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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

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

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

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

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

Story telling of myocarditis.

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

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

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

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

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

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

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

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

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

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

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

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

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

Unique cardiovascular risk factors in women.

Young L, Cho L

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Copyright © 2019 Massachusetts Medical Society.

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

Gilteritinib or Chemotherapy for Relapsed or Refractory -Mutated AML.

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

Copyright © 2019 Massachusetts Medical Society.

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

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

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

Copyright © 2019 Massachusetts Medical Society.

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

Drug-Resistant Bacteremia Transmitted by Fecal Microbiota Transplant.

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

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

Copyright © 2019 Massachusetts Medical Society.

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

Risk of Mortality Following Catheter Ablation of Atrial Fibrillation.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Copyright © 2019. Published by Elsevier Inc.

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

Ticagrelor Alone Versus Dual Antiplatelet Therapy From 1 Month After Drug-Eluting Coronary Stenting.

Franzone A, McFadden E, Leonardi S, Piccolo R, ... Valgimigli M,
Background
The GLOBAL LEADERS (GLOBAL LEADERS: A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) study randomly assigned 15,991 patients undergoing percutaneous coronary intervention to 1-month dual antiplatelet therapy (DAPT) followed by 23-month ticagrelor monotherapy or conventional 12-month DAPT followed by 12-month aspirin. Apart from Q-wave myocardial infarction (MI), all study endpoints were analyzed as investigator reported.
Objectives
This was a pre-specified ancillary study assessing whether experimental therapy is noninferior, and if met, superior, to conventional treatment for the coprimary efficacy endpoint of all-cause death, nonfatal MI, nonfatal stroke, or urgent target vessel revascularization and superior in preventing BARC 3 (Bleeding Academic Research Consortium) or 5 bleeding (coprimary safety endpoint) at 2 years with a 0.025 significance level to preserve nominal 5% alpha error.
Methods
An independent clinical event committee adjudicated investigator-reported and eventually unreported events of 7,585 patients from the 20 top-enrolling participating sites.
Results
The 2-year coprimary efficacy endpoint occurred in 271 (7.14%) and in 319 (8.41%) patients in the experimental and conventional groups, respectively (rate ratio [RR]: 0.85; 95% confidence interval [CI]: 0.72 to 0.99), fulfilling noninferiority (p noninferiority <0.001), but not superiority (p superiority = 0.0465). The rates of BARC 3 or 5 bleeding did not differ (RR: 1.00; 95% CI: 0.75 to 1.33; p = 0.986). A time-dependent treatment effect was observed with the experimental strategy being associated with a lower risk of MI (RR: 0.54; 95% CI: 0.33 to 0.88; p interaction = 0.062) and definite stent thrombosis (RR: 0.14; 95% CI: 0.03 to 0.63; p interaction = 0.007) after 1-year post-percutaneous coronary intervention.
Conclusions
Ticagrelor monotherapy after 1-month DAPT was noninferior, but not superior, to conventional treatment in the prevention of ischemic events, and it did not decrease major bleeding risk as compared with conventional treatment. (GLOBAL LEADERS Adjudication Sub-Study [GLASSY]; NCT03231059).

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

J Am Coll Cardiol: 04 Nov 2019; 74:2223-2234
Franzone A, McFadden E, Leonardi S, Piccolo R, ... Valgimigli M,
J Am Coll Cardiol: 04 Nov 2019; 74:2223-2234 | PMID: 31672177
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Abstract

Direct Current Cardioversion of Atrial Fibrillation in Patients With Left Atrial Appendage Occlusion Devices.

Sharma SP, Turagam MK, Gopinathannair R, Reddy V, ... Natale A, Lakkireddy D
Background
Direct current cardioversion (DCCV) is a common rhythm control strategy in patients with symptomatic atrial fibrillation or flutter. There is no long-term data regarding the safety of DCCV in patients with endocardial left atrial appendage occlusion (LAAO) devices.
Objectives
The purpose of this study was to assess the feasibility and safety of DCCV in patients with an LAAO device.
Methods
This multicenter retrospective study included 148 patients with an LAAO device who underwent DCCV for symptomatic atrial fibrillation or atrial flutter.
Results
The average age of the included patients was 72 ± 7 years and 59% were men. All patients (100%) had a transesophageal echocardiogram prior to DCCV. Device-related thrombus was seen in 2.7%. They were all successfully treated with oral anticoagulation (OAC) and were able to undergo DCCV after 6 to 8 weeks. DCCV restored sinus rhythm in all patients. None of the patients had DCCV-related thromboembolic complications. A total of 22% of patients were newly started on OAC after DCCV. There was no difference in DCCV-related complications between patients treated with or without OAC post-DCCV. Patients receiving OAC post-DCCV were found to undergo cardioversion at an earlier time after implantation (3.6 months [interquartile range (IQR): 0.7 to 8.6 months] vs. 8.6 months [IQR: 2.5 to 13.3 months]; p = 0.003). Three transient ischemic attacks, unrelated to DCCV, were found during follow-up. During a median follow-up of 12.8 months (IQR: 11.8 to 14.2 months), no device or left atrial thrombosis, device dislodgement, or a new device leak were observed. One patient died during follow-up due to noncardiac cause.
Conclusions
DCCV is feasible in high-risk AF patients with an LAAO device without the need for oral anticoagulation if pre-procedural transesophageal echocardiography shows good device position, absence of device-related thrombus, and peridevice leak of ≤5 mm. The preliminary results are encouraging, but further large studies are warranted to establish safety.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 04 Nov 2019; 74:2267-2274
Sharma SP, Turagam MK, Gopinathannair R, Reddy V, ... Natale A, Lakkireddy D
J Am Coll Cardiol: 04 Nov 2019; 74:2267-2274 | PMID: 31672183
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Abstract

Aortic Valve Stenosis Treatment Disparities in the Underserved: JACC Council Perspectives.

Batchelor W, Anwaruddin S, Ross L, Alli O, ... Welt F, Mehran R

Underserved minorities make up a disproportionately small subset of patients in the United States undergoing transcatheter and surgical aortic valve replacement for aortic stenosis. The reasons for these treatment gaps include differences in disease prevalence and patient, health care system, and disease-related factors. This has major implications not only for minority patients, but also for other groups who face similar challenges in accessing state-of-the-art care for structural heart disease. The authors propose the following key strategies to address these treatment disparities: 1) implementation of measure-based quality improvement programs; 2) effective culturally competent communication and team-based care; 3) improving patient health care access, education, and effective diagnosis; and 4) changing the research paradigm that creates an innovation pipeline for patients. Only a concerted effort from all stakeholders will achieve equitable and broad application of this and other novel structural heart disease treatment modalities in the future.

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

J Am Coll Cardiol: 04 Nov 2019; 74:2313-2321
Batchelor W, Anwaruddin S, Ross L, Alli O, ... Welt F, Mehran R
J Am Coll Cardiol: 04 Nov 2019; 74:2313-2321 | PMID: 31672188
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Impact:
Abstract

Prevention of Early Ventilator-Associated Pneumonia after Cardiac Arrest.

François B, Cariou A, Clere-Jehl R, Dequin PF, ... Le Gouge A,
Background
Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown.
Methods
We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia.
Results
A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups.
Conclusions
A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 06 Nov 2019; 381:1831-1842
François B, Cariou A, Clere-Jehl R, Dequin PF, ... Le Gouge A,
N Engl J Med: 06 Nov 2019; 381:1831-1842 | PMID: 31693806
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Impact:
Abstract

Changes in exercise frequency and cardiovascular outcomes in older adults.

Kim K, Choi S, Hwang SE, Son JS, ... Oh J, Park SM
Aims
Little is known about the association of changes in moderate to vigorous physical activity (MVPA) level with cardiovascular disease (CVD), especially in older adults whose ability to engage in frequent MVPA naturally wanes as they age. We aimed to examine the association of changes in MVPA and CVD in older adults.
Methods and results
In a nationwide cohort study of older adults aged 60 years or older, we identified more than 1.1 million subjects without previous history of CVD at baseline who underwent two consecutive national health screening from 2009 to 2012. We prospectively assessed the risk of CVD occurred between 2013 and 2016 according to changes in frequency of MVPA by initial MVPA status. Compared to those who were continuously physically inactive, those who increased their frequency of MVPA from physically inactive to 1-2 times per week [0.7/1000 person-years (PY) decrease in incidence rate (IR); adjusted hazard ratio (aHR) 0.95; 95% confidence interval (CI) 0.92-0.99], 3-4 times per week (1.5/1000 PY decrease in IR; aHR 0.89; 95% CI 0.84-0.94), ≥5 times per week (0.4/1000 PY decrease in IR; aHR 0.91; 95% CI 0.85-0.97) had a significantly reduced risk for total CVD (P for trend <0.001). Older adults who became physically inactive from engaging in more than 1-2 times of MVPA per week had a higher CVD risk compared to those who maintained their frequency of MVPA.
Conclusion
Among older adults, engaging in higher frequency of MVPA or maintaining MVPA level was associated with reduced risk of CVD.

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: 07 Nov 2019; epub ahead of print
Kim K, Choi S, Hwang SE, Son JS, ... Oh J, Park SM
Eur Heart J: 07 Nov 2019; epub ahead of print | PMID: 31698425
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Impact:
Abstract

Genome-Wide Assessment for Resting Heart Rate and Shared Genetics With Cardiometabolic Traits and Type 2 Diabetes.

Guo Y, Chung W, Zhu Z, Shan Z, ... Liu S, Liang L
Background
High resting heart rate (RHR) occurs in parallel with type 2 diabetes (T2D) and metabolic disorders, implying shared etiology between them. However, it is unknown if they are causally related, and no study has been conducted to investigate the shared mechanisms underlying these associations.
Objectives
The objective of this study was to understand the genetic basis of the association between resting heart rate and cardiometabolic disorders/T2D.
Methods
This study examined the genetic correlation, causality, and shared genetics between RHR and T2D using LD Score regression, generalized summary data-based Mendelian randomization, and transcriptome wide association scan (TWAS) in UK Biobank data (n = 428,250) and summary-level data for T2D (74,124 cases and 824,006 control subjects) and 8 cardiometabolic traits (sample size ranges from 51,750 to 236,231).
Results
Significant genetic correlation between RHR and T2D (r = 0.22; 95% confidence interval: 0.18 to 0.26; p = 1.99 × 10), and 6 cardiometabolic traits (fasting insulin, fasting glucose, waist-hip ratio, triglycerides, high-density lipoprotein, and body mass index; r range -0.12 to 0.24; all p < 0.05) were observed. RHR has significant estimated causal effect on T2D (odds ratio: 1.12 per 10-beats/min increment; p = 7.79 × 10) and weaker causal estimates from T2D to RHR (0.32 beats/min per doubling increment in T2D prevalence; p = 6.14 × 10). Sensitivity analysis by controlling for the included cardiometabolic traits did not modify the relationship between RHR and T2D. TWAS found locus chr2q23.3 (rs1260326) was highly pleiotropic among RHR, cardiometabolic traits, and T2D, and identified 7 genes (SMARCAD1, RP11-53O19.3, CTC-498M16.4, PDE8B, AKTIP, KDM4B, and TSHZ3) that were statistically independent and shared between RHR and T2D in tissues from the nervous and cardiovascular systems. These shared genes suggested the involvement of epigenetic regulation of energy and glucose metabolism, and AKT activation-related telomere dysfunction and vascular endothelial aging in the shared etiologies between RHR and T2D. Finally, FADS1 was found to be shared among RHR, fasting glucose, high-density lipoprotein, and triglycerides.
Conclusions
These findings provide evidence of significant genetic correlations and causation between RHR and T2D/cardiometabolic traits, advance our understanding of RHR, and provide insight into shared etiology for high RHR and T2D.

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

J Am Coll Cardiol: 28 Oct 2019; 74:2162-2174
Guo Y, Chung W, Zhu Z, Shan Z, ... Liu S, Liang L
J Am Coll Cardiol: 28 Oct 2019; 74:2162-2174 | PMID: 31648709
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Impact:
Abstract

Anticoagulation in Concomitant Chronic Kidney Disease and Atrial Fibrillation: JACC Review Topic of the Week.

Kumar S, Lim E, Covic A, Verhamme P, ... Camm AJ, Goldsmith D

Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist as they share multiple risk factors, including hypertension, diabetes mellitus, and coronary artery disease. Although there is irrefutable evidence supporting anticoagulation in AF in the general population, these data may not be transferable to the setting of advanced CKD, where the decision to commence anticoagulation poses a conundrum. In this cohort, there is a progressively increased risk of both ischemic stroke and hemorrhage as renal function declines, complicating the decision to initiate anticoagulation. No definitive clinical guidelines derived from randomized controlled trials exist to aid clinical decision-making, and the findings from observational studies are conflicting. In this review, the authors outline the pathophysiological mechanisms at play and summarize the limited existing data related to anticoagulation in those with concomitant CKD and AF. Finally, the authors suggest how to approach the decision of whether and how to use oral anticoagulation in these patients.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 28 Oct 2019; 74:2204-2215
Kumar S, Lim E, Covic A, Verhamme P, ... Camm AJ, Goldsmith D
J Am Coll Cardiol: 28 Oct 2019; 74:2204-2215 | PMID: 31648714
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Impact:
Abstract

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia.

Koren MJ, Sabatine MS, Giugliano RP, Langslet G, ... Wasserman SM, Raal FJ
Background
Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over <3 years median treatment duration.
Objectives
The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years.
Methods
Patients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation.
Results
A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed.
Conclusions
The OSLER-1 trial demonstrated consistently excellent LDL-C-lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880).

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

J Am Coll Cardiol: 28 Oct 2019; 74:2132-2146
Koren MJ, Sabatine MS, Giugliano RP, Langslet G, ... Wasserman SM, Raal FJ
J Am Coll Cardiol: 28 Oct 2019; 74:2132-2146 | PMID: 31648705
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Abstract

Anticoagulation With an Inhibitor of Factors XIa and XIIa During Cardiopulmonary Bypass.

Pireaux V, Tassignon J, Demoulin S, Derochette S, ... Guyaux M, Godfroid E
Background
Exposure of blood to polyanionic artificial surfaces, for example, during cardiopulmonary bypass (CPB), induces a highly procoagulant condition requiring strong anticoagulation. Unfractionated heparin (UFH) is currently used during CPB but can lead to serious bleeding complications or development of a hypercoagulable state culminating in life-threatening thrombosis, highlighting the need for safer antithrombotics. Ixodes ricinus contact phase inhibitor (Ir-CPI) is a protein expressed by I. ricinus ticks, which specifically inhibits both factors XIIa and XIa, 2 factors contributing to thrombotic disease while playing a limited role in hemostasis.
Objectives
This study assessed the antithrombotic activity of Ir-CPI in animal contact phase-initiated thrombosis models, including CPB. The safety of Ir-CPI also was evaluated.
Methods
The authors evaluated the antithrombotic activity of Ir-CPI by using in vitro catheter-induced clotting assays and rabbit experimental models of catheter occlusion and arteriovenous shunt. During CPB with cardiac surgery in sheep, the clinical applicability of Ir-CPI was investigated and its efficacy compared to that of UFH using an uncoated system suitable for adult therapy. Taking advantage of the similar hemostatic properties of pigs and humans, the authors performed pig liver bleeding assays to evaluate the safety of Ir-CPI.
Results
Ir-CPI prevented clotting in catheter and arteriovenous shunt rabbit models. During CPB, Ir-CPI was as efficient as UFH in preventing clot formation within the extracorporeal circuit and maintained physiological parameters during and post-surgery. Unlike UFH, Ir-CPI did not promote bleeding.
Conclusions
Preclinical animal models used in this study showed that Ir-CPI is an effective and safe antithrombotic agent that provides a clinically relevant approach to thrombosis prevention in bypass systems, including highly thrombogenic CPB.

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

J Am Coll Cardiol: 28 Oct 2019; 74:2178-2189
Pireaux V, Tassignon J, Demoulin S, Derochette S, ... Guyaux M, Godfroid E
J Am Coll Cardiol: 28 Oct 2019; 74:2178-2189 | PMID: 31648711
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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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Abstract

Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials.

Gargiulo G, Goette A, Tijssen J, Eckardt L, ... Vranckx P, Valgimigli M
Aims
To investigate the safety and efficacy of double vs. triple antithrombotic therapy (DAT vs. TAT) in patients with atrial fibrillation (AF) and acute coronary syndrome or who underwent percutaneous coronary intervention (PCI).
Methods and results
A systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials comparing DAT vs. TAT in AF patients undergoing PCI. Four trials encompassing 10 234 patients (DAT = 5496 vs. TAT = 4738) were included. The primary safety endpoint (ISTH major or clinically relevant non-major bleeding) was significantly lower with DAT compared with TAT [risk ratio (RR) 0.66, 95% confidence interval (CI) 0.56-0.78; P < 0.0001; I2 = 69%], which was consistent across all available bleeding definitions. This benefit was counterbalanced by a significant increase of stent thrombosis (RR 1.59, 95% CI 1.01-2.50; P = 0.04; I2 = 0%) and a trend towards higher risk of myocardial infarction with DAT. There were no significant differences in all-cause and cardiovascular death, stroke and major adverse cardiovascular events. The comparison of NOAC-based DAT vs. vitamin K antagonist (VKA)-TAT yielded consistent results and a significant reduction of intracranial haemorrhage (RR 0.33, 95% CI 0.17-0.65; P = 0.001; I2 = 0%).
Conclusion
Double antithrombotic therapy, particularly if consisting of a NOAC instead of VKA and a P2Y12 inhibitor, is associated with a reduction of bleeding, including major and intracranial haemorrhages. This benefit is however counterbalanced by a higher risk of cardiac-mainly stent-related-but not cerebrovascular ischaemic occurrences.

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

Eur Heart J: 24 Oct 2019; epub ahead of print
Gargiulo G, Goette A, Tijssen J, Eckardt L, ... Vranckx P, Valgimigli M
Eur Heart J: 24 Oct 2019; epub ahead of print | PMID: 31651946
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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

Subclinical and Device-Detected Atrial Fibrillation: Pondering the Knowledge Gap: A Scientific Statement From the American Heart Association.

Noseworthy PA, Kaufman ES, Chen LY, Chung MK, ... Yao X,

The widespread use of cardiac implantable electronic devices and wearable monitors has led to the detection of subclinical atrial fibrillation in a substantial proportion of patients. There is evidence that these asymptomatic arrhythmias are associated with increased risk of stroke. Thus, detection of subclinical atrial fibrillation may offer an opportunity to reduce stroke risk by initiating anticoagulation. However, it is unknown whether long-term anticoagulation is warranted and in what populations. This scientific statement explores the existing data on the prevalence, clinical significance, and management of subclinical atrial fibrillation and identifies current gaps in knowledge and areas of controversy and consensus.



Circulation: 06 Nov 2019:CIR0000000000000740; epub ahead of print
Noseworthy PA, Kaufman ES, Chen LY, Chung MK, ... Yao X,
Circulation: 06 Nov 2019:CIR0000000000000740; epub ahead of print | PMID: 31694402
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Impact:
Abstract

ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons.

Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.



Hypertension: 30 Oct 2019; 74:1181-1191
Mukerjee S, Gao H, Xu J, Sato R, Zsombok A, Lazartigues E
Hypertension: 30 Oct 2019; 74:1181-1191 | PMID: 31564162
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Impact:
Abstract

Superiority of Out-of-Office Blood Pressure for Predicting Hypertensive Heart Disease in Non-Hispanic Black Adults.

Rader F, Franklin SS, Mirocha J, Vongpatanasin W, Haley RW, Victor RG

Black Americans suffer disproportionately from hypertension and hypertensive heart disease. Out-of-office blood pressure (BP) is more predictive for cardiovascular complications than clinic BP; however, the relative abilities of clinic and out-of-office BP to predict left ventricular hypertrophy in black and white adults have not been established. Thus, we aimed to compare associations of out-of-office and clinic BP measurement with left ventricular hypertrophy by cardiac magnetic resonance imaging among non-Hispanic black and white adults. In this cross-sectional study, 1262 black and 927 white participants of the Dallas Heart Study ages 30 to 64 years underwent assessment of standardized clinic and out-of-office (research staff-obtained) BP and left ventricular mass index. In multivariable-adjusted analyses of treated and untreated participants, out-of-office BP was a stronger determinant of left ventricular hypertrophy than clinic BP (odds ratio per 10 mm Hg, 1.48; 95% CI, 1.34-1.64 for out-of-office systolic BP and 1.15 [1.04-1.28] for clinic systolic BP; 1.71 [1.43-2.05] for out-of-office diastolic BP, and 1.03 [0.86-1.24] for clinic diastolic BP). Non-Hispanic black race/ethnicity, treatment status, and lower left ventricular ejection fraction were also independent determinants of hypertrophy. Among treated Blacks, the differential association between out-of-office and clinic BP with hypertrophy was more pronounced than in treated white or untreated participants. In conclusion, protocol-driven supervised out-of-office BP monitoring provides important information that cannot be gleaned from clinic BP assessment alone. Our results underscore the importance of hypertension management programs outside the medical office to prevent hypertensive heart disease, especially in high-risk black adults. Clinical trial registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00344903.



Hypertension: 30 Oct 2019; 74:1192-1199
Rader F, Franklin SS, Mirocha J, Vongpatanasin W, Haley RW, Victor RG
Hypertension: 30 Oct 2019; 74:1192-1199 | PMID: 31522619
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Impact:
Abstract

Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications.

Zhang Z, Luo X, Lv Y, Yan L, ... Pan Y, Du L

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension-like pathophysiological features in adulthood.



Hypertension: 30 Oct 2019; 74:1160-1171
Zhang Z, Luo X, Lv Y, Yan L, ... Pan Y, Du L
Hypertension: 30 Oct 2019; 74:1160-1171 | PMID: 31596625
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Impact:
Abstract

Impact of the Duration and Degree of Hypertension and Body Weight on New-Onset Atrial Fibrillation: A Nationwide Population-Based Study.

Kim YG, Han KD, Choi JI, Yung Boo K, ... Kim JS, Kim YH

Hypertension and obesity are known risk factors for atrial fibrillation (AF). However, it is unclear whether uncontrolled, long-standing hypertension has a particularly profound effect on AF. Because they have a similar underlying pathophysiology, hypertension and obesity could act synergistically in the context of AF. We evaluated how various stages of hypertension and body weight status affect new-onset AF. We analyzed a total of 9 797 418 participants who underwent a national health checkup. Hypertension was classified into 5 stages: nonhypertension, prehypertension, hypertension without medication, hypertension with medication <5 years, and hypertension with medication ≥5 years. The participants were also stratified based on body mass index and waist circumference. During the 80 130 161 person×years follow-up, a total of 196 136 new-onset AF cases occurred. The incidence of new-onset AF gradually increased among the 5 stages of hypertension: the adjusted hazard ratio for each group was 1 (reference), 1.145, 1.390, 1.853, and 2.344 for each stage of hypertension. A graded escalation in the risk of new-onset AF was also observed in response to increased systolic and diastolic blood pressure. The incidence of new-onset AF correlated with body mass index and waist circumference, with obese people having a higher risk than others. Hypertension and obesity acted synergistically: obese people with hypertension on medication ≥5 years had the highest risk of AF. In conclusion, the degree and duration of hypertension, as well as the presence of hypertension, were important factors for new-onset AF. Body weight status was significantly associated with new-onset AF and acted synergistically with hypertension.



Hypertension: 30 Oct 2019; 74:e45-e51
Kim YG, Han KD, Choi JI, Yung Boo K, ... Kim JS, Kim YH
Hypertension: 30 Oct 2019; 74:e45-e51 | PMID: 31522617
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Impact:
Abstract

Increased Vascular Contractility in Hypertension Results From Impaired Endothelial Calcium Signaling.

Wilson C, Zhang X, Buckley C, Heathcote HR, Lee MD, McCarron JG

Endothelial cells line all blood vessels and are critical regulators of vascular tone. In hypertension, disruption of endothelial function alters the release of endothelial-derived vasoactive factors and results in increased vascular tone. Although the release of endothelial-derived vasodilators occurs in a Ca-dependent manner, little is known on how Ca signaling is altered in hypertension. A key element to endothelial control of vascular tone is Ca signals at specialized regions (myoendothelial projections) that connect endothelial cells and smooth muscle cells. This work describes disruption in the operation of this key Ca signaling pathway in hypertension. We show that vascular reactivity to phenylephrine is increased in hypertensive (spontaneously hypertensive rat) when compared with normotensive (Wistar Kyoto) rats. Basal endothelial Ca activity limits vascular contraction, but that Ca-dependent control is impaired in hypertension. When changes in endothelial Ca levels are buffered, vascular contraction to phenylephrine increased, resulting in similar responses in normotension and hypertension. Local endothelial IP(inositol trisphosphate)-mediated Ca signals are smaller in amplitude, shorter in duration, occur less frequently, and arise from fewer sites in hypertension. Spatial control of endothelial Ca signaling is also disrupted in hypertension: local Ca signals occur further from myoendothelial projections in hypertension. The results demonstrate that the organization of local Ca signaling circuits occurring at myoendothelial projections is disrupted in hypertension, giving rise to increased contractile responses.



Hypertension: 30 Oct 2019; 74:1200-1214
Wilson C, Zhang X, Buckley C, Heathcote HR, Lee MD, McCarron JG
Hypertension: 30 Oct 2019; 74:1200-1214 | PMID: 31542964
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Impact:
Abstract

Targeted VEGF (Vascular Endothelial Growth Factor) Therapy Induces Long-Term Renal Recovery in Chronic Kidney Disease via Macrophage Polarization.

Engel JE, Williams E, Williams ML, Bidwell GL, Chade AR

Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.



Hypertension: 30 Oct 2019; 74:1113-1123
Engel JE, Williams E, Williams ML, Bidwell GL, Chade AR
Hypertension: 30 Oct 2019; 74:1113-1123 | PMID: 31542966
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Abstract

ANO4 (Anoctamin 4) Is a Novel Marker of Zona Glomerulosa That Regulates Stimulated Aldosterone Secretion.

Maniero C, Scudieri P, Haris Shaikh L, Zhao W, ... Galietta LJV, Brown MJ

Microarray comparison of the transcriptomes of human adrenal zona glomerulosa (ZG) and zona fasciculata found several ZG-specific genes that negatively regulate aldosterone secretion. The third and most significantly upregulated ZG-gene (19.9-fold compared with zona fasciculata, =6.58×10) was , a putative Ca-activated chloride channel. We have investigated the role ofin human adrenal, and whether it functions like the prototype anoctamin, . We evaluatedmRNA and protein expression in human adrenal by qPCR and immunohistochemistry, compared the effects ofandoverexpression on baseline and stimulated aldosterone secretion and cell proliferation in H295R cells, and analyzed ANO4 activity as a Ca-activated chloride channel in comparison with other anoctamins by a fluorescence-based functional assay. The expression ofin ZG was confirmed by qPCR as 23.21-fold upregulated compared with zona fasciculata (n=18; =4.93×10). Immunohistochemistry found cytoplasmic, ZG-selective expression of ANO4 (anoctamin 4) protein.overexpression in H295R cells attenuated calcium-mediated aldosterone secretion and cell proliferation in comparison to controls. The latter effects were in a different direction to those of ANO1. The functional assay showed that, in contrast to ANO1, ANO4 expression results in low levels of calcium-dependent anion transport. In conclusion, ANO4 is one of the most highly expressed genes in ZG. It attenuates stimulated aldosterone secretion and cell proliferation. Although belonging to a family of Ca-activated chloride channels, it does not generate significant plasma membrane chloride channel activity.



Hypertension: 30 Oct 2019; 74:1152-1159
Maniero C, Scudieri P, Haris Shaikh L, Zhao W, ... Galietta LJV, Brown MJ
Hypertension: 30 Oct 2019; 74:1152-1159 | PMID: 31564164
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Abstract

Blood Pressure Variability and Progression of Clinical Alzheimer Disease.

de Heus RAA, Olde Rikkert MGM, Tully PJ, Lawlor BA, Claassen JAHR

Blood pressure variability (BPV) has been shown to have predictive value over blood pressure (BP) levels alone in stroke patients. We assessed whether BPV predicts cognitive and functional decline in Alzheimer disease, using data from a randomized trial (NILVAD [A European Multicentre Double-blind Placebo-controlled Phase III Trial of Nilvadipine in Mild to Moderate Alzheimer\'s Disease]). Patients with mild-to-moderate Alzheimer disease were included if they had ≥3 office BP measurements available to determine visit-to-visit BPV. Day-to-day BPV was assessed using home BP measurements in a subsample. The variation independent of mean was used to calculate BPV. Outcomes were change in Alzheimer\'s Disease Assessment Scale-cognitive subscale-12 and Disability Assessment for Dementia after 1 and 1.5 years. A total of 460 patients aged 72.1 (SD=8.1) years, with mean BP of 134.0/75.1 (10.9/6.3) mm Hg were included. After 1 year, patients in the highest quartile of BPV had deteriorated more on Alzheimer\'s Disease Assessment Scale-cognitive subscale compared with patients in the lowest quartile (systolic: β, 2.24 [95% CI, 0.11-4.38], =0.040; diastolic: β, 2.54 [95% CI, 0.33-4.75] =0.024). This association was still present after 1.5 years (systolic: β, 2.86 [95% CI, 0.35-5.36], =0.026; diastolic: β, 3.30 [95% CI, 0.67-5.93], =0.014). There was no effect of visit-to-visit BPV on Disability Assessment for Dementia. Day-to-day BPV was available for 46 patients. Significant associations were observed between day-to-day BPV and deterioration on Alzheimer\'s Disease Assessment Scale-cognitive subscale (systolic: =0.036) and Disability Assessment for Dementia (systolic: =0.020; diastolic: =0.007) after 1 year, but not after 1.5 years. All associations were adjusted for potential confounders, including intervention group. In conclusion, this post hoc analysis indicates that higher visit-to-visit and day-to-day BPV might be associated with progression of Alzheimer disease. Targeting BPV may be a future target to slow decline in patients with Alzheimer disease. Clinical Trial registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340.



Hypertension: 30 Oct 2019; 74:1172-1180
de Heus RAA, Olde Rikkert MGM, Tully PJ, Lawlor BA, Claassen JAHR
Hypertension: 30 Oct 2019; 74:1172-1180 | PMID: 31542965
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Abstract

Pregnancy-Related Acute Kidney Injury in Preeclampsia: Risk Factors and Renal Outcomes.

Conti-Ramsden FI, Nathan HL, De Greeff A, Hall DR, ... Shennan AH, Bramham K

Preeclampsia is a common cause of acute kidney injury (AKI) in low- and middle-income countries, but AKI incidence in preeclampsia, its risk factors, and renal outcomes are unknown. A prospective observational multicenter study of women admitted with preeclampsia in South Africa was conducted. Creatinine concentrations were extracted from national laboratory databases for women with maximum creatinine of ≥90 μmol/L (≥1.02 mg/dL). Renal injury and recovery were defined by Kidney Disease Improving Global Outcomes creatinine criteria. Predefined risk factors, maternal outcomes, and neonatal outcomes were compared between AKI stages. Of 1547 women admitted with preeclampsia 237 (15.3%) met AKI criteria: 6.9% (n=107) stage 1, 4.3% (n=67) stage 2, and 4.1% (n=63) stage 3. There was a higher risk of maternal death (n=7; relative risk, 4.3; 95% CI, 1.6-11.4) and stillbirth (n=80; relative risk, 2.2; 95% CI, 1.8-2.8) in women with AKI compared with those without. Perinatal mortality was also increased (89 of 240; 37.1%). Hypertension in a previous pregnancy was the strongest predictor of AKI stage 2 or 3 (odds ratio, 2.24; 95% CI, 1.21-4.17). Renal recovery rate reduced with increasing AKI stage. A third of surviving women (76 of 230 [33.0%]) had not recovered baseline renal function by discharge. Approximately half (39 of 76; 51.3%) of these women had no further creatinine testing post-discharge. In summary, AKI was common in women with preeclampsia and had high rates of associated maternal and perinatal mortality. Only two-thirds of women had confirmed renal recovery. History of a previous hypertensive pregnancy was an important risk factor.



Hypertension: 30 Oct 2019; 74:1144-1151
Conti-Ramsden FI, Nathan HL, De Greeff A, Hall DR, ... Shennan AH, Bramham K
Hypertension: 30 Oct 2019; 74:1144-1151 | PMID: 31564161
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Abstract

Predictive Performance of PlGF (Placental Growth Factor) for Screening Preeclampsia in Asymptomatic Women: A Systematic Review and Meta-Analysis.

Agrawal S, Shinar S, Cerdeira AS, Redman C, Vatish M

Preeclampsia is a systemic syndrome that seems to originate from the placenta and is associated with an imbalance between angiogenic factors in the maternal circulation. One of the well-studied and widely used factors is PlGF (placental growth factor), the levels of which drop in women destined to develop preeclampsia. This drop is known to precede the development of actual signs and symptoms of preeclampsia, thus proving to be a useful screening tool in predicting the disease. The literature varies widely in terms of the clinical usefulness of the test. We conducted a meta-analysis to study the predictive accuracy of PlGF in asymptomatic women. Our analysis included 40 studies with 3189 cases of preeclampsia and 89 498 controls. The overall predictive odds ratio of the test was 9 (6-13). Subgroup analysis evaluating various PlGF thresholds demonstrated that the predictive values were highest for PlGF levels between 80 and 120 pg/mL with a high predictive odds ratio of 25 (7-88), a sensitivity of 0.78 (95% CI, 0.67-0.86), a specificity of 0.88 (95% CI, 0.75-0.95), a positive likelihood ratio of 6.3 (95% CI, 2.7-14.7), and a negative likelihood ratio of 0.26 (95% CI, 0.16-0.42). Additionally, the accuracy was higher when the test was performed after 14 weeks of gestation (OR, 10 [7-15]) and for prediction of early onset preeclampsia (OR, 18 [9-37]). We conclude that PlGF is a useful screening tool to predict preeclampsia. Nonetheless, its utility should be judged with caution and randomized controlled trials are warranted to explore if its implementation improves perinatal outcomes in asymptomatic women.



Hypertension: 30 Oct 2019; 74:1124-1135
Agrawal S, Shinar S, Cerdeira AS, Redman C, Vatish M
Hypertension: 30 Oct 2019; 74:1124-1135 | PMID: 31522621
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Abstract

NaHCO Dilates Mouse Afferent Arteriole Via Na/HCO Cotransporters NBCs.

Jiang S, Wang X, Wei J, Zhang G, ... Lai EY, Liu R

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na/HCO cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6, <0.05) in response to NaHCO (44 mmol/L). Whereas, NaCl solution containing the same Na concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2\',7\'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6; <0.05) in the presence of NaHCO, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 μM nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7; <0.005) and increases NO generation by 22±3% (n=7; <0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO increased NO generation in Af-Art by 19±4% (n=5; <0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9-10; <0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.



Hypertension: 30 Oct 2019; 74:1104-1112
Jiang S, Wang X, Wei J, Zhang G, ... Lai EY, Liu R
Hypertension: 30 Oct 2019; 74:1104-1112 | PMID: 31522618
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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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Abstract

Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study.

Bougouin W, Dumas F, Lamhaut L, Marijon E, ... Jouven X,
Aims
Out-of-hospital cardiac arrest (OHCA) without return of spontaneous circulation (ROSC) despite conventional resuscitation is common and has poor outcomes. Adding extracorporeal membrane oxygenation (ECMO) to cardiopulmonary resuscitation (extracorporeal-CPR) is increasingly used in an attempt to improve outcomes.
Methods and results
We analysed a prospective registry of 13 191 OHCAs in the Paris region from May 2011 to January 2018. We compared survival at hospital discharge with and without extracorporeal-CPR and identified factors associated with survival in patients given extracorporeal-CPR. Survival was 8% in 525 patients given extracorporeal-CPR and 9% in 12 666 patients given conventional-CPR (P = 0.91). By adjusted multivariate analysis, extracorporeal-CPR was not associated with hospital survival [odds ratio (OR), 1.3; 95% confidence interval (95% CI), 0.8-2.1; P = 0.24]. By conditional logistic regression with matching on a propensity score (including age, sex, occurrence at home, bystander CPR, initial rhythm, collapse-to-CPR time, duration of resuscitation, and ROSC), similar results were found (OR, 0.8; 95% CI, 0.5-1.3; P = 0.41). In the extracorporeal-CPR group, factors associated with hospital survival were initial shockable rhythm (OR, 3.9; 95% CI, 1.5-10.3; P = 0.005), transient ROSC before ECMO (OR, 2.3; 95% CI, 1.1-4.7; P = 0.03), and prehospital ECMO implantation (OR, 2.9; 95% CI, 1.5-5.9; P = 0.002).
Conclusions
In a population-based registry, 4% of OHCAs were treated with extracorporeal-CPR, which was not associated with increased hospital survival. Early ECMO implantation may improve outcomes. The initial rhythm and ROSC may help select patients for extracorporeal-CPR.

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

Eur Heart J: 30 Oct 2019; epub ahead of print
Bougouin W, Dumas F, Lamhaut L, Marijon E, ... Jouven X,
Eur Heart J: 30 Oct 2019; epub ahead of print | PMID: 31670793
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Abstract

Rapamycin-Loaded Leukosomes Reverse Vascular Inflammation.

Boada C, Zinger A, Tsao CJ, Zhao P, ... Cooke JP, Tasciotti E

Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation, and thus the progression of vascular disease.Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in-vivo model of atherosclerosis after a short dosing schedule.Biomimetic nanoparticles (\"leukosomes\") were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108 +/- 2.3 nm, a surface charge of -15.4 +/- 14.4 mV and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either phosphate-buffered saline, free rapamycin (5mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa) (5mg/kg) once daily for seven days. In mice treated with Leuko-Rapa flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6 +/- 9.79 %) compared to untreated mice (30.2 +/- 13.34 %) and rapamycin alone (26.8 +/- 9.87 %). Decreased macrophage proliferation correlated with decreased levels of monocyte chemoattractant protein (MCP-1) and Il-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa treated mice also displayed significantly decreased MMP activity in the aorta (Mean Difference 2554 {plus minus} 363.9, p= 9.95122E-06). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa treated mice.We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key pro-inflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (seven days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.



Circ Res: 23 Oct 2019; epub ahead of print
Boada C, Zinger A, Tsao CJ, Zhao P, ... Cooke JP, Tasciotti E
Circ Res: 23 Oct 2019; epub ahead of print | PMID: 31647755
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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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Abstract

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

Nassif ME, Windsor SL, Tang F, Khariton Y, ... Umpierrez G, Kosiborod M
Background
Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown.
Methods
DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP.
Results
Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), =0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal =0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (allvalues for interaction=NS).
Conclusions
In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.



Circulation: 28 Oct 2019; 140:1463-1476
Nassif ME, Windsor SL, Tang F, Khariton Y, ... Umpierrez G, Kosiborod M
Circulation: 28 Oct 2019; 140:1463-1476 | PMID: 31524498
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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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Abstract

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

Middleton PG, Mall MA, Dřevínek P, Lands LC, ... Jain R,
Background
Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508delmutation. In a phase 2 trial involving patients who were heterozygous for the Phe508delmutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.
Methods
We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV) at week 4.
Results
A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.
Conclusions
Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 06 Nov 2019; 381:1809-1819
Middleton PG, Mall MA, Dřevínek P, Lands LC, ... Jain R,
N Engl J Med: 06 Nov 2019; 381:1809-1819 | PMID: 31697873
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Abstract

Osteoporotic Fractures in Patients With Atrial Fibrillation Treated With Conventional Versus Direct Anticoagulants.

Binding C, Bjerring Olesen J, Abrahamsen B, Staerk L, Gislason G, Nissen Bonde A
Background
Elderly patients in long-term treatment with vitamin K antagonists (VKAs) are at high risk of osteoporotic fractures compared with the background population. It has been speculated that the choice of oral anticoagulant (OAC) may affect the risk of osteoporotic fractures.
Objectives
The risk of osteoporotic fractures was evaluated among patients with atrial fibrillation treated with VKA or direct oral anticoagulants (DOACs).
Methods
Patients were identified using the Danish national registries. Patients were included only if they had no prior use of osteoporosis medication and they had undergone 180 days of OAC treatment. Outcomes were hip fracture, major osteoporotic fracture, any fracture, initiation of osteoporosis medication, and a combined endpoint.
Results
Overall, 37,350 patients were included. The standardized absolute 2-year risk of any fracture was low among DOAC-treated patients (3.1%; 95% CI: 2.9% to 3.3%) and among VKA-treated patients (3.8%; 95% CI: 3.4% to 4.2%). DOAC was associated with a significantly lower relative risk of any fracture (hazard ratio [HR]: 0.85; 95% CI: 0.74 to 0.97), major osteoporotic fractures (HR: 0.85; 95% CI: 0.72 to 0.99), and initiating osteoporotic medication (HR: 0.82; 95% CI: 0.71 to 0.95). A combined endpoint showed that patients treated with DOAC had a significantly lower relative risk of experiencing any fracture or initiating osteoporosis medication (HR: 0.84; 95% CI: 0.76 to 0.93).
Conclusions
In a nationwide population, the absolute risk of osteoporotic fractures was low among patients with atrial fibrillation on OAC, but DOAC was associated with a significantly lower risk of osteoporotic fractures compared with VKA.

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

J Am Coll Cardiol: 28 Oct 2019; 74:2150-2158
Binding C, Bjerring Olesen J, Abrahamsen B, Staerk L, Gislason G, Nissen Bonde A
J Am Coll Cardiol: 28 Oct 2019; 74:2150-2158 | PMID: 31648707
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Abstract

Clinical and Prognostic Significance of sST2 in Heart Failure: JACC Review Topic of the Week.

Aimo A, Januzzi JL, Bayes-Genis A, Vergaro G, ... Passino C, Emdin M

Soluble suppression of tumorigenesis-2 (sST2) is released in response to vascular congestion and inflammatory and pro-fibrotic stimuli, and is a strong, independent predictor of mortality and heart failure (HF) hospitalization in patients with acute or chronic HF. sST2 meets 2 fundamental criteria for clinically useful biomarkers: accurate, repeated measurements are available at a reasonable cost, and the biomarker provides information not already available from a careful clinical assessment. In particular, the prognostic value of sST2 is additive to natriuretic peptides and (in the case of chronic HF) to high-sensitivity troponin T. Nevertheless, the need for a multibiomarker approach to risk stratification and the role of sST2 as a guide to therapy decision-making remain to be established. Four years after a consensus document on sST2, and following major advances in the comprehension of the clinical value of this biomarker, the authors felt it worthwhile to reappraise current knowledge on sST2 in HF.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 28 Oct 2019; 74:2193-2203
Aimo A, Januzzi JL, Bayes-Genis A, Vergaro G, ... Passino C, Emdin M
J Am Coll Cardiol: 28 Oct 2019; 74:2193-2203 | PMID: 31648713
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Abstract

Emerging Drug Classes and Their Potential Use in Hypertension.

Azizi M, Rossignol P, Hulot JS

Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure-lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure-lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.



Hypertension: 30 Oct 2019; 74:1075-1083
Azizi M, Rossignol P, Hulot JS
Hypertension: 30 Oct 2019; 74:1075-1083 | PMID: 31495277
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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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Abstract

Metabolomics Identifies Placental Dysfunction and Confirms Flt-1 (FMS-Like Tyrosine Kinase Receptor 1) Biomarker Specificity.

Austdal M, Silva GB, Bowe S, Thomsen LCV, ... Bathen TF, Iversen AC

Clinical end-stage parameters define the pregnancy disorders preeclampsia and fetal growth restriction while classification of the underlying placental dysfunction is missing and urgently needed. Flt-1 (FMS-like tyrosine kinase receptor 1) is the most promising placenta-derived predictive biomarker for preeclampsia. We aimed to classify placental dysfunction in preeclampsia and fetal growth restriction at delivery by metabolic profiling and authenticate the biomarker Flt-1 for placental dysfunction. We studied 143 pregnancies with or without preeclampsia and/or fetal growth restriction delivered by cesarean section. Metabolic placenta profiles were created by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and the resulting placental phenotypes obtained by hierarchical clustering. Placental Flt-1 expression (membrane-bound and soluble isoforms combined) and maternal serum Flt-1 expression (soluble isoforms) were analyzed by immunohistochemistry and ELISA, respectively. We identified 3 distinct placenta groups by 21 metabolites and diagnostic outcome parameters; normal placentas, moderate placental dysfunction, and severe placental dysfunction. Increased placental Flt-1 was associated with severe placental dysfunction, and increased serum Flt-1 was associated with moderate and severe placental dysfunction. The preeclamptic pregnancies with and without placental dysfunction could be distinguished by 5 metabolites and placental Flt-1. Placental Flt-1 alone could separate normal pregnancies with and without placental dysfunction. In conclusion, metabolomics could classify placental dysfunction and provide information not identified by traditional diagnostics and metabolites with biomarker potential were identified. Flt-1 was confirmed as precision biomarker for placental dysfunction, substantiating its usefulness for identification of high-risk pregnancies for preeclampsia and fetal growth restriction with placental involvement.



Hypertension: 30 Oct 2019; 74:1136-1143
Austdal M, Silva GB, Bowe S, Thomsen LCV, ... Bathen TF, Iversen AC
Hypertension: 30 Oct 2019; 74:1136-1143 | PMID: 31495279
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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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