary Resuscitation and Cardiac Arrest Centers: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Panchal AR, Berg KM, Cabañas JG, Kurz MC, ... Donnino MW, Kudenchuk PJ

Survival after out-of-hospital cardiac arrest requires an integrated system of care (chain of survival) between the community elements responding to an event and the healthcare professionals who continue to care for and transport the patient for appropriate interventions. As a result of the dynamic nature of the prehospital setting, coordination and communication can be challenging, and identification of methods to optimize care is essential. This 2019 focused update to the American Heart Association systems of care guidelines summarizes the most recent published evidence for and recommendations on the use of dispatcher-assisted cardiopulmonary resuscitation and cardiac arrest centers. This article includes the revised recommendations that emergency dispatch centers should offer and instruct bystanders in cardiopulmonary resuscitation during out-of-hospital cardiac arrest and that a regionalized approach to post-cardiac arrest care may be reasonable when comprehensive postarrest care is not available at local facilities.



Circulation: 13 Nov 2019:CIR0000000000000733; epub ahead of print
Panchal AR, Berg KM, Cabañas JG, Kurz MC, ... Donnino MW, Kudenchuk PJ
Circulation: 13 Nov 2019:CIR0000000000000733; epub ahead of print | PMID: 31722563
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Abstract

2019 American Heart Association and American Red Cross Focused Update for First Aid: Presyncope: An Update to the American Heart Association and American Red Cross Guidelines for First Aid.

Charlton NP, Pellegrino JL, Kule A, Slater TM, ... Singletary EM, Swain JM

This 2019 focused update to the American Heart Association and American Red Cross first aid guidelines follows the completion of a systematic review of treatments for presyncope of vasovagal or orthostatic origin. This review was commissioned by the International Liaison Committee on Resuscitation and resulted in the development of an international summary statement of the International Liaison Committee on Resuscitation First Aid Task Force Consensus on Science With Treatment Recommendations. This focused update highlights the evidence supporting specific interventions for presyncope of orthostatic or vasovagal origin and recommends the use of physical counterpressure maneuvers. These maneuvers include the contraction of muscles of the body such as the legs, arms, abdomen, or neck, with the goal of elevating blood pressure and alleviating symptoms. Although lower-body counterpressure maneuvers are favored over upper-body counterpressure maneuvers, multiple methods can be beneficial, depending on the situation.



Circulation: 13 Nov 2019:CIR0000000000000730; epub ahead of print
Charlton NP, Pellegrino JL, Kule A, Slater TM, ... Singletary EM, Swain JM
Circulation: 13 Nov 2019:CIR0000000000000730; epub ahead of print | PMID: 31722559
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Impact:
Abstract

2019 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Duff JP, Topjian AA, Berg MD, Chan M, ... Hazinski MF, Atkins DL

This 2019 focused update to the American Heart Association pediatric advanced life support guidelines follows the 2018 and 2019 systematic reviews performed by the Pediatric Life Support Task Force of the International Liaison Committee on Resuscitation. It aligns with the continuous evidence review process of the International Liaison Committee on Resuscitation, with updates published when the International Liaison Committee on Resuscitation completes a literature review based on new published evidence. This update provides the evidence review and treatment recommendations for advanced airway management in pediatric cardiac arrest, extracorporeal cardiopulmonary resuscitation in pediatric cardiac arrest, and pediatric targeted temperature management during post-cardiac arrest care. The writing group analyzed the systematic reviews and the original research published for each of these topics. For airway management, the writing group concluded that it is reasonable to continue bag-mask ventilation (versus attempting an advanced airway such as endotracheal intubation) in patients with out-of-hospital cardiac arrest. When extracorporeal membrane oxygenation protocols and teams are readily available, extracorporeal cardiopulmonary resuscitation should be considered for patients with cardiac diagnoses and in-hospital cardiac arrest. Finally, it is reasonable to use targeted temperature management of 32°C to 34°C followed by 36°C to 37.5°C, or to use targeted temperature management of 36°C to 37.5°C, for pediatric patients who remain comatose after resuscitation from out-of-hospital cardiac arrest or in-hospital cardiac arrest.



Circulation: 13 Nov 2019:CIR0000000000000731; epub ahead of print
Duff JP, Topjian AA, Berg MD, Chan M, ... Hazinski MF, Atkins DL
Circulation: 13 Nov 2019:CIR0000000000000731; epub ahead of print | PMID: 31722551
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Impact:
Abstract

2019 American Heart Association Focused Update on Pediatric Basic Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Duff JP, Topjian AA, Berg MD, Chan M, ... Hazinski MF, Atkins DL

This 2019 focused update to the American Heart Association pediatric basic life support guidelines follows the 2019 systematic review of the effects of dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) on survival of infants and children with out-of-hospital cardiac arrest. This systematic review and the primary studies identified were analyzed by the Pediatric Task Force of the International Liaison Committee on Resuscitation. It aligns with the International Liaison Committee on Resuscitation\'s continuous evidence review process, with updates published when the International Liaison Committee on Resuscitation completes a literature review based on new published evidence. This update summarizes the available pediatric evidence supporting DA-CPR and provides treatment recommendations for DA-CPR for pediatric out-of-hospital cardiac arrest. Four new pediatric studies were reviewed. A systematic review of this data identified the association of a significant improvement in the rates of bystander CPR and in survival 1 month after cardiac arrest with DA-CPR. The writing group recommends that emergency medical dispatch centers offer DA-CPR for presumed pediatric cardiac arrest, especially when no bystander CPR is in progress. No recommendation could be made for or against DA-CPR instructions when bystander CPR is already in progress.



Circulation: 13 Nov 2019:CIR0000000000000736; epub ahead of print
Duff JP, Topjian AA, Berg MD, Chan M, ... Hazinski MF, Atkins DL
Circulation: 13 Nov 2019:CIR0000000000000736; epub ahead of print | PMID: 31722546
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Impact:
Abstract

2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support; Advanced Life Support; Pediatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Aid Task Forces.

Soar J, Maconochie I, Wyckoff MH, Olasveengen TM, ... Nolan JP, Hazinski MF

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research.



Circulation: 13 Nov 2019:CIR0000000000000734; epub ahead of print
Soar J, Maconochie I, Wyckoff MH, Olasveengen TM, ... Nolan JP, Hazinski MF
Circulation: 13 Nov 2019:CIR0000000000000734; epub ahead of print | PMID: 31722543
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Abstract

Structures of a RAG-like transposase during cut-and-paste transposition.

Liu C, Yang Y, Schatz DG

Transposons have had a pivotal role in genome evolution and are believed to be the evolutionary progenitors of the RAG1-RAG2 recombinase, an essential component of the adaptive immune system in jawed vertebrates. Here we report one crystal structure and five cryo-electron microscopy structures of Transib, a RAG1-like transposase from Helicoverpa zea, that capture the entire transposition process from the apo enzyme to the terminal strand transfer complex with transposon ends covalently joined to target DNA, at resolutions of 3.0-4.6 Å. These structures reveal a butterfly-shaped complex that undergoes two cycles of marked conformational changes in which the \'wings\' of the transposase unfurl to bind substrate DNA, close to execute cleavage, open to release the flanking DNA and close again to capture and attack target DNA. Transib possesses unique structural elements that compensate for the absence of a RAG2 partner, including a loop that interacts with the transposition target site and an accordion-like C-terminal tail that elongates and contracts to help to control the opening and closing of the enzyme and assembly of the active site. Our findings reveal the detailed reaction pathway of a eukaryotic cut-and-paste transposase and illuminate some of the earliest steps in the evolution of the RAG recombinase.



Nature: 12 Nov 2019; epub ahead of print
Liu C, Yang Y, Schatz DG
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723264
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Abstract

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Duan Y, Llorente C, Lang S, Brandl K, ... Fouts DE, Schnabl B

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.



Nature: 12 Nov 2019; epub ahead of print
Duan Y, Llorente C, Lang S, Brandl K, ... Fouts DE, Schnabl B
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723265
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Impact:
Abstract

High-resolution lineage tracking reveals travelling wave of adaptation in laboratory yeast.

Nguyen Ba AN, Cvijović I, Rojas Echenique JI, Lawrence KR, ... Levy SF, Desai MM

In rapidly adapting asexual populations, including many microbial pathogens and viruses, numerous mutant lineages often compete for dominance within the population. These complex evolutionary dynamics determine the outcomes of adaptation, but have been difficult to observe directly. Previous studies have used whole-genome sequencing to follow molecular adaptation; however, these methods have limited resolution in microbial populations. Here we introduce a renewable barcoding system to observe evolutionary dynamics at high resolution in laboratory budding yeast. We find nested patterns of interference and hitchhiking even at low frequencies. These events are driven by the continuous appearance of new mutations that modify the fates of existing lineages before they reach substantial frequencies. We observe how the distribution of fitness within the population changes over time, and find a travelling wave of adaptation that has been predicted by theory. We show that clonal competition creates a dynamical \'rich-get-richer\' effect: fitness advantages that are acquired early in evolution drive clonal expansions, which increase the chances of acquiring future mutations. However, less-fit lineages also routinely leapfrog over strains of higher fitness. Our results demonstrate that this combination of factors, which is not accounted for in existing models of evolutionary dynamics, is critical in determining the rate, predictability and molecular basis of adaptation.



Nature: 12 Nov 2019; epub ahead of print
Nguyen Ba AN, Cvijović I, Rojas Echenique JI, Lawrence KR, ... Levy SF, Desai MM
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723263
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Impact:
Abstract

Activity of caspase-8 determines plasticity between cell death pathways.

Newton K, Wickliffe KE, Maltzman A, Dugger DL, ... Webster JD, Dixit VM

Caspase-8 is a protease with both pro-death and pro-survival functions: it mediates apoptosis induced by death receptors such as TNFR1, and suppresses necroptosis mediated by the kinase RIPK3 and the pseudokinase MLKL. Mice that lack caspase-8 display MLKL-dependent embryonic lethality, as do mice that express catalytically inactive CASP8(C362A). Casp8Mlkl mice die during the perinatal period, whereas Casp8Mlkl mice are viable, which indicates that inactive caspase-8 also has a pro-death scaffolding function. Here we show that mutant CASP8(C362A) induces the formation of ASC (also known as PYCARD) specks, and caspase-1-dependent cleavage of GSDMD and caspases 3 and 7 in MLKL-deficient mouse intestines around embryonic day 18. Caspase-1 and its adaptor ASC contributed to the perinatal lethal phenotype because a number of Casp8MlklCasp1 and Casp8MlklAsc mice survived beyond weaning. Transfection studies suggest that inactive caspase-8 adopts a distinct conformation to active caspase-8, enabling its prodomain to engage ASC. Upregulation of the lipopolysaccharide sensor caspase-11 in the intestines of both Casp8Mlkl and Casp8MlklCasp1 mice also contributed to lethality because Casp8MlklCasp1Casp11 (Casp11 is also known as Casp4) neonates survived more often than Casp8MlklCasp1 neonates. Finally, Casp8Ripk3Casp1Casp11 mice survived longer than Casp8MlklCasp1Casp11 mice, indicating that a necroptosis-independent function of RIPK3 also contributes to lethality. Thus, unanticipated plasticity in death pathways is revealed when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited.



Nature: 12 Nov 2019; epub ahead of print
Newton K, Wickliffe KE, Maltzman A, Dugger DL, ... Webster JD, Dixit VM
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723262
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Abstract

Enamel proteome shows that Gigantopithecus was an early diverging pongine.

Welker F, Ramos-Madrigal J, Kuhlwilm M, Liao W, ... Marques-Bonet T, Cappellini E

Gigantopithecus blacki was a giant hominid that inhabited densely forested environments of Southeast Asia during the Pleistocene epoch. Its evolutionary relationships to other great ape species, and the divergence of these species during the Middle and Late Miocene epoch (16-5.3 million years ago), remain unclear. Hypotheses regarding the relationships between Gigantopithecus and extinct and extant hominids are wide ranging but difficult to substantiate because of its highly derived dentognathic morphology, the absence of cranial and post-cranial remains, and the lack of independent molecular validation. We retrieved dental enamel proteome sequences from a 1.9-million-year-old G. blacki molar found in Chuifeng Cave, China. The thermal age of these protein sequences is approximately five times greater than that of any previously published mammalian proteome or genome. We demonstrate that Gigantopithecus is a sister clade to orangutans (genus Pongo) with a common ancestor about 12-10 million years ago, implying that the divergence of Gigantopithecus from Pongo forms part of the Miocene radiation of great apes. In addition, we hypothesize that the expression of alpha-2-HS-glycoprotein, which has not been previously observed in enamel proteomes, had a role in the biomineralization of the thick enamel crowns that characterize the large molars in Gigantopithecus. The survival of an Early Pleistocene dental enamel proteome in the subtropics further expands the scope of palaeoproteomic analysis into geographical areas and time periods previously considered incompatible with the preservation of substantial amounts of genetic information.



Nature: 12 Nov 2019; epub ahead of print
Welker F, Ramos-Madrigal J, Kuhlwilm M, Liao W, ... Marques-Bonet T, Cappellini E
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723270
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Abstract

Quantifying secondary transport at single-molecule resolution.

Fitzgerald GA, Terry DS, Warren AL, Quick M, Javitch JA, Blanchard SC

Secondary active transporters, which are vital for a multitude of physiological processes, use the energy of electrochemical ion gradients to power substrate transport across cell membranes. Efforts to investigate their mechanisms of action have been hampered by their slow transport rates and the inherent limitations of ensemble methods. Here we quantify the activity of individual MhsT transporters, which are representative of the neurotransmitter:sodium symporter family of secondary transporters, by imaging the transport of individual substrate molecules across lipid bilayers at both single- and multi-turnover resolution. We show that MhsT is active only when physiologically oriented and that the rate-limiting step of the transport cycle varies with the nature of the transported substrate. These findings are consistent with an extracellular allosteric substrate-binding site that modulates the rate-limiting aspects of the transport mechanism, including the rate at which the transporter returns to an outward-facing state after the transported substrate is released.



Nature: 12 Nov 2019; epub ahead of print
Fitzgerald GA, Terry DS, Warren AL, Quick M, Javitch JA, Blanchard SC
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723269
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Abstract

Cryo-EM structure of the spinach cytochrome bf complex at 3.6 Å resolution.

Malone LA, Qian P, Mayneord GE, Hitchcock A, ... Hunter CN, Johnson MP

The cytochrome b f (cytb f ) complex has a central role in oxygenic photosynthesis, linking electron transfer between photosystems I and II and converting solar energy into a transmembrane proton gradient for ATP synthesis. Electron transfer within cytb f occurs via the quinol (Q) cycle, which catalyses the oxidation of plastoquinol (PQH) and the reduction of both plastocyanin (PC) and plastoquinone (PQ) at two separate sites via electron bifurcation. In higher plants, cytb f also acts as a redox-sensing hub, pivotal to the regulation of light harvesting and cyclic electron transfer that protect against metabolic and environmental stresses. Here we present a 3.6 Å resolution cryo-electron microscopy (cryo-EM) structure of the dimeric cytb f complex from spinach, which reveals the structural basis for operation of the Q cycle and its redox-sensing function. The complex contains up to three natively bound PQ molecules. The first, PQ1, is located in one cytb f monomer near the PQ oxidation site (Q) adjacent to haem b and chlorophyll a. Two conformations of the chlorophyll a phytyl tail were resolved, one that prevents access to the Q site and another that permits it, supporting a gating function for the chlorophyll a involved in redox sensing. PQ2 straddles the intermonomer cavity, partially obstructing the PQ reduction site (Q) on the PQ1 side and committing the electron transfer network to turnover at the occupied Q site in the neighbouring monomer. A conformational switch involving the haem c propionate promotes two-electron, two-proton reduction at the Q site and avoids formation of the reactive intermediate semiquinone. The location of a tentatively assigned third PQ molecule is consistent with a transition between the Q and Q sites in opposite monomers during the Q cycle. The spinach cytb f structure therefore provides new insights into how the complex fulfils its catalytic and regulatory roles in photosynthesis.



Nature: 12 Nov 2019; epub ahead of print
Malone LA, Qian P, Mayneord GE, Hitchcock A, ... Hunter CN, Johnson MP
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723268
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Abstract

CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle.

Sarek G, Kotsantis P, Ruis P, Van Ly D, ... Cesare AJ, Boulton SJ

The protection of telomere ends by the shelterin complex prevents DNA damage signalling and promiscuous repair at chromosome ends. Evidence suggests that the 3\' single-stranded telomere end can assemble into a lasso-like t-loop configuration, which has been proposed to safeguard chromosome ends from being recognized as DNA double-strand breaks. Mechanisms must also exist to transiently disassemble t-loops to allow accurate telomere replication and to permit telomerase access to the 3\' end to solve the end-replication problem. However, the regulation and physiological importance of t-loops in the protection of telomere ends remains unknown. Here we identify a CDK phosphorylation site in the shelterin subunit at Ser365 of TRF2, whose dephosphorylation in S phase by the PP6R3 phosphatase provides a narrow window during which the RTEL1 helicase can transiently access and unwind t-loops to facilitate telomere replication. Re-phosphorylation of TRF2 at Ser365 outside of S phase is required to release RTEL1 from telomeres, which not only protects t-loops from promiscuous unwinding and inappropriate activation of ATM, but also counteracts replication conflicts at DNA secondary structures that arise within telomeres and across the genome. Hence, a phospho-switch in TRF2 coordinates the assembly and disassembly of t-loops during the cell cycle, which protects telomeres from replication stress and an unscheduled DNA damage response.



Nature: 12 Nov 2019; epub ahead of print
Sarek G, Kotsantis P, Ruis P, Van Ly D, ... Cesare AJ, Boulton SJ
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723267
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Impact:
Abstract

Thermoelectric performance of a metastable thin-film Heusler alloy.

Hinterleitner B, Knapp I, Poneder M, Shi Y, ... Chen XQ, Bauer E

Thermoelectric materials transform a thermal gradient into electricity. The efficiency of this process relies on three material-dependent parameters: the Seebeck coefficient, the electrical resistivity and the thermal conductivity, summarized in the thermoelectric figure of merit. A large figure of merit is beneficial for potential applications such as thermoelectric generators. Here we report the thermal and electronic properties of thin-film Heusler alloys based on FeVWAl prepared by magnetron sputtering. Density functional theory calculations suggest that the thin films are metastable states, and measurements of the power factor-the ratio of the Seebeck coefficient squared divided by the electrical resistivity-suggest a high intrinsic figure of merit for these thin films. This may arise from a large differential density of states at the Fermi level and a Weyl-like electron dispersion close to the Fermi level, which indicates a high mobility of charge carriers owing to linear crossing in the electronic bands.



Nature: 12 Nov 2019; epub ahead of print
Hinterleitner B, Knapp I, Poneder M, Shi Y, ... Chen XQ, Bauer E
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723266
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Impact:
Abstract

Marine Proteobacteria metabolize glycolate via the β-hydroxyaspartate cycle.

Schada von Borzyskowski L, Severi F, Krüger K, Hermann L, ... Amann RI, Erb TJ

One of the most abundant sources of organic carbon in the ocean is glycolate, the secretion of which by marine phytoplankton results in an estimated annual flux of one petagram of glycolate in marine environments. Although it is generally accepted that glycolate is oxidized to glyoxylate by marine bacteria, the further fate of this C metabolite is not well understood. Here we show that ubiquitous marine Proteobacteria are able to assimilate glyoxylate via the β-hydroxyaspartate cycle (BHAC) that was originally proposed 56 years ago. We elucidate the biochemistry of the BHAC and describe the structure of its key enzymes, including a previously unknown primary imine reductase. Overall, the BHAC enables the direct production of oxaloacetate from glyoxylate through only four enzymatic steps, representing-to our knowledge-the most efficient glyoxylate assimilation route described to date. Analysis of marine metagenomes shows that the BHAC is globally distributed and on average 20-fold more abundant than the glycerate pathway, the only other known pathway for net glyoxylate assimilation. In a field study of a phytoplankton bloom, we show that glycolate is present in high nanomolar concentrations and taken up by prokaryotes at rates that allow a full turnover of the glycolate pool within one week. During the bloom, genes that encode BHAC key enzymes are present in up to 1.5% of the bacterial community and actively transcribed, supporting the role of the BHAC in glycolate assimilation and suggesting a previously undescribed trophic interaction between autotrophic phytoplankton and heterotrophic bacterioplankton.



Nature: 12 Nov 2019; epub ahead of print
Schada von Borzyskowski L, Severi F, Krüger K, Hermann L, ... Amann RI, Erb TJ
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723261
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Impact:
Abstract

Effect of Electronic Health Record-Based Coaching on Weight Maintenance: A Randomized Trial.

Conroy MB, McTigue KM, Bryce CL, Tudorascu D, ... Simkin-Silverman LR, Fischer GS
Background
Weight regain after intentional loss is common. Most evidence-based weight management programs focus on short-term loss rather than long-term maintenance.
Objective
To evaluate the benefit of coaching in an electronic health record (EHR)-based weight maintenance intervention.
Design
Randomized controlled trial. (ClinicalTrials.gov: NCT01946191).
Setting
Practices affiliated with an academic medical center.
Participants
Adult outpatients with body mass index (BMI) of 25 kg/m2 or higher, intentional weight loss of at least 5% in the previous 2 years, and no bariatric procedures in the previous 5 years.
Intervention
Participants were randomly assigned to EHR tools (tracking group) versus EHR tools plus coaching (coaching group). The EHR tools included weight, diet, and physical activity tracking flow sheets; standardized surveys; and reminders. The coaching group received 24 months of personalized coaching through the EHR patient portal, with 24 scheduled contacts.
Measurements
The primary outcome was weight change at 24 months. Secondary outcomes included 5% weight loss maintenance and changes in BMI, waist circumference, number of steps per day, health-related quality of life, physical function, blood pressure, and satisfaction.
Results
Among 194 randomly assigned participants (mean age, 53.4 years [SD, 12.2]; 143 [74%] women; 171 [88%] white), 157 (81%) completed the trial. Mean baseline weight and BMI were 85.8 kg (SD, 19.1) and 30.4 kg/m2 (SD, 5.9). At 24 months, mean weight regain (± SE) was 2.1 ± 0.62 kg and 4.9 ± 0.63 kg in the coaching and tracking groups, respectively. The between-group difference in weight change at 24 months was significant (-2.86 kg [95% CI, -4.60 to -1.11 kg]) in the linear mixed model. At 24 months, 65% of participants in the coaching group and 50% in the tracking group maintained weight loss of at least 5%.
Limitation
Single-site trial, which limits generalizability.
Conclusion
Among adults with intentional weight loss of at least 5%, use of EHR tools plus coaching resulted in less weight regain than EHR tools alone.
Primary funding source
Agency for Healthcare Research and Quality and National Institutes of Health.



Ann Intern Med: 11 Nov 2019; epub ahead of print
Conroy MB, McTigue KM, Bryce CL, Tudorascu D, ... Simkin-Silverman LR, Fischer GS
Ann Intern Med: 11 Nov 2019; epub ahead of print | PMID: 31711168
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Abstract

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Kent DM, Paulus JK, van Klaveren D, D\'Agostino R, ... Wong JB, Steyerberg EW

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined \"1 variable at a time\" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, \"predictive HTE analysis.\" The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a \"risk-modeling\" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an \"effect-modeling\" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.



Ann Intern Med: 11 Nov 2019; epub ahead of print
Kent DM, Paulus JK, van Klaveren D, D'Agostino R, ... Wong JB, Steyerberg EW
Ann Intern Med: 11 Nov 2019; epub ahead of print | PMID: 31711134
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Abstract

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration.

Kent DM, van Klaveren D, Paulus JK, D\'Agostino R, ... Wong JB, Steyerberg EW

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a \"risk-modeling\" and an \"effect-modeling\" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.



Ann Intern Med: 11 Nov 2019; epub ahead of print
Kent DM, van Klaveren D, Paulus JK, D'Agostino R, ... Wong JB, Steyerberg EW
Ann Intern Med: 11 Nov 2019; epub ahead of print | PMID: 31711094
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Abstract

Policy Recommendations for Public Health Plans to Stem the Escalating Costs of Prescription Drugs: A Position Paper From the American College of Physicians.

Daniel H, Bornstein SS

The increasing price of prescription drugs is an ongoing concern for Medicare and Medicaid, particularly for patients with chronic health conditions who are using multiple medications and patients in these programs taking high-priced brand-name specialty drugs. Shifts in benefit design, including higher deductibles and a movement away from copayments to coinsurance, have increased patient out-of-pocket costs and put pressure on program budgets. In this paper, the American College of Physicians expands on its position paper from 2016 and offers additional recommendations to decrease out-of-pocket costs for patients, enhance the government\'s purchasing power, and address existing policies that add costs to the health care system.



Ann Intern Med: 11 Nov 2019; epub ahead of print
Daniel H, Bornstein SS
Ann Intern Med: 11 Nov 2019; epub ahead of print | PMID: 31711137
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Abstract

Compassionate End-of-Life Care: Mixed-Methods Multisite Evaluation of the 3 Wishes Project.

Vanstone M, Neville TH, Clarke FJ, Swinton M, ... Boyle A, Cook DJ
Background
The 3 Wishes Project (3WP) is an end-of-life program that aims to honor the dignity of dying patients by creating meaningful patient- and family-centered memories while promoting humanistic interprofessional care.
Objective
To determine whether this palliative intervention could be successfully implemented-defined as demonstrating value, transferability, affordability, and sustainability-beyond the intensive care unit in which it was created.
Design
Mixed-methods formative program evaluation. (ClinicalTrials.gov: NCT04147169).
Setting
4 North American intensive care units.
Participants
Dying patients, their families, clinicians, hospital managers, and administrators.
Intervention
Wishes from dying patients, family members, and clinicians were elicited and implemented.
Measurements
Patient characteristics and processes of care; the number, type, and cost of each wish; and semistructured interviews and focus groups with family members, clinicians, and managers.
Results
A total of 730 patients were enrolled, and 3407 wishes were elicited. Qualitative data were gathered from 75 family members, 72 clinicians, and 20 managers or hospital administrators. Value included intentional comforting of families as they honored the lives and legacies of their loved ones while inspiring compassionate clinical care. Factors promoting transferability included family appreciation and a collaborative intensive care unit culture committed to dignity-conserving end-of-life care. Staff participation evolved from passive support to professional agency. Program initiation required minimal investment for reusable materials; thereafter, the mean cost was $5.19 (SD, $17.14) per wish. Sustainability was demonstrated by the continuation of 3WP at each site after study completion.
Limitation
This descriptive formative evaluation describes tertiary care center-specific experiences rather than aiming for generalizability to all jurisdictions.
Conclusion
The 3WP is a transferrable, affordable, and sustainable program that provides value to dying patients, their families, clinicians, and institutions.
Primary funding source
Greenwall Foundation.



Ann Intern Med: 11 Nov 2019; epub ahead of print
Vanstone M, Neville TH, Clarke FJ, Swinton M, ... Boyle A, Cook DJ
Ann Intern Med: 11 Nov 2019; epub ahead of print | PMID: 31711111
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Impact:
Abstract

Policy Recommendations for Pharmacy Benefit Managers to Stem the Escalating Costs of Prescription Drugs: A Position Paper From the American College of Physicians.

Daniel H, Bornstein SS

Recent discussions about the increasing prices of prescription drugs have focused on pharmacy benefit managers (PBMs), third-party intermediaries for various types of employers and government purchasers who negotiate drug prices in health plans and thus play a crucial role in determining the amount millions of Americans pay for medications. In this position paper, the American College of Physicians expands on its position paper from 2016 by offering additional recommendations to improve transparency in the PBM industry and highlighting the need for reliable, timely, and relevant information on prescription drug pricing for physicians and patients.



Ann Intern Med: 11 Nov 2019; epub ahead of print
Daniel H, Bornstein SS
Ann Intern Med: 11 Nov 2019; epub ahead of print | PMID: 31711103
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Abstract

Importance of Early Diagnosis in Peripartum Cardiomyopathy.

Lewey J, Levine LD, Elovitz MA, Irizarry OC, Arany Z

Peripartum cardiomyopathy (PPCM) can lead to long-term systolic dysfunction, especially among black women. Hypertensive disorders of pregnancy (HDP) are the strongest risk factor for PPCM, but controversy remains on whether HDP predict a favorable outcome. Women with HDP are also often diagnosed with PPCM earlier than those without HDP. Our objective is to determine recovery of systolic function in patients with PPCM stratified by HDP, timing of diagnosis, and race. We conducted a retrospective cohort study of 220 patients (55% black) diagnosed with PPCM. Patients with PPCM and HDP were diagnosed earlier postpartum than patients without HDP (=0.013), an effect that was most pronounced in nonblack patients. Rates of left ventricular ejection fraction (LVEF) recovery were similar among PPCM patients with and without HDP (68.4% versus 62.6%, =0.425). In contrast, patients with PPCM diagnosed after 1-month postpartum had lower rates of LVEF recovery than patients diagnosed <1-month postpartum (53.7% versus 69.9%, =0.035). LVEF at time of diagnosis is a strong predictor of LVEF recovery, and patients with PPCM diagnosed after 1-month postpartum had lower baseline LVEF compared to patients presenting earlier (=0.041). The presence of HDP does not correlate with LVEF recovery in our racially diverse PPCM cohort. In contrast, early diagnosis portends a favorable outcome. Early diagnosis is associated with higher LVEF at presentation, likely explaining the improved outcomes in these women. These findings underscore the need for early monitoring and diagnosis, especially in at-risk and underserved populations.



Hypertension: 10 Nov 2019:HYPERTENSIONAHA11913291; epub ahead of print
Lewey J, Levine LD, Elovitz MA, Irizarry OC, Arany Z
Hypertension: 10 Nov 2019:HYPERTENSIONAHA11913291; epub ahead of print | PMID: 31707840
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Abstract

Macrophages in Atherosclerosis Regression.

Barrett TJ

Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery disease, cerebrovascular disease, and aortic atherosclerosis. In each vascular bed, macrophages contribute to the maintenance of the local inflammatory response, propagate plaque development, and promote thrombosis. These central roles, coupled with their plasticity, makes macrophages attractive therapeutic targets in stemming the development of and stabilizing existing atherosclerosis. In the context of ASCVD, classically activated M1 macrophages initiate and sustain inflammation, and alternatively activated M2 macrophages resolve inflammation. However, this classification is now considered an oversimplification, and a greater understanding of plaque macrophage physiology in ASCVD is required to aid in the development of therapeutics to promote ASCVD regression. Reviewed herein are the macrophage phenotypes and molecular regulators characteristic of ASCVD regression, and the current murine models of ASCVD regression.



Arterioscler Thromb Vasc Biol: 13 Nov 2019:ATVBAHA119312802; epub ahead of print
Barrett TJ
Arterioscler Thromb Vasc Biol: 13 Nov 2019:ATVBAHA119312802; epub ahead of print | PMID: 31722535
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Abstract

Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis.

Ritterhoff J, Young S, Villet O, Shao D, ... Raftery D, Tian R

Hypertrophied hearts switch from mainly using fatty acids (FA) to an increased reliance on glucose for energy production. It has been shown that preserving fatty acid oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte (CM) hypertrophy during cardiac stresses. However, it remains elusive if substrate metabolism regulates CM hypertrophy directly or via a secondary effect of improving cardiac energetics.The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.We cultured adult rat CMs in a medium containing glucose and mixed chain fatty acids and induced pathological hypertrophy by phenylephrine (PE). PE-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA and proteins. These changes could be prevented by increasing FAO via deletion of acetyl-CoA-carboxylase 2 (ACC2) in PE stimulated CMs and in pressure overload induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the anti-hypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in CM hypertrophy. N and C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate which supplied nitrogen for nucleotide synthesis during CM hypertrophy.Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.



Circ Res: 10 Nov 2019; epub ahead of print
Ritterhoff J, Young S, Villet O, Shao D, ... Raftery D, Tian R
Circ Res: 10 Nov 2019; epub ahead of print | PMID: 31709908
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Abstract

In peripartum cardiomyopathy Plasminogen Activator Inhibitor-1 is a potential new biomarker with controversial roles.

Ricke-Hoch M, Hoes MF, Pfeffer TJ, Schlothauer S, ... van der Meer P, Hilfiker-Kleiner D
Aims
Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease occurring in previously healthy women. A common pathomechanism in PPCM involves the angiostatic 16kDa-prolactin (16kDa-PRL) fragment, which via NF-κB-mediated upregulation of microRNA-(miR)-146a induces vascular damage and heart failure. We analyze whether the plasminogen-activator-inhibitor-1 (PAI-1) is involved in PPCM pathophysiology.
Methods/results
In healthy age-matched postpartum women (PP-Ctrl, n = 53, left-ventricular-ejection-fraction, LVEF>55%), PAI-1 plasma levels were within the normal range (21±10 ng/ml), but significantly elevated (64±38 ng/ml, p < 0.01) in postpartum PPCM patients at baseline (BL, n = 64, mean LVEF: 23±8%). At 6-months follow-up (FU, n = 23) PAI-1 levels decreased (36±14 ng/ml, p < 0.01 vs BL) and LVEF (49±11%) improved. Increased NT-proBNP and TroponinT did not correlate with PAI-1. C-reactive protein (CRP), interleukin (IL)-6 and IL-1β did not differ between PPCM patients and PP-Ctrl. MiR-146a) was 3.6-fold (p < 0.001) higher in BL-PPCM plasma compared with PP-Ctrl and correlated positively with PAI-1. In BL-PPCM serum, 16kDa-PRL coprecipitated with PAI-1, which was associated with higher (p < 0.05) uPAR-mediated NF-κB activation in endothelial cells compared with PP-Ctrl serum. Cardiac biopsies and dermal fibroblasts from PPCM patients displayed higher PAI-1 mRNA levels (p < 0.05) than healthy controls. In PPCM mice (due to a cardiomyocyte-specific-knockout for STAT3, CKO), cardiac PAI-1 expression was higher than in postpartum wildtype controls whereas a systemic PAI-1-knockout in CKO mice accelerated peripartum cardiac fibrosis, inflammation, heart failure, and mortality.
Conclusion
In PPCM patients, circulating and cardiac PAI-1 expression are upregulated. While circulating PAI-1 may add 16kDa-PRL to induce vascular impairment via the uPAR/NF-κB/miR-146a pathway, experimental data suggest that cardiac PAI-1 expression seems to protect the PPCM heart from fibrosis. Thus, measuring circulating PAI-1 and miR-146a, together with an uPAR/NF-κB-activity assay could be developed into a specific diagnostic marker assay for PPCM, but unrestricted reduction of PAI-1 for therapy may not be advised.
Translational perspective


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

Cardiovasc Res: 10 Nov 2019; epub ahead of print
Ricke-Hoch M, Hoes MF, Pfeffer TJ, Schlothauer S, ... van der Meer P, Hilfiker-Kleiner D
Cardiovasc Res: 10 Nov 2019; epub ahead of print | PMID: 31711127
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Abstract

Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide.

Horimatsu T, Blomkalns AL, Ogbi M, Moses M, ... Weintraub NL, Kim HW
Aims
Chronic adventitial and medial infiltration of immune cells plays an important role in the pathogenesis of abdominal aortic aneurysms (AAA). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation.
Methods and results
Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation.
Conclusions
Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.
Translational perspective
AAA are associated with pronounced adventitial and medial inflammation leading to matrix degradation and progressive aortic expansion. We report that niacin blunts aortic inflammation and matrix degradation, thereby suppressing AAA formation. These effects are independent of the niacin receptor GPR109A and mimicked by nicotinamide, which does not induce flushing. These results suggest that nicotinamide and related biomolecules that replete cellular NAD+ may be an effective medical therapy for AAA.

Published on behalf of the European Society of Cardiology 2019.

Cardiovasc Res: 08 Nov 2019; epub ahead of print
Horimatsu T, Blomkalns AL, Ogbi M, Moses M, ... Weintraub NL, Kim HW
Cardiovasc Res: 08 Nov 2019; epub ahead of print | PMID: 31710686
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Older ...

This program is still in alpha version.