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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

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

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

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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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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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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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

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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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

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

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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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

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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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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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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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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Abstract

Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis.

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

Copyright © 2019 Massachusetts Medical Society.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Echocardiographic Features of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction.

Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
Background
The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity.
Objectives
The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies.
Methods
Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors.
Results
Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e\' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e\' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e\' ratio, pulmonary artery systolic pressure, and event rates.
Conclusions
Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

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

J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873
Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873 | PMID: 31806129
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Impact:
Abstract

Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders.

Diederichsen SZ, Haugan KJ, Brandes A, Lanng MB, ... Højberg S, Svendsen JH
Background
As new heart rhythm monitoring technologies emerge, subclinical atrial fibrillation (AF) signifies a future challenge to health care systems. The pathological characteristics of this condition are largely unknown.
Objectives
This study sought to characterize the natural history of subclinical AF in at-risk patients from the general population.
Methods
The authors studied 590 individuals ≥70 years of age with ≥1 of hypertension, diabetes, previous stroke, or heart failure, without history of AF, undergoing long-term implantable loop recorder monitoring as part of the LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals) study. Baseline assessments included N-terminal pro-B-type natriuretic peptide (NT-proBNP). All day-to-day heart rhythm and symptom data were extracted from the device. Endpoints included AF burden, AF progression, symptom reports, and heart rate during AF.
Results
A total of 685,445 monitoring days were available for analysis. Adjudicated AF episodes lasting ≥6 min were detected in 205 participants (35%). The AF burden was median 0.13% (interquartile range: 0.03% to 1.05%) of the monitoring time and changed by a factor of 1.31 (95% CI: 1.02 to 1.68) per doubling of NT-proBNP. AF episodes were present 2.7% (interquartile range: 1.0% to 15.7%) of monitoring days after debut. Progression to 24-h episodes was seen in 33 of the AF patients (16%), whereas 46 (22%) had no AF episodes in the last 6 months of monitoring or longer. Symptoms were absent in 185 (90%) at debut, and 178 (87%) never reported AF-related symptoms during follow-up. The averaged heart rate during AF was 96 (interquartile range: 83 to 114) beats/min, 24 (interquartile range: 9 to 41) beats/min faster than daytime sinus rates.
Conclusions
Although previously unknown AF was highly prevalent, the burden was low, and progression was limited. In addition, symptoms were scarce, and the heart rate was only modestly elevated. (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-risk Individuals [LOOP]; NCT02036450).

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

J Am Coll Cardiol: 02 Dec 2019; 74:2771-2781
Diederichsen SZ, Haugan KJ, Brandes A, Lanng MB, ... Højberg S, Svendsen JH
J Am Coll Cardiol: 02 Dec 2019; 74:2771-2781 | PMID: 31779791
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Impact:
Abstract

Long-Term Safety and Efficacy in Continued Access Left Atrial Appendage Closure Registries.

Holmes DR, Reddy VY, Gordon NT, Delurgio D, ... Stone JE, Kar S
Background
Long-term data on the safety and efficacy of left atrial appendage closure (LAAC) for stroke prevention in patients with nonvalvular atrial fibrillation remain limited.
Objectives
The purpose of this study was to evaluate 4.5- to 5-year data in 2 U.S. Food and Drug Association LAAC mandated registries (CAP [Continued Access to PROTECT-AF] and CAP2 [Continued Access to PREVAIL]) for safety and efficacy.
Methods
Two registries of patients implanted with LAAC devices provide the largest source of follow-up data. Both accompanied their respective randomized clinical trials, PROTECT-AF (Watchman Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device In Patients with Atrial Fibrillation versus Long Term Warfarin Therapy), which used the same endpoints (primary efficacy of composite of stroke, systemic embolism, cardiovascular/unexplained death, and safety).
Results
CAP included 566 patients with an average follow-up of 50.1 months (2,293 patient-years), and CAP2 included 578 patients with an average follow-up of 50.3 months (2,227 patient-years). CAP2 patients were significantly older and had higher CHADS-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) scores (4.51 vs. 3.88; p < 0.001). Procedural success was similar in both (94%). The primary composite endpoint occurred at a rate of 3.05 per 100 patient-years in CAP and 4.80 per 100 patient-years in CAP2; events contributing to this endpoint were most commonly cardiovascular/unexplained death (1.69 per 100 patient-years for CAP and 2.92 per 100 patient-years for CAP2). Hemorrhagic stroke was significantly less than ischemic stroke (0.17 per 100 patient-years in CAP and 0.09 per 100 patient-years in CAP2), and total stroke rates were significantly less than predicted by CHADS-VASc score (78% reduction with CAP, 69% reduction with CAP2).
Conclusions
These registries, which contain the longest and largest follow-up data of patients with the Watchman device, support LAAC as a safe and effective therapy for long-term anticoagulation in patients with nonvalvular atrial fibrillation, and document the lowest rate of hemorrhagic stroke identified in this population.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 09 Dec 2019; 74:2878-2889
Holmes DR, Reddy VY, Gordon NT, Delurgio D, ... Stone JE, Kar S
J Am Coll Cardiol: 09 Dec 2019; 74:2878-2889 | PMID: 31806131
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Abstract

Effects of Statins on Memory, Cognition, and Brain Volume in the Elderly.

Samaras K, Makkar SR, Crawford JD, Kochan NA, ... Brodaty H, Sachdev PS
Background
There is widespread consumer concern that statin use may be associated with impaired memory and cognitive decline.
Objectives
This study sought to examine the association between statin use and changes in memory and global cognition in the elderly population over 6 years and brain volumes over 2 years. Interactions between statin use and known dementia risk factors were examined.
Methods
Prospective observational study of community-dwelling elderly Australians age 70 to 90 years (the MAS [Sydney Memory and Ageing Study], n = 1,037). Outcome measures were memory and global cognition (by neuropsychological testing every 2 years) and total brain, hippocampal and parahippocampal volumes (by magnetic resonance) in a subgroup (n = 526). Analyses applied linear mixed modeling, including the covariates of age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Interactions were sought between statin use and dementia risk factors.
Results
Over 6 years there was no difference in the rate of decline in memory or global cognition between statin users and never users. Statin initiation during the observation period was associated with blunting the rate of memory decline. Exploratory analyses found statin use was associated with attenuated decline in specific memory test performance in participants with heart disease and apolipoprotein Eε4 carriage. There was no difference in brain volume changes between statin users and never users.
Conclusions
In community-dwelling elderly Australians, statin therapy was not associated with any greater decline in memory or cognition over 6 years. These data are reassuring for consumers concerned about statin use and risk of memory decline.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Nov 2019; 74:2554-2568
Samaras K, Makkar SR, Crawford JD, Kochan NA, ... Brodaty H, Sachdev PS
J Am Coll Cardiol: 25 Nov 2019; 74:2554-2568 | PMID: 31753200
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Abstract

Efficacy and Safety of Stents in ST-Segment Elevation Myocardial Infarction.

Chichareon P, Modolo R, Collet C, Tenekecioglu E, ... Onuma Y, Serruys PW
Background
To date, no specific drug-eluting stent (DES) has fully proven its superiority over others in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention.
Objectives
The purpose of this study was to compare the safety and efficacy of coronary artery stents in STEMI patients in a patient-level network meta-analysis.
Methods
Eligible studies were dedicated randomized controlled trials comparing different stents in STEMI patients undergoing percutaneous coronary intervention with at least 12 months of clinical follow-up. Of 19 studies identified from the published data, individual patient data were collected in 15 studies with 10,979 patients representing 87.7% of patients in the overall network of evidence. The primary endpoint was the composite of cardiac death, reinfarction, or target lesion revascularization.
Results
Overall, 8,487 (77.3%) of 10,979 STEMI patients were male and the mean age was 60.7 years. At a median follow-up of 3 years, compared with bare-metal stents (BMS), patients treated with paclitaxel-, sirolimus-, everolimus-, or biolimus-eluting stents had a significantly lower risk of the primary endpoint (adjusted hazard ratios [HRs]: 0.74 [95% confidence interval (CI): 0.63 to 0.88], 0.65 [95% CI: 0.49 to 0.85], 0.70 [95% CI: 0.53 to 0.91], and 0.66 [95% CI: 0.49 to 0.88], respectively). The risk of primary endpoint was not different between patients treated with BMS and zotarolimus-eluting stents (adjusted HR: 0.83 [95% CI: 0.51 to 1.38]). Among patients treated with DES, no significant difference in the risk of the primary outcome was demonstrated. Treatment with second-generation DES was associated with significantly lower risk of definite or probable stent thrombosis compared with BMS (adjusted HR: 0.61 [95% CI: 0.42 to 0.89]) and first-generation DES (adjusted HR: 0.56 [95% CI: 0.36 to 0.88]).
Conclusions
In STEMI patients, DES were superior to BMS with respect to long-term efficacy. No difference in long-term efficacy and safety was observed among specific DES. Second-generation were superior to first-generation DES in reducing stent thrombosis. (Clinical Outcomes After Primary Percutaneous Coronary Intervention [PCI] Using Contemporary Drug-Eluting Stent [DES]: Evidence From the Individual Patient Data Network Meta-Analysis; CRD42018104053).

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

J Am Coll Cardiol: 25 Nov 2019; 74:2572-2584
Chichareon P, Modolo R, Collet C, Tenekecioglu E, ... Onuma Y, Serruys PW
J Am Coll Cardiol: 25 Nov 2019; 74:2572-2584 | PMID: 31753202
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Abstract

A realistic appraisal of the use of embryonic stem cell-based therapies for cardiac repair.

Wysoczynski M, Bolli R

Despite the well-documented capacity of embryonic stem cells (ESCs) to differentiate into cardiomyocytes, transplantation of ESCs or ESC-derived cells is plagued by several formidable problems, including graft rejection, arrhythmias, and potential risk of teratomas. Life-long immunosuppression is a disease in itself. Transplantation of human ESC-derived cells in primates causes life-threatening arrhythmias, and the doses used to show efficacy are not clinically relevant. In contemporary clinical research, the margin of tolerance for such catastrophic effects as malignancies is zero, and although the probability of tumours can be reduced by ESC differentiation, it is unlikely to be completely eliminated, particularly when billions of cells are injected. Although ESCs and ESC-derived cells were touted as capable of long-term regeneration, these cells disappear rapidly after transplantation and there is no evidence of long-term engraftment, let alone regeneration. There is, however, mounting evidence that they act via paracrine mechanisms-just like adult cells. To date, no controlled clinical trial of ESC-derived cells in cardiovascular disease has been conducted or even initiated. In contrast, adult cells have been used in thousands of patients with heart disease, with no significant adverse effects and with results that were sufficiently encouraging to warrant Phase II and III trials. Furthermore, induced pluripotent stem cells offer pluripotency similar to ESCs without the need for lifelong immunosuppression. After two decades, the promise that ESC-derived cells would regenerate dead myocardium has not been fulfilled. The most reasonable interpretation of current data is that ESC-based therapies are not likely to have clinical application for heart disease.

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: 27 Nov 2019; epub ahead of print
Wysoczynski M, Bolli R
Eur Heart J: 27 Nov 2019; epub ahead of print | PMID: 31778154
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Abstract

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus.

Kapur J, Elm J, Chamberlain JM, Barsan W, ... Silbergleit R,
Background
The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.
Methods
In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.
Results
A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.
Conclusions
In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Nov 2019; 381:2103-2113
Kapur J, Elm J, Chamberlain JM, Barsan W, ... Silbergleit R,
N Engl J Med: 27 Nov 2019; 381:2103-2113 | PMID: 31774955
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Abstract

Aortic Stenosis and Cardiac Amyloidosis: JACC Review Topic of the Week.

Ternacle J, Krapf L, Mohty D, Magne J, ... Pibarot P, Damy T

The prevalence of calcific aortic stenosis (AS) and of cardiac amyloidosis (CA) increases with age, and their association is not uncommon in the elderly. The identification of CA is particularly challenging in patients with AS because these 2 conditions share several features. It is estimated that ≤15% of the AS population and ≤30% of the subset with low-flow, low-gradient pattern may have CA. In patients with AS, CA is associated with increased risk of heart failure, mortality, and treatment futility with aortic valve replacement. In case of suspicion of CA, it is thus crucial to confirm the diagnosis to guide therapeutic management of AS and eventually implement recently developed pharmacological treatment dedicated to transthyretin amyloidosis. Given the high surgical risk of patients with AS and concomitant CA, transcatheter aortic valve replacement may be preferred to surgery in these patients.

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

J Am Coll Cardiol: 25 Nov 2019; 74:2638-2651
Ternacle J, Krapf L, Mohty D, Magne J, ... Pibarot P, Damy T
J Am Coll Cardiol: 25 Nov 2019; 74:2638-2651 | PMID: 31753206
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Abstract

Cardiac Pacing in Sub-Saharan Africa: JACC International.

Jouven X, Diop BI, Narayanan K, Adoubi A, ... Marijon E,

Many parts of the developing world, especially Sub-Saharan Africa, completely lack access to cardiac pacing. The authors initiated a multinational program to implement cardiac pacing in 14 countries in Sub-Saharan Africa (1996 to 2018), aiming to eventually build self-sustainable capacity in each country. This was based on an \"on-site training\" approach of performing procedures locally and educating local health care teams to work within resource-limited settings, with prospective evaluation of the program. In 64 missions, a total of 542 permanent pacemakers were implanted. In 11 of these countries, the first pacemaker implant in the country was through the mission. More than one-half of those initially listed as suitable died before the mission(s) arrived. The proportion of implantations that were completely handled by local teams increased from 3% in 1996 to 98% in 2018. These findings demonstrate the feasibility and effectiveness of a proctorship-based approach to the development of local cardiac pacing capabilities in Sub-Saharan African nations.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 25 Nov 2019; 74:2652-2660
Jouven X, Diop BI, Narayanan K, Adoubi A, ... Marijon E,
J Am Coll Cardiol: 25 Nov 2019; 74:2652-2660 | PMID: 31753207
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Impact:
Abstract

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

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

Copyright © 2019 Elsevier Ltd. All rights reserved.

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

Sex differences in heart failure.

Lam CSP, Arnott C, Beale AL, Chandramouli C, ... Sliwa K, Voors AA

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

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: 03 Dec 2019; epub ahead of print
Lam CSP, Arnott C, Beale AL, Chandramouli C, ... Sliwa K, Voors AA
Eur Heart J: 03 Dec 2019; epub ahead of print | PMID: 31800034
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Abstract

Effects of Interatrial Shunt on Pulmonary Vascular Function in Heart Failure With Preserved Ejection Fraction.

Obokata M, Reddy YNV, Shah SJ, Kaye DM, ... Burkhoff D, Borlaug BA
Background
Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion.
Objectives
The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs).
Methods
This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded.
Results
Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise.
Conclusions
Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234).

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

J Am Coll Cardiol: 25 Nov 2019; 74:2539-2550
Obokata M, Reddy YNV, Shah SJ, Kaye DM, ... Burkhoff D, Borlaug BA
J Am Coll Cardiol: 25 Nov 2019; 74:2539-2550 | PMID: 31753198
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Impact:
Abstract

Primary Aldosteronism: JACC State-of-the-Art Review.

Rossi GP

Primary aldosteronism (PA) is a common, but frequently overlooked, cause of arterial hypertension and excess cardiovascular events, particularly atrial fibrillation. As timely diagnosis and treatment can provide a cure of hyperaldosteronism and hypertension, even when the latter is resistant to drug treatment, strategies to screen patients for PA early with a simplified diagnostic algorithm are justified. They can be particularly beneficial in some subgroups of hypertensive patients, as those who are at highest cardiovascular risk. However, identification of the surgically curable cases of PA and achievement of optimal results require subtyping with adrenal vein sampling, which, as it is technically challenging and currently performed only in tertiary referral centers, represents the bottleneck in the work-up of PA. Measures aimed at improving the clinical use of adrenal vein sampling and at developing alternative techniques for subtyping, alongside recommendations for drug treatment, including new development in the field, and for follow-up are discussed.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 02 Dec 2019; 74:2799-2811
Rossi GP
J Am Coll Cardiol: 02 Dec 2019; 74:2799-2811 | PMID: 31779795
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Abstract

Incidence and Risk Factors for Permanent Pacemaker Implantation Following Mitral or Aortic Valve Surgery.

Moskowitz G, Hong KN, Giustino G, Gillinov AM, ... Gelijns AC, Egorova NN
Background
Risk factors for post-operative conduction disturbances after cardiac valve surgery requiring a permanent pacemaker (PPM) are poorly characterized.
Objectives
The aim of this study was to investigate the timing and risk factors for PPM implantation after mitral or aortic valve surgery.
Methods
All patients who underwent open aortic or mitral valve surgery between January 1996 and December 2014 were reviewed using New York State\'s mandatory hospital discharge database. Patients with prior cardiac surgery or pre-existing PPM were excluded. The primary endpoint was PPM implantation within 1 year.
Results
Among 77,882 patients, 63.8% (n = 49,706) underwent aortic valve replacement (AVR), 18.9% (n = 14,686) underwent mitral valve replacement (MVR), 10.5% (n = 8,219) underwent mitral valve repair (MVr), 5.4% (n = 4,202) underwent AVR plus MVR, and 1.4% (n = 1,069) underwent AVR plus MVr. The 1-year PPM implantation rate was 4.5% after MVr, 6.6% after AVR, 9.3% after AVR plus MVr, 10.5% after MVR, and 13.3% after AVR plus MVR (p < 0.001). Across all groups, the majority of PPMs were implanted during the index hospitalization (79.9%). MVr was associated with the lowest risk for PPM and AVR plus MVR with the highest risk. Older age, history of arrhythmias, pre-operative conduction disturbances, and concomitant index procedures were associated with increased risk for PPM during the index hospitalization. Conversely, beyond 30 days, chronic comorbidities were associated with increased risk for PPM.
Conclusions
Conduction disturbances requiring PPM remain a common adverse event after valve surgery. Identifying patients at risk for PPM will help facilitate perioperative planning and inform clinical decision making regarding post-operative rhythm surveillance.

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

J Am Coll Cardiol: 25 Nov 2019; 74:2607-2620
Moskowitz G, Hong KN, Giustino G, Gillinov AM, ... Gelijns AC, Egorova NN
J Am Coll Cardiol: 25 Nov 2019; 74:2607-2620 | PMID: 31753204
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Impact:
Abstract

Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

Kotecha D, Gill SK, Flather MD, Holmes J, ... Coats AJS,
Background
Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy.
Objectives
This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR).
Methods
Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm.
Results
Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR.
Conclusions
Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.

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

J Am Coll Cardiol: 09 Dec 2019; 74:2893-2904
Kotecha D, Gill SK, Flather MD, Holmes J, ... Coats AJS,
J Am Coll Cardiol: 09 Dec 2019; 74:2893-2904 | PMID: 31806133
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Impact:
Abstract

A neurobiological mechanism linking transportation noise to cardiovascular disease in humans.

Osborne MT, Radfar A, Hassan MZO, Abohashem S, ... Pitman RK, Tawakol A
Aims
Chronic noise exposure associates with increased cardiovascular disease (CVD) risk; however, the role of confounders and the underlying mechanism remain incompletely defined. The amygdala, a limbic centre involved in stress perception, participates in the response to noise. Higher amygdalar metabolic activity (AmygA) associates with increased CVD risk through a mechanism involving heightened arterial inflammation (ArtI). Accordingly, in this retrospective study, we tested whether greater noise exposure associates with higher: (i) AmygA, (ii) ArtI, and (iii) risk for major adverse cardiovascular disease events (MACE).
Methods and results
Adults (N = 498) without CVD or active cancer underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Amygdalar metabolic activity and ArtI were measured, and MACE within 5 years was adjudicated. Average 24-h transportation noise and potential confounders were estimated at each individual\'s home address. Over a median 4.06 years, 40 individuals experienced MACE. Higher noise exposure (per 5 dBA increase) predicted MACE [hazard ratio (95% confidence interval, CI) 1.341 (1.147-1.567), P < 0.001] and remained robust to multivariable adjustments. Higher noise exposure associated with increased AmygA [standardized β (95% CI) 0.112 (0.051-0.174), P < 0.001] and ArtI [0.045 (0.001-0.090), P = 0.047]. Mediation analysis suggested that higher noise exposure associates with MACE via a serial mechanism involving heightened AmygA and ArtI that accounts for 12-26% of this relationship.
Conclusion
Our findings suggest that noise exposure associates with MACE via a mechanism that begins with increased stress-associated limbic (amygdalar) activity and includes heightened arterial inflammation. This potential neurobiological mechanism linking noise to CVD merits further evaluation in a prospective population.

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: 25 Nov 2019; epub ahead of print
Osborne MT, Radfar A, Hassan MZO, Abohashem S, ... Pitman RK, Tawakol A
Eur Heart J: 25 Nov 2019; epub ahead of print | PMID: 31769799
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Impact:
Abstract

Vascular responses to coronary calcification following implantation of newer-generation drug-eluting stents in humans: impact on healing.

Torii S, Jinnouchi H, Sakamoto A, Mori H, ... Virmani R, Finn AV
Aims
Vascular calcification is routinely encountered in percutaneous coronary intervention (PCI) and severe coronary calcification is a known predictor of in-stent restenosis and stent thrombosis. However, the histopathologic mechanisms behind such events have not been systematically described.
Methods and results
From our registry of 1211 stents, a total of 134 newer-generation drug-eluting stents (DES) (Xience, Resolute-Integrity, PROMUS-Element, and Synergy) with duration of implant ≥30 days were histologically analysed. The extent of calcification of the stented lesions was evaluated radiographically and divided into severe (SC, n = 46) and non-severely calcified lesions (NC, n = 88). The percent-uncovered struts per section {SC vs. NC; median 2.4 [interquartile range (IQR) 0.0-19.0] % vs. 0.0 (IQR 0.0-4.6) %, P = 0.02} and the presence of severe medial tears (MTs) (59% vs. 44%, respectively, P = 0.03) were greater in SC than NC. In addition, SC had a higher prevalence of ≥3 consecutive struts lying directly in contact with surface calcified area (3SC) (52% vs. 8%, respectively, P < 0.0001). Multivariate analysis demonstrated that sections with duration of implantation ≤6 months [odds ratio (OR): 7.7, P < 0.0001], 3SC (OR: 6.5, P < 0.0001), strut malapposition (OR: 5.0, P < 0.0001), and lack of MTs (OR: 2.5, P = 0.0005) were independent predictors of uncovered struts. Prevalence of neoatherosclerosis was significantly lower in SC than that of NC (24% vs. 44%, P = 0.02).
Conclusion
Severe calcification, especially surface calcified area is an independent predictor of uncovered struts and delayed healing after newer-generation DES implantation. These data expand of knowledge of the vascular responses of stenting of calcified arteries and suggests further understand of how best to deal with calcification in patients undergoing PCI.

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: 04 Dec 2019; epub ahead of print
Torii S, Jinnouchi H, Sakamoto A, Mori H, ... Virmani R, Finn AV
Eur Heart J: 04 Dec 2019; epub ahead of print | PMID: 31803916
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Abstract

Timing of Staged Nonculprit Artery Revascularization in Patients With ST-Segment Elevation Myocardial Infarction: COMPLETE Trial.

Wood DA, Cairns JA, Wang J, Mehran R, ... Mehta SR,
Background
The COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI) trial demonstrated that staged nonculprit lesion percutaneous coronary intervention (PCI) reduced major cardiovascular (CV) events in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD).
Objectives
The purpose of this study was to determine the effect of nonculprit-lesion PCI timing on major CV outcomes and also the time course of the benefit of complete revascularization.
Methods
Following culprit-lesion PCI, 4,041 patients with STEMI and multivessel CAD were randomized to staged nonculprit-lesion PCI or culprit-lesion only PCI. Randomization was stratified according to investigator-planned timing of nonculprit-lesion PCI: during or after the index hospitalization. The first coprimary outcome was the composite of CV death or myocardial infarction (MI). In pre-specified analyses, hazard ratios (HRs) were calculated for each time stratum. Landmark analyses of the entire population were performed within 45 days and after 45 days.
Results
For nonculprit-lesion PCI planned during the index hospitalization (actual time: median 1 day), CV death or MI was reduced with complete revascularization compared with culprit-lesion only PCI (HR: 0.77; 95% confidence interval [CI]: 0.59 to 1.00). For nonculprit lesion PCI planned to occur after hospital discharge (actual time: median 23 days), CV death or MI was also reduced with complete revascularization (HR: 0.69; 95% CI: 0.49 to 0.97; interaction p = 0.62). Landmark analyses demonstrated an HR of 0.86 (95% CI: 0.59 to 1.24) during the first 45 days and 0.69 (95% CI: 0.54 to 0.89) from 45 days to the end of follow-up for intended nonculprit lesion PCI versus culprit lesion only PCI.
Conclusions
Among STEMI patients with multivessel disease, the benefit of complete revascularization over culprit-lesion only PCI was consistent irrespective of the investigator-determined timing of nonculprit-lesion intervention. The benefit of complete revascularization on hard clinical outcomes emerged mainly over the long term.

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

J Am Coll Cardiol: 02 Dec 2019; 74:2713-2723
Wood DA, Cairns JA, Wang J, Mehran R, ... Mehta SR,
J Am Coll Cardiol: 02 Dec 2019; 74:2713-2723 | PMID: 31779786
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Abstract

Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder.

Yamamura T, Kleiter I, Fujihara K, Palace J, ... Wright P, De Seze J
Background
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system and is associated with autoantibodies to anti-aquaporin-4 (AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involved in the pathogenesis of the disorder. Satralizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor. The efficacy of satralizumab added to immunosuppressant treatment in patients with NMOSD is unclear.
Methods
In a phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with NMOSD who were seropositive or seronegative for AQP4-IgG to receive either satralizumab, at a dose of 120 mg, or placebo, administered subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter, added to stable immunosuppressant treatment. The primary end point was the first protocol-defined relapse in a time-to-event analysis. Key secondary end points were the change from baseline to week 24 in the visual-analogue scale (VAS) pain score (range, 0 to 100, with higher scores indicating more pain) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (range, 0 to 52, with lower scores indicating more fatigue). Safety was also assessed.
Results
A total of 83 patients were enrolled, with 41 assigned to the satralizumab group and 42 to the placebo group. The median treatment duration with satralizumab in the double-blind period was 107.4 weeks. Relapse occurred in 8 patients (20%) receiving satralizumab and in 18 (43%) receiving placebo (hazard ratio, 0.38; 95% confidence interval [CI], 0.16 to 0.88). Multiple imputation for censored data resulted in hazard ratios ranging from 0.34 to 0.44 (with corresponding P values of 0.01 to 0.04). Among 55 AQP4-IgG-seropositive patients, relapse occurred in 11% of those in the satralizumab group and in 43% of those in the placebo group (hazard ratio, 0.21; 95% CI, 0.06 to 0.75); among 28 AQP4-IgG-seronegative patients, relapse occurred in 36% and 43%, respectively (hazard ratio, 0.66; 95% CI, 0.20 to 2.24). The between-group difference in the change in the mean VAS pain score was 4.08 (95% CI, -8.44 to 16.61); the between-group difference in the change in the mean FACIT-F score was -3.10 (95% CI, -8.38 to 2.18). The rates of serious adverse events and infections did not differ between groups.
Conclusions
Among patients with NMOSD, satralizumab added to immunosuppressant treatment led to a lower risk of relapse than placebo but did not differ from placebo in its effect on pain or fatigue. (Funded by Chugai Pharmaceutical; ClinicalTrials.gov number, NCT02028884.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Nov 2019; 381:2114-2124
Yamamura T, Kleiter I, Fujihara K, Palace J, ... Wright P, De Seze J
N Engl J Med: 27 Nov 2019; 381:2114-2124 | PMID: 31774956
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Impact:
Abstract

Improvement in Pediatric Cardiac Surgical Outcomes Through Interhospital Collaboration.

Gaies M, Pasquali SK, Banerjee M, Dimick JB, ... Tabbutt S, Charpie JR
Background
Patients undergoing complex pediatric cardiac surgery remain at considerable risk of mortality and morbidity, and variation in outcomes exists across hospitals. The Pediatric Cardiac Critical Care Consortium (PC4) was formed to improve the quality of care for these patients through transparent data sharing and collaborative learning between participants.
Objectives
The purpose of this study was to determine whether outcomes improved over time within PC4.
Methods
The study analyzed 19,600 hospitalizations (18 hospitals) in the PC4 clinical registry that included cardiovascular surgery from August 2014 to June 2018. The primary exposure was 2 years of PC4 participation; this provided adequate time for hospitals to accrue data and engage in collaborative learning. Aggregate case mix-adjusted outcomes were compared between the first 2 years of participation (baseline) and all months post-exposure. We also evaluated outcomes from the same era in a cohort of similar, non-PC4 hospitals.
Results
During the baseline period, there was no evidence of improvement. We observed significant improvement in the post-exposure period versus baseline for post-operative intensive care unit mortality (2.1% vs. 2.7%; 22% relative reduction [RR]; p = 0.001), in-hospital mortality (2.5% vs. 3.3%; 24% RR; p = 0.001), major complications (10.1% vs. 11.5%; 12% RR; p < 0.001), intensive care unit length of stay (7.3 days vs. 7.7 days; 5% RR; p < 0.001), and duration of ventilation (61.3 h vs. 70.6 h; 13% RR; p = 0.01). Non-PC4 hospitals showed no significant improvement in mortality, complications, or hospital length of stay.
Conclusions
This analysis demonstrates improving cardiac surgical outcomes at children\'s hospitals participating in PC4. This change appears unrelated to secular improvement trends, and likely reflects PC4\'s commitment to transparency and collaboration.

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

J Am Coll Cardiol: 02 Dec 2019; 74:2786-2795
Gaies M, Pasquali SK, Banerjee M, Dimick JB, ... Tabbutt S, Charpie JR
J Am Coll Cardiol: 02 Dec 2019; 74:2786-2795 | PMID: 31779793
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Abstract

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

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

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

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

Acute myocardial infarction treatments and outcomes in 6.5 million patients with a current or historical diagnosis of cancer in the USA.

Bharadwaj A, Potts J, Mohamed MO, Parwani P, ... Michos ED, Mamas MA
Aims
The aim of this study is to evaluate temporal trends, treatment, and clinical outcomes of patients who present with an acute myocardial infarction (AMI) and have a current or historical diagnosis of cancer, according to cancer type and presence of metastases.
Methods and results
Data from 6 563 255 patients presenting with an AMI between 2004 and 2014 from the US National Inpatient Sample (NIS) database were analysed. A total of 5 966 955 had no cancer, 186 604 had current cancer, and 409 697 had a historical diagnosis of cancer. Prostate, breast, colon, and lung cancer were the four most common types of cancer. Patients with cancer were older with more comorbidities. Differences in invasive treatment were noted, 43.9% received percutaneous coronary intervention (PCI) in patients without cancer, whilst only 21.0% of patients with lung cancer received PCI. Lung cancer was associated with the highest in-hospital mortality [odds ratio (OR) 2.71, 95% confidence interval (CI) 2.62-2.80], major adverse cardiovascular and cerebrovascular complications (OR 2.38, 95% CI 2.31-2.45), and stroke (OR 1.91, 95% CI 1.80-2.02), while colon cancer was associated with highest risk of bleeding (OR 2.82, 95% CI 2.68-2.98). Irrespective of the type of cancer, presence of metastasis was associated with worse in-hospital outcomes, and historical cancer did not adversely impact on survival (OR 0.90, 95% CI 0.89-0.91).
Conclusion
A concomitant cancer diagnosis is associated with a conservative medical management strategy for AMI, and worse clinical outcomes, compared to patients without cancer. Survival and clinical outcomes in the context of AMI vary significantly according to the type of cancer and metastasis status. The management of this high-risk group is challenging and requires a multidisciplinary and patient-centred approach to improve their outcomes.

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

Eur Heart J: 03 Dec 2019; epub ahead of print
Bharadwaj A, Potts J, Mohamed MO, Parwani P, ... Michos ED, Mamas MA
Eur Heart J: 03 Dec 2019; epub ahead of print | PMID: 31800032
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Abstract

Femoral Versus Nonfemoral Peripheral Access for Transcatheter Aortic Valve Replacement.

Beurtheret S, Karam N, Resseguier N, Houel R, ... Le Breton H, Lafont A
Background
Femoral access is the gold standard for transcatheter aortic valve replacement (TAVR). Guidelines recommend reconsidering surgery when this access is not feasible. However, alternative peripheral accesses exist, although they have not been accurately compared with femoral access.
Objectives
This study compared nonfemoral peripheral (n-FP) TAVR with femoral TAVR.
Methods
Using the data from the national prospective French registry (FRANCE TAVI [French Transcatheter Aortic Valve Implantation]), this study compared the characteristics and outcomes of TAVR procedures according to whether they were performed through a femoral or a n-FP access, using a pre-specified propensity score-based matching between groups. Subanalysis during 2 study periods (2013 to 2015 and 2016 to 2017) and among low/intermediate-low and intermediate-high/high volume centers were performed.
Results
Among 21,611 patients, 19,995 (92.5%) underwent femoral TAVR and 1,616 (7.5%) underwent n-FP TAVR (transcarotid, n = 914 or trans-subclavian, n = 702). Patients in the n-FP access group had more severe disease (mean logistic EuroSCORE 19.95 vs. 16.95; p < 0.001), with a higher rate of peripheral vascular disease, known coronary artery disease, chronic pulmonary disease, and renal failure. After matching, there was no difference in the rate of post-procedural death and complications according to access site, except for a 2-fold lower rate of major vascular complications (odds ratio: 0.45; 95% confidence interval: 0.21 to 0.93; p = 0.032) and unplanned vascular repairs (odds ratio: 0.41; 95% confidence interval: 0.29 to 0.59; p < 0.001) in those who underwent n-FP access. The comparison of outcomes provided similar results during the second study period and in intermediate-high/high volume centers.
Conclusions
n-FP TAVR is associated with similar outcomes compared with femoral peripheral TAVR, except for a 2-fold lower rate of major vascular complications and unplanned vascular repairs. n-FP TAVR may be favored over surgery in patients who are deemed ineligible for femoral TAVR and may be a safe alternative when femoral access risk is considered too high.

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

J Am Coll Cardiol: 02 Dec 2019; 74:2728-2739
Beurtheret S, Karam N, Resseguier N, Houel R, ... Le Breton H, Lafont A
J Am Coll Cardiol: 02 Dec 2019; 74:2728-2739 | PMID: 31779788
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Abstract

Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.

Bakker MF, de Lange SV, Pijnappel RM, Mann RM, ... van Gils CH,
Background
Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients.
Methods
In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Results
The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening.
Conclusions
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Nov 2019; 381:2091-2102
Bakker MF, de Lange SV, Pijnappel RM, Mann RM, ... van Gils CH,
N Engl J Med: 27 Nov 2019; 381:2091-2102 | PMID: 31774954
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Impact:
Abstract

Diagnosis of Pulmonary Embolism with d-Dimer Adjusted to Clinical Probability.

Kearon C, de Wit K, Parpia S, Schulman S, ... Julian JA,
Background
Retrospective analyses suggest that pulmonary embolism is ruled out by a d-dimer level of less than 1000 ng per milliliter in patients with a low clinical pretest probability (C-PTP) and by a d-dimer level of less than 500 ng per milliliter in patients with a moderate C-PTP.
Methods
We performed a prospective study in which pulmonary embolism was considered to be ruled out without further testing in outpatients with a low C-PTP and a d-dimer level of less than 1000 ng per milliliter or with a moderate C-PTP and a d-dimer level of less than 500 ng per milliliter. All other patients underwent chest imaging (usually computed tomographic pulmonary angiography). If pulmonary embolism was not diagnosed, patients did not receive anticoagulant therapy. All patients were followed for 3 months to detect venous thromboembolism.
Results
A total of 2017 patients were enrolled and evaluated, of whom 7.4% had pulmonary embolism on initial diagnostic testing. Of the 1325 patients who had a low C-PTP (1285 patients) or moderate C-PTP (40 patients) and a negative d-dimer test (i.e., <1000 or <500 ng per milliliter, respectively), none had venous thromboembolism during follow-up (95% confidence interval [CI], 0.00 to 0.29%). These included 315 patients who had a low C-PTP and a d-dimer level of 500 to 999 ng per milliliter (95% CI, 0.00 to 1.20%). Of all 1863 patients who did not receive a diagnosis of pulmonary embolism initially and did not receive anticoagulant therapy, 1 patient (0.05%; 95% CI, 0.01 to 0.30) had venous thromboembolism. Our diagnostic strategy resulted in the use of chest imaging in 34.3% of patients, whereas a strategy in which pulmonary embolism is considered to be ruled out with a low C-PTP and a d-dimer level of less than 500 ng per milliliter would result in the use of chest imaging in 51.9% (difference, -17.6 percentage points; 95% CI, -19.2 to -15.9).
Conclusions
A combination of a low C-PTP and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up. (Funded by the Canadian Institutes of Health Research and others; PEGeD ClinicalTrials.gov number, NCT02483442.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 27 Nov 2019; 381:2125-2134
Kearon C, de Wit K, Parpia S, Schulman S, ... Julian JA,
N Engl J Med: 27 Nov 2019; 381:2125-2134 | PMID: 31774957
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Abstract

Improved Outcomes of Heart Transplantation in Adults With Congenital Heart Disease Receiving Regionalized Care.

Nguyen VP, Dolgner SJ, Dardas TF, Verrier ED, McMullan DM, Krieger EV
Background
The number of adult congenital heart disease (CHD) patients undergoing heart transplantation is increasing rapidly. CHD patients have higher surgical risk at transplantation. High-volume adult CHD transplant centers may have better transplant outcomes.
Objectives
This study aimed to evaluate the effect of center CHD transplant volume and expertise on transplant outcomes in CHD patients.
Methods
The authors studied heart transplantations in CHD patients age ≥18 years using the United Network of Organ Sharing (UNOS) database for the primary outcomes of waitlist mortality and post-transplant outcomes at 30 days and 1 year. Transplant centers were assessed by status as the highest CHD transplant volume center in a UNOS region versus all others, presence of Adult Congenital Heart Association accreditation, and adult versus pediatric hospital designation.
Results
Between January of 2000 and June of 2018, 1,746 adult CHD patients were listed for transplant; 1,006 (57.6%) of these underwent heart transplantation. After adjusting for age, sex, listing status, and inotrope requirement, waitlist mortality risk was lower at Adult Congenital Heart Association accredited centers (hazard ratio: 0.730; p = 0.020). Post-transplant 30-day mortality was lower at the highest volume CHD transplant center in each UNOS region (hazard ratio: 0.706; p = 0.014).
Conclusions
Designated expertise in CHD care is associated with improved waitlist outcomes for CHD patients listed for transplantation. Post-transplant survival was improved at the highest volume regional center. These findings suggest a possible advantage of regionalization of CHD transplantation.

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

J Am Coll Cardiol: 09 Dec 2019; 74:2908-2918
Nguyen VP, Dolgner SJ, Dardas TF, Verrier ED, McMullan DM, Krieger EV
J Am Coll Cardiol: 09 Dec 2019; 74:2908-2918 | PMID: 31806135
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Abstract

The cardiac sympathetic co-transmitter neuropeptide Y is pro-arrhythmic following ST-elevation myocardial infarction despite beta-blockade.

Kalla M, Hao G, Tapoulal N, Tomek J, ... Paterson DJ, Herring N
Aims
ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors.
Methods and results
In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged (10 Hz, 2 min) stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 μmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 μmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304.
Conclusions
The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy.

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

Eur Heart J: 12 Dec 2019; epub ahead of print
Kalla M, Hao G, Tapoulal N, Tomek J, ... Paterson DJ, Herring N
Eur Heart J: 12 Dec 2019; epub ahead of print | PMID: 31834357
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Impact:
Abstract

Utilization and Outcomes of Measuring Fractional Flow Reserve in Patients With Stable Ischemic Heart Disease.

Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
Background
The use and clinical outcomes of fractional flow reserve (FFR) measurement in patients with stable ischemic heart disease (SIHD) are uncertain, as prior studies have been based on selected populations.
Objectives
This study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes among unselected patients with SIHD and angiographically intermediate stenoses.
Methods
The authors used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program to analyze patients who underwent coronary angiography between January 1, 2009, and September 30, 2017, and had SIHD with angiographically intermediate disease (40% to 69% diameter stenosis on visual inspection). The authors documented trends in FFR utilization and evaluated predictors using generalized mixed models. They applied Cox proportional hazards models to determine the association between an FFR-guided revascularization strategy and all-cause mortality at 1 year.
Results
A total of 17,989 patients at 66 sites were included. The rate of FFR use gradually increased from 14.8% to 18.5% among all patients with intermediate lesions, and from 44% to 75% among patients who underwent percutaneous coronary intervention. One-year mortality was 2.8% in the FFR group and 5.9% in the angiography-only group (p < 0.0001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization (hazard ratio: 0.57; 95% confidence interval: 0.45 to 0.71; p < 0.0001).
Conclusions
In patients with SIHD and angiographically intermediate stenoses, use of FFR has slowly risen, and was associated with significantly lower 1-year mortality.

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

J Am Coll Cardiol: 03 Feb 2020; 75:409-419
Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
J Am Coll Cardiol: 03 Feb 2020; 75:409-419 | PMID: 32000953
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Impact:
Abstract

Risk Factors for Infections Involving Cardiac Implanted Electronic Devices.

Birnie DH, Wang J, Alings M, Philippon F, ... Longtin Y, Krahn AD
Background
Cardiac implantable electronic device infection is a major complication that usually requires device removal. PADIT (Prevention of Arrhythmia Device Infection Trial) was a large cluster crossover trial of conventional versus incremental antibiotics.
Objectives
This study sought to investigate independent predictors of device infection in PADIT and develop a novel infection risk score.
Methods
In brief, over 4 6-month periods, 28 centers used either conventional or incremental prophylactic antibiotic treatment in all patients. The primary outcome was hospitalization for device infection within 1 year (blinded endpoint adjudication). Multivariable logistic prediction modeling was used to identify the independent predictors and develop a risk score for device infection. The prediction models were internally validated with bootstrap methods.
Results
Device procedures were performed in 19,603 patients, and hospitalization for infection occurred in 177 (0.90%) within 1 year of follow-up. The final prediction model identified 5 independent predictors of device infection (prior procedures [P], age [A], depressed renal function [D], immunocompromised [I], and procedure type [T]) with an optimism-corrected C-statistic of 0.704 (95% confidence interval: 0.660 to 0.744). A PADIT risk score ranging from 0 to 15 points classified patients into low (0 to 4), intermediate (5 to 6) and high (≥7) risk groups with rates of hospitalization for infection of 0.51%, 1.42%, and 3.41%, respectively.
Conclusions
This study identified 5 independent predictors of device infection and developed a novel infection risk score in the largest cardiac implantable electronic device trial to date, warranting validation in an independent cohort. The 5 independent predictors in the PADIT score are readily adopted into clinical practice. (Prevention of Arrhythmia Device Infection Trial [PADIT Pilot]; NCT01002911).

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 09 Dec 2019; 74:2845-2854
Birnie DH, Wang J, Alings M, Philippon F, ... Longtin Y, Krahn AD
J Am Coll Cardiol: 09 Dec 2019; 74:2845-2854 | PMID: 31806127
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Abstract

Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice.

Liu CL, Ren J, Wang Y, Zhang X, ... Zhang J, Shi GP
Aims
Obesity is a risk factor of abdominal aortic aneurysm (AAA). Inflammatory cytokine interleukin-18 (IL18) has two receptors: IL18 receptor (IL18r) and Na-Cl co-transporter (NCC). In human and mouse AAA lesions, IL18 colocalizes to its receptors at regions rich in adipocytes, suggesting a role of adipocytes in promoting IL18 actions in AAA development.
Methods and results
We localized both IL18r and NCC in human and mouse AAA lesions. Murine AAA development required both receptors. In mouse AAA lesions, IL18 binding to these receptors increased at regions enriched in adipocytes or adjacent to perivascular adipose tissue. 3T3-L1 adipocytes enhanced IL18 binding to macrophages, aortic smooth muscle cells (SMCs), and endothelial cells by inducing the expression of both IL18 receptors on these cells. Adipocytes also enhanced IL18r and IL18 expression from T cells and macrophages, AAA-pertinent protease expression from macrophages, and SMC apoptosis. Perivascular implantation of adipose tissue from either diet-induced obese mice or lean mice but not that from leptin-deficient ob/ob mice exacerbated AAA development in recipient mice. Further experiments established an essential role of adipocyte leptin and fatty acid-binding protein 4 (FABP4) in promoting IL18 binding to macrophages and possibly other inflammatory and vascular cells by inducing their expression of IL18, IL18r, and NCC.
Conclusion
Interleukin-18 uses both IL18r and NCC to promote AAA formation. Lesion adipocyte and perivascular adipose tissue contribute to AAA pathogenesis by releasing leptin and FABP4 that induce IL18, IL18r, and NCC expression and promote IL18 actions.

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: 09 Dec 2019; epub ahead of print
Liu CL, Ren J, Wang Y, Zhang X, ... Zhang J, Shi GP
Eur Heart J: 09 Dec 2019; epub ahead of print | PMID: 31821481
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Abstract

European Society of Cardiology: Cardiovascular Disease Statistics 2019.

Timmis A, Townsend N, Gale CP, Torbica A, ... Vardas P,
Aims
The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets.
Methods and results
In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5-23.1%] vs. 15.7% (IQR 14.5-21.1%)}, diabetes [7.7% (IQR 7.1-10.1%) vs. 5.6% (IQR 4.8-7.0%)], and among males smoking [43.8% (IQR 37.4-48.0%) vs. 26.0% (IQR 20.9-31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0-10.8) vs. 16.7% (IQR 13.9-19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655-8115)] compared with high-income [2235 (IQR 1896-3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures.
Conclusion
A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest.

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: 09 Dec 2019; epub ahead of print
Timmis A, Townsend N, Gale CP, Torbica A, ... Vardas P,
Eur Heart J: 09 Dec 2019; epub ahead of print | PMID: 31820000
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Abstract

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

Mulangu S, Dodd LE, Davey RT, Tshiani Mbaya O, ... Vallée D, Nordwall J
Background
Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial.
Methods
We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days.
Results
A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs.
Conclusions
Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 26 Nov 2019; epub ahead of print
Mulangu S, Dodd LE, Davey RT, Tshiani Mbaya O, ... Vallée D, Nordwall J
N Engl J Med: 26 Nov 2019; epub ahead of print | PMID: 31774950
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Abstract

Sleep patterns, genetic susceptibility, and incident cardiovascular disease: a prospective study of 385 292 UK biobank participants.

Fan M, Sun D, Zhou T, Heianza Y, ... Li L, Qi L
Aims
To quantify the association of combined sleep behaviours and genetic susceptibility with the incidence of cardiovascular disease (CVD).
Methods and results
This study included 385 292 participants initially free of CVD from UK Biobank. We newly created a healthy sleep score according to five sleep factors and defined the low-risk groups as follows: early chronotype, sleep 7-8 h per day, never/rarely insomnia, no snoring, and no frequent excessive daytime sleepiness. Weighted genetic risk scores of coronary heart disease (CHD) or stroke were calculated. During a median of 8.5 years of follow-up, we documented 7280 incident CVD cases including 4667 CHD and 2650 stroke cases. Compared to those with a sleep score of 0-1, participants with a score of 5 had a 35% (19-48%), 34% (22-44%), and 34% (25-42%) reduced risk of CVD, CHD, and stroke, respectively. Nearly 10% of cardiovascular events in this cohort could be attributed to poor sleep pattern. Participants with poor sleep pattern and high genetic risk showed the highest risk of CHD and stroke.
Conclusion
In this large prospective study, a healthy sleep pattern was associated with reduced risks of CVD, CHD, and stroke among participants with low, intermediate, or high genetic risk.

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: 17 Dec 2019; epub ahead of print
Fan M, Sun D, Zhou T, Heianza Y, ... Li L, Qi L
Eur Heart J: 17 Dec 2019; epub ahead of print | PMID: 31848595
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Abstract

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.

Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
Background
It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.
Objectives
The purpose of this study was to demonstrate that C-Pittsburgh B compound positron emission tomography (C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.
Methods
This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.
Results
The degree of myocardial C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).
Conclusions
These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

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

J Am Coll Cardiol: 03 Feb 2020; 75:380-390
Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
J Am Coll Cardiol: 03 Feb 2020; 75:380-390 | PMID: 32000949
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Abstract

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

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

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

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

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

Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.

Hughes TP, Mauro MJ, Cortes JE, Minami H, ... Lang F, Kim DW
Background
Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.
Methods
In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.
Results
Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.
Conclusions
Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 11 Dec 2019; 381:2315-2326
Hughes TP, Mauro MJ, Cortes JE, Minami H, ... Lang F, Kim DW
N Engl J Med: 11 Dec 2019; 381:2315-2326 | PMID: 31826340
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Abstract

Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.

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

J Am Coll Cardiol: 03 Feb 2020; 75:422-434
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:422-434 | PMID: 32000955
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Abstract

Blood Pressure Management in Afferent Baroreflex Failure: JACC Review Topic of the Week.

Biaggioni I, Shibao CA, Diedrich A, Muldowney JAS, Laffer CL, Jordan J

Afferent baroreflex failure is most often due to damage of the carotid sinus nerve because of neck surgery or radiation. The clinical picture is characterized by extreme blood pressure lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage. There is little evidence-based data to guide treatment. Recommendations rely on understanding the underlying pathophysiology, relevant clinical pharmacology, and anecdotal experience. The goal of treatment should be improving quality of life rather than normalization of blood pressure, which is rarely achievable. Long-acting central sympatholytic drugs are the mainstay of treatment, used at the lowest doses that prevent the largest hypertensive surges. Short-acting clonidine should be avoided because of rebound hypertension, but can be added to control residual hypertensive episodes, often triggered by mental stress or exertion. Hypotensive episodes can be managed with countermeasures and short-acting pressor agents if necessary.

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

J Am Coll Cardiol: 09 Dec 2019; 74:2939-2947
Biaggioni I, Shibao CA, Diedrich A, Muldowney JAS, Laffer CL, Jordan J
J Am Coll Cardiol: 09 Dec 2019; 74:2939-2947 | PMID: 31806138
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Abstract

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

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

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

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

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

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
Background
Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves.
Objectives
This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves.
Methods
Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves.
Results
Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm vs. 15.1 ± 1.6 cm, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group.
Conclusions
In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

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

J Am Coll Cardiol: 03 Feb 2020; 75:395-405
Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
J Am Coll Cardiol: 03 Feb 2020; 75:395-405 | PMID: 32000951
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Abstract

One-year outcomes in atrial fibrillation presenting during infections: a nationwide registry-based study.

Gundlund A, Olesen JB, Butt JH, Christensen MA, ... Kümler T, Fosbøl EL
Aims
Thromboprophylaxis guidelines for patients with concurrent atrial fibrillation (AF) during infections are unclear and not supported by data. We compared 1-year outcomes in patients with infection-related AF and infection without AF.
Methods and results
By crosslinking Danish nationwide registry data, AF naïve patients admitted with infection (1996-2016) were identified. Those with AF during the infection (infection-related AF) were matched 1:3 according to age, sex, type of infection, and year with patients with infection without AF. Outcomes (AF, thromboembolic events) were assessed by multivariable Cox regression. The study population comprised 30 307 patients with infection-related AF and 90 912 patients with infection without AF [median age 79 years (interquartile range 71-86), 47.6% males in both groups]. The 1-year absolute risk of AF and thromboembolic events were 36.4% and 7.6%, respectively (infection-related AF) and 1.9% and 4.4%, respectively (infection without AF). In the multivariable analyses, infection-related AF was associated with an increased long-term risk of AF and thromboembolic events compared with infection without AF: hazard ratio (HR) 25.98, 95% confidence interval (CI) 24.64-27.39 for AF and HR 2.10, 95% CI 1.98-2.22 for thromboembolic events. Further, differences in risks existed across different subtypes of infections.
Conclusion
During the first year after discharge, 36% of patients with infection-related AF had a new hospital contact with AF. Infection-related AF was associated with increased risk of thromboembolic events compared with infection without AF and our results suggest that AF related to infection may merit treatment and follow-up similar to that of AF not related to infection.

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: 16 Dec 2019; epub ahead of print
Gundlund A, Olesen JB, Butt JH, Christensen MA, ... Kümler T, Fosbøl EL
Eur Heart J: 16 Dec 2019; epub ahead of print | PMID: 31848584
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Abstract

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.

Modi S, Saura C, Yamashita T, Park YH, ... Krop I,
Background
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
Methods
In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.
Results
Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).
Conclusions
Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 10 Dec 2019; epub ahead of print
Modi S, Saura C, Yamashita T, Park YH, ... Krop I,
N Engl J Med: 10 Dec 2019; epub ahead of print | PMID: 31825192
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Abstract

Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction.

Haider N, Boscá L, Zandbergen HR, Kovacic JC, ... Ibañez B, Narula J
Background
Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content.
Objectives
This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.
Methods
Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre);ROSA26(EYFP) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.
Results
Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3Col1A1 cells in the heart after MI.
Conclusions
The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.

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

J Am Coll Cardiol: 23 Dec 2019; 74:3124-3135
Haider N, Boscá L, Zandbergen HR, Kovacic JC, ... Ibañez B, Narula J
J Am Coll Cardiol: 23 Dec 2019; 74:3124-3135 | PMID: 31856969
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Impact:
Abstract

Early High-Dose Vitamin D for Critically Ill, Vitamin D-Deficient Patients.

, Ginde AA, Brower RG, Caterino JM, ... Yealy DM, Talmor D
Background
Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.
Methods
We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D or matched placebo. The primary end point was 90-day all-cause, all-location mortality.
Results
A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.
Conclusions
Early administration of high-dose enteral vitamin D did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 10 Dec 2019; epub ahead of print
, Ginde AA, Brower RG, Caterino JM, ... Yealy DM, Talmor D
N Engl J Med: 10 Dec 2019; epub ahead of print | PMID: 31826336
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Impact:
Abstract

Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

Slamon DJ, Neven P, Chia S, Fasching PA, ... Taran T, Jerusalem G
Background
In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival.
Methods
Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
Results
This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed.
Conclusions
Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 10 Dec 2019; epub ahead of print
Slamon DJ, Neven P, Chia S, Fasching PA, ... Taran T, Jerusalem G
N Engl J Med: 10 Dec 2019; epub ahead of print | PMID: 31826360
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Impact:
Abstract

Obesity as a Causal Risk Factor for Aortic Valve Stenosis.

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

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

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

Precision Medicine in the Management of Dilated Cardiomyopathy: JACC State-of-the-Art Review.

Fatkin D, Huttner IG, Kovacic JC, Seidman JG, Seidman CE

Precision medicine promises to dramatically improve patient outcomes and reduce health care costs through a shift in focus from disease treatment to prevention and individualized therapies. For families with inherited cardiomyopathies, efforts to date have been directed toward discovery and functional characterization of single disease-causing variants. With advances in sequencing, the cataloging of personal genetic variation has been expedited, providing improved insights into the key importance of the genes in which variants occur. These advances have propelled seminal opportunities for successful variant-targeted disease-reversing therapy. New challenges have also emerged-particularly interpretation of the rapidly rising numbers of \"variants of unknown significance.\" For treatments based on patient genotype to be feasible on a wider scale, these obstacles need to be overcome. Here the authors focus on genetics of dilated cardiomyopathy and provide a roadmap for implementing genomic information into future patient management.

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

J Am Coll Cardiol: 09 Dec 2019; 74:2921-2938
Fatkin D, Huttner IG, Kovacic JC, Seidman JG, Seidman CE
J Am Coll Cardiol: 09 Dec 2019; 74:2921-2938 | PMID: 31806137
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Impact:
Abstract

Adverse Events, Radiation Exposure, and Reinterventions Following Transcatheter Pulmonary Valve Replacement.

Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
Background
Transcatheter pulmonary valve replacement (TPVR) is associated with a risk of procedural serious adverse events (SAE) and exposure to ionizing radiation.
Objectives
The purpose of this study was to define the risk of, and associations with, SAE and high-dose radiation exposure using large-scale registry data.
Methods
The analysis of the multicenter C3PO-QI registry was limited to patients who underwent TPVR from January 1, 2014, to December 31, 2016. SAE were defined as the occurrence of ≥1 moderate, major, or catastrophic events. Radiation dose was reported as dose area product adjusted for weight. Associations with outcome measures were explored in univariate and multivariable analyses.
Results
A total of 530 patients (59% male) underwent TPVR at a median age of 18.3 years (interquartile range [IQR]: 12.9 to 27.3 years) and weight of 58 kg (IQR: 43 to 77 kg) at 14 centers. Implant substrate included homograft (41%), bioprosthesis (30%), native right ventricular outflow tract (RVOT) (27%) and other (2%). TPVR indications were pulmonary insufficiency (28%), stenosis (23%), and mixed (49%). AE and SAE occurred in 26% and 13% of cases, respectively, including 1 mortality. SAE were more frequent in homograft conduit than other RVOT substrates, although SAE type and severity differed between implant substrates. Median radiation dose was 198 μGy·m/kg (IQR: 94 to 350 μGy·m/kg). Higher radiation dose was associated with older age, greater RVOT obstruction, and concomitant interventions (p < 0.001). During a median follow-up duration of 1 year, 13.3% underwent catheterization, surgery, or both, unrelated to infection. Younger age, smaller size, and hemodynamic and anatomic factors indicative of greater RVOT obstruction were associated with TPV reintervention.
Conclusions
The incidence of SAE during TPVR in the C3PO-QI registry is high, but mortality is uncommon. Radiation dose is greater than for other congenital interventions and is associated with patient and procedural factors. Reintervention is common during early follow-up.

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

J Am Coll Cardiol: 03 Feb 2020; 75:363-376
Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
J Am Coll Cardiol: 03 Feb 2020; 75:363-376 | PMID: 32000947
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Impact:
Abstract

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

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

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

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

Clinical Benefit of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research.

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

J Am Coll Cardiol: 03 Feb 2020; 75:435-447
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:435-447 | PMID: 32000956
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Impact:
Abstract

Screening for atrial fibrillation: a call for evidence.

Jones NR, Taylor CJ, Hobbs FDR, Bowman L, Casadei B

Atrial fibrillation (AF) is the most common cardiac arrhythmia and prevalence is predicted to double over the next 30 years due to changing demographics and the rise in prevalence of risk factors such as hypertension and diabetes. Atrial fibrillation is associated with a five-fold increased stroke risk, but anticoagulation in eligible patients can reduce this risk by around 65%. Many people with AF currently go undetected and therefore untreated, either because they are asymptomatic or because they have paroxysmal AF. Screening has been suggested as one approach to increase AF detection rates and reduce the incidence of ischaemic stroke by earlier initiation of anticoagulation therapy. However, international taskforces currently recommend against screening, citing the cost implications and uncertainty over the benefits of a systematic screening programme compared to usual care. A number of large randomized controlled trials have commenced to determine the cost-effectiveness and clinical benefit of screening using a range of devices and across different populations. The recent AppleWatch study demonstrates how advances in technology are providing the public with self-screening devices that are increasingly affordable and accessible. Health care professionals should be aware of the implications of these emerging data for diagnostic pathways and treatment. This review provides an overview of the gaps in the current evidence and a summary of the arguments for and against screening.

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

Eur Heart J: 06 Dec 2019; epub ahead of print
Jones NR, Taylor CJ, Hobbs FDR, Bowman L, Casadei B
Eur Heart J: 06 Dec 2019; epub ahead of print | PMID: 31811716
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Impact:
Abstract

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

Murthy RK, Loi S, Okines A, Paplomata E, ... Feng W, Winer EP
Background
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
Methods
We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
Results
Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
Conclusions
In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).

Copyright © 2019 Massachusetts Medical Society.

N Engl J Med: 10 Dec 2019; epub ahead of print
Murthy RK, Loi S, Okines A, Paplomata E, ... Feng W, Winer EP
N Engl J Med: 10 Dec 2019; epub ahead of print | PMID: 31825569
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Impact:
Abstract

Short-Term Hemodynamic and Electrophysiological Effects of Cardiac Resynchronization by Left Ventricular Septal Pacing.

Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
Background
Cardiac resynchronization therapy (CRT) is usually performed by biventricular (BiV) pacing. Previously, feasibility of transvenous implantation of a lead at the left ventricular (LV) endocardial side of the interventricular septum, referred to as LV septal (LVs) pacing, was demonstrated.
Objectives
The authors sought to compare the acute electrophysiological and hemodynamic effects of LVs with BiV and His bundle (HB) pacing in CRT patients.
Methods
Temporary LVs pacing (transaortic approach) alone or in combination with right ventricular (RV) (LVs+RV), BiV, and HB pacing was performed in 27 patients undergoing CRT implantation. Electrophysiological changes were assessed using electrocardiography (QRS duration), vectorcardiography (QRS area), and multielectrode body surface mapping (standard deviation of activation times [SDAT]). Hemodynamic changes were assessed as the first derivative of LV pressure (LVdP/dtmax).
Results
As compared with baseline, LVs pacing resulted in a larger reduction in QRS area (to 73 ± 22 μVs) and SDAT (to 26 ± 7 ms) than BiV (to 93 ± 26 μVs and 31 ± 7 ms; both p < 0.05) and LVs+RV pacing (to 108 ± 37 μVs; p < 0.05; and 29 ± 8 ms; p = 0.05). The increase in LVdP/dtmax was similar during LVs and BiV pacing (17 ± 10% vs. 17 ± 9%, respectively) and larger than during LVs+RV pacing (11 ± 9%; p < 0.05). There were no significant differences between basal, mid-, or apical LVs levels in LVdP/dtmax and SDAT. In a subgroup of 16 patients, changes in QRS area, SDAT, and LVdP/dtmax were comparable between LVs and HB pacing.
Conclusions
LVs pacing provides short-term hemodynamic improvement and electrical resynchronization that is at least as good as during BiV and possibly HB pacing. These results indicate that LVs pacing may serve as a valuable alternative for CRT.

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

J Am Coll Cardiol: 03 Feb 2020; 75:347-359
Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
J Am Coll Cardiol: 03 Feb 2020; 75:347-359 | PMID: 32000945
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Impact:
Abstract

Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

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

J Am Coll Cardiol: 10 Feb 2020; 75:525-538
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:525-538 | PMID: 32029136
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Impact:
Abstract

A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

George J, Rappaport M, Shimoni S, Goland S, ... Tshori S, Fassler M
Aims
Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis.
Methods and results
We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing.
Conclusion
We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

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: 21 Dec 2019; epub ahead of print
George J, Rappaport M, Shimoni S, Goland S, ... Tshori S, Fassler M
Eur Heart J: 21 Dec 2019; epub ahead of print | PMID: 31865366
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Impact:
Abstract

Contribution of income and job strain to the association between education and cardiovascular disease in 1.6 million Danish employees.

Framke E, Sørensen JK, Andersen PK, Svane-Petersen AC, ... Rugulies R, Madsen IEH
Aims
We examined the extent to which associations between education and cardiovascular disease (CVD) morbidity and mortality are attributable to income and work stress.
Methods and results
We included all employed Danish residents aged 30-59 years in 2000. Cardiovascular disease morbidity analyses included 1 638 270 individuals, free of cardiometabolic disease (CVD or diabetes). Mortality analyses included 41 944 individuals with cardiometabolic disease. We assessed education and income annually from population registers and work stress, defined as job strain, with a job-exposure matrix. Outcomes were ascertained until 2014 from health registers and risk was estimated using Cox regression. During 10 957 399 (men) and 10 776 516 person-years (women), we identified 51 585 and 24 075 incident CVD cases, respectively. For men with low education, risk of CVD was 1.62 [95% confidence interval (CI) 1.58-1.66] before and 1.46 (95% CI 1.42-1.50) after adjustment for income and job strain (25% reduction). In women, estimates were 1.66 (95% CI 1.61-1.72) and 1.53 (95% CI 1.47-1.58) (21% reduction). Of individuals with cardiometabolic disease, 1736 men (362 234 person-years) and 341 women (179 402 person-years) died from CVD. Education predicted CVD mortality in both sexes. Estimates were reduced with 54% (men) and 33% (women) after adjustment for income and job strain.
Conclusion
Low education predicted incident CVD in initially healthy individuals and CVD mortality in individuals with prevalent cardiometabolic disease. In men with cardiometabolic disease, income and job strain explained half of the higher CVD mortality in the low education group. In healthy men and in women regardless of cardiometabolic disease, these factors explained 21-33% of the higher CVD morbidity and mortality.

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

Eur Heart J: 16 Dec 2019; epub ahead of print
Framke E, Sørensen JK, Andersen PK, Svane-Petersen AC, ... Rugulies R, Madsen IEH
Eur Heart J: 16 Dec 2019; epub ahead of print | PMID: 31844881
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Impact:
Abstract

Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives.

Ganatra S, Carver JR, Hayek SS, Ky B, ... Barac A, Liu JE

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.

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

J Am Coll Cardiol: 23 Dec 2019; 74:3153-3163
Ganatra S, Carver JR, Hayek SS, Ky B, ... Barac A, Liu JE
J Am Coll Cardiol: 23 Dec 2019; 74:3153-3163 | PMID: 31856973
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Impact:
Abstract

Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54.

Furtado RHM, Nicolau JC, Magnani G, Im K, ... Sabatine MS, Bonaca MP
Aims
PEGASUS-TIMI 54 demonstrated that long-term dual antiplatelet therapy (DAPT) with aspirin and ticagrelor reduced the risk of major adverse cardiovascular events (MACE), with an acceptable increase in bleeding, in patients with prior myocardial infarction (MI). While much of the discussion around prolonged DAPT has been focused on stented patients, patients with prior MI without prior coronary stenting comprise a clinically important subgroup.
Methods and results
This was a pre-specified analysis from PEGASUS-TIMI 54, which randomized 21 162 patients with prior MI (1-3 years) and additional high-risk features to ticagrelor 60 mg, 90 mg, or placebo twice daily in addition to aspirin. A total of 4199 patients had no history of coronary stenting at baseline. The primary efficacy outcome (MACE) was the composite of cardiovascular death, MI, or stroke. Patients without history of coronary stenting had higher baseline risk of MACE [13.2% vs. 8.0%, adjusted hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.15-1.73, in the placebo arm]. The relative risk reduction in MACE with ticagrelor (pooled doses) was similar in patients without (HR 0.82, 95% CI 0.68-0.99) and with prior stenting (HR 0.85, 95% CI 0.75-0.96; P for interaction = 0.76).
Conclusion
Long-term ticagrelor reduces thrombotic events in patients with prior MI regardless of whether they had prior coronary stenting. These data highlight the benefits of DAPT in prevention of spontaneous atherothrombotic events and indicate that long-term ticagrelor may be considered in high-risk patients with prior MI even if they have not been treated with stenting.
Clinicaltrials.gov identifier
NCT01225562.

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: 06 Dec 2019; epub ahead of print
Furtado RHM, Nicolau JC, Magnani G, Im K, ... Sabatine MS, Bonaca MP
Eur Heart J: 06 Dec 2019; epub ahead of print | PMID: 31811715
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Impact:
Abstract

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

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

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

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

Acute Stroke During Pregnancy and Puerperium.

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

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

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

Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T).

Alvi RM, Frigault MJ, Fradley MG, Jain MD, ... Locke FL, Neilan TG
Background
Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T.
Objectives
The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T.
Methods
The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death.
Results
The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab.
Conclusions
Among adults, cardiac injury and CV events are common post-CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.

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

J Am Coll Cardiol: 23 Dec 2019; 74:3099-3108
Alvi RM, Frigault MJ, Fradley MG, Jain MD, ... Locke FL, Neilan TG
J Am Coll Cardiol: 23 Dec 2019; 74:3099-3108 | PMID: 31856966
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Abstract

Alcohol Abstinence in Drinkers with Atrial Fibrillation.

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

Copyright © 2020 Massachusetts Medical Society.

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

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
Background
Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.
Objectives
This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.
Methods
MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.
Results
This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.
Conclusions
This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

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

J Am Coll Cardiol: 27 Jan 2020; 75:273-285
Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
J Am Coll Cardiol: 27 Jan 2020; 75:273-285 | PMID: 31976865
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Abstract

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

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

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

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

J Am Coll Cardiol: 27 Jan 2020; 75:320-332
DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M
J Am Coll Cardiol: 27 Jan 2020; 75:320-332 | PMID: 31976871
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This program is still in alpha version.