Topic: Heart Failure

Abstract

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

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

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

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

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

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

Copyright © 2019. Published by Elsevier B.V.

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

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

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

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

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

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

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

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

Story telling of myocarditis.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.

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

Copyright © 2019 Massachusetts Medical Society.

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

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

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

Copyright © 2019 Massachusetts Medical Society.

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

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

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



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

Risk of Mortality Following Catheter Ablation of Atrial Fibrillation.

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

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

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

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

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

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

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

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

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

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

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

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

Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial.

Hermida RC, Crespo JJ, Domínguez-Sardiña M, Otero A, ... Ayala DE,
Aims
The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction.
Methods and results
In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)].
Conclusion
Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events.
Trial registration
ClinicalTrials.gov, number NCT00741585.

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 Oct 2019; epub ahead of print
Hermida RC, Crespo JJ, Domínguez-Sardiña M, Otero A, ... Ayala DE,
Eur Heart J: 21 Oct 2019; epub ahead of print | PMID: 31641769
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Abstract

Altered fibrin clot properties and fibrinolysis in patients with atrial fibrillation: practical implications.

Undas A

Compelling evidence indicates that a hypercoagulable state occurs in patients with atrial fibrillation (AF) including those in sinus rhythm following paroxysmal and persistent AF. Activation of blood coagulation in AF reflects heightened thrombin generation with the subsequent increased formation of fibrin as evidenced by elevated soluble fibrin monomers and D-dimer. Formation of denser fibrin meshworks, relatively resistant to plasmin-mediated lysis has been demonstrated in patients with AF. The presence of stroke risk factors in AF, such as diabetes, heart failure, hypertension, previous myocardial infarction, or stroke, advanced age have been shown to be linked to the prothrombotic clot characteristics, including reduced clot permeability and lysability. Importantly, biomarkers, including cardiac troponins and N-terminal pro-brain natriuretic peptide, are associated with thrombin generation and fibrin-related markers in AF patients. Recently, increased fibrin clot density (low clot permeability measured in plasma-based assays) and impaired fibrinolysis measured off anticoagulation have been demonstrated to predict ischaemic cerebrovascular events in patients with AF receiving vitamin K antagonists and those on rivaroxaban. The current review summarizes evidence for a role of altered fibrin clot properties and hypofibrinolysis in AF and their prognostic value in terms of adverse events.

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

Europace: 17 Oct 2019; epub ahead of print
Undas A
Europace: 17 Oct 2019; epub ahead of print | PMID: 31625555
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Abstract

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

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

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

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

Nuclear miR-320 Mediates Diabetes-Induced Cardiac Dysfunction by Activating Transcription of Fatty Acid Metabolic Genes to Cause Lipotoxicity in the Heart.

Li H, Fan J, Zhao Y, Zhang X, ... Chen C, Wang DW

Diabetes mellitus is often associated with cardiovascular complications, which is the leading cause of morbidity and mortality among diabetes patients, but little is known about the mechanism that connects diabetes to the development of cardiovascular dysfunction.We aim to elucidate the mechanism underlying hyperglycemia-induced cardiac dysfunction on a well-established db/db mouse model for diabetes and diabetic complications that lead to heart failure.We first profiled the expression of miRNAs by microarray and qRT-PCR on db/db mice, and identified miR-320 as a key miRNA associated with the disease phenotype. We next established the clinical relevance of this finding by showing the up-regulation of the same miRNA in the failing heart of diabetes patients. We demonstrated the causal role of miR-320 in inducing diabetic cardiomyopathy, showing that miR-320 overexpression exacerbated while its inhibition improved the cardiac phenotype in db/db mice. Unexpectedly, we found that miR-320 acts as a small activating RNA (saRNA) in the nucleus at the level of transcription. By ChIP-seq and ChIP-qPCR analysis of Ago2 and RNA Pol II in response to miR-320 induction, we identified CD36 as a key target gene for this miRNA and showed that the induced expression of CD36 is responsible for increased fatty acid uptake, thereby causing lipotoxicity in the heart.These findings uncover a novel mechanism for diabetes-triggered cardiac dysfunction, provide an endogenous case for saRNA that has been demonstrated so far only with synthetic RNAs in transfected cells, and suggest a potential strategy to develop a miRNA-based therapy to treat diabetes-associated cardiovascular complications.



Circ Res: 21 Oct 2019; epub ahead of print
Li H, Fan J, Zhao Y, Zhang X, ... Chen C, Wang DW
Circ Res: 21 Oct 2019; epub ahead of print | PMID: 31638474
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Abstract

Heightened Risk of Intensive Rate Control in Patients With Atrial Fibrillation Who Are Obese or Have Type 2 Diabetes: A Critical Review and Re-Evaluation.

Packer M

Atrial fibrillation (AF) is common in patients with obesity and diabetes; the arrhythmia (if long-standing) is typically managed by rate-control and anticoagulation. However, the coexistence of these two metabolic disorders complicates therapeutic options for rate-control. The likely pathogenesis of AF in these patients is an expansion of epicardial adipose tissue, whose inflammation is transmitted to the left atrium causing electromechanical remodeling. However, this same process is also transmitted to the left ventricle, impairing its distensibility and its ability to tolerate volume, leading to heart failure with preserved ejection fraction. Unfortunately, the latter diagnosis (although commonly present in patients with AF and a coexistent metabolic disorder) is often ignored. To achieve rate control, physicians prescribe intensive treatment with atrioventricular (AV)-nodal blocking drugs, often at doses that are titrated to blunt exercise as well as resting heart rate responses. However, strict rate control (target rate <80/min) is associated with somewhat worse outcomes than lenient rate control (target rate <110/min). Furthermore, any rate slowing that facilitates diastolic filling may aggravate filling pressures that are already disproportionately increased because the left ventricle is stiff and overfilled as a result of cardiac inflammation. Rate slowing in AF with beta-blockers may not achieve the benefit expected from the blockade of adrenergically-mediated cardiotoxicity, and some AV-nodal blocking drugs (digoxin and dronedarone) can increase the risk of death in patients with AF. Finally, cardiac fibrosis in obesity and diabetes may affect the conduction system, which can predispose to serious bradyarrhythmias if patients are prescribed AV-nodal blocking drugs. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print
Packer M
J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print | PMID: 31626365
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Abstract

Alteration of Cardiac Performance and Serum B-Type Natriuretic Peptide Level in Healthy Aging.

Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, ... Homma S, Komuro I
Background
The impact of aging on cardiac function is not fully elucidated. Speckle-tracking echocardiography can unmask subclinical cardiac dysfunction.
Objectives
This study investigated the impact of healthy aging on left ventricular (LV), right ventricular (RV), and left atrial (LA) performance and their relationship with serum B-type natriuretic peptide (BNP) levels in a sample of the general population without prevalent cardiovascular risk factors and structural heart disease.
Methods
Speckle-tracking echocardiography was performed to assess LV global longitudinal strain (LVGLS), RV free wall strain, and LA phasic strain in 481 normal weight healthy participants who underwent extensive cardiovascular examination. Elevated BNP was defined as BNP >37.82 pg/ml for men and >50.86 pg/ml for women, which was the 90th percentile of BNP value distribution in the study population.
Results
Mean age was 60 ± 12 years (range: 24 to 86 years), and 46% of the participants were men. The earliest alteration of age-related cardiac performance was observed in LA reservoir and conduit strain starting from decade 5, followed by elevated E/e\' from decade 6. LVGLS decreased starting from decade 7, whereas there were no significant differences in RV strain, LV ejection fraction, or LV mass index across the decades. In the multivariable linear regression analyses, age was an independent predictor of decreased LVGLS (standardized β = 0.21; p < 0.001) and decreased LA phasic strain (standardized β = -0.40 and -0.61 for reservoir and conduit strain; both p < 0.001). Age and LA strain were significantly associated with elevated BNP values (adjusted odds ratios: 1.10 and 0.93; both p < 0.05, respectively), independent of ventricular morphology and function.
Conclusions
Decreases in LA reservoir and conduit strain are the earliest markers of age-related cardiac remodeling, and LA reservoir strain is an independent predictor of elevated serum BNP level, with both possibly being markers of increased risk of heart failure in older adults.

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

J Am Coll Cardiol: 08 Oct 2019; 74:1789-1800
Yoshida Y, Nakanishi K, Daimon M, Ishiwata J, ... Homma S, Komuro I
J Am Coll Cardiol: 08 Oct 2019; 74:1789-1800 | PMID: 31582139
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Abstract

The quest for physiological pacing - does one size fit all?

Kaye G

Pacing is an established and ubiquitous treatment of bradycardias and some types of heart failure. The optimal pacing lead position which maximises cardiac function and minimises deterioration of ventricular function remains controversial. The desire to achieve a physiological pacing system which mimics cardiac function has led to investigation of several potential pacing sites. This editorial provides an overview of past and current pacing lead position and summaries the current and future direction of physiological pacing. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print
Kaye G
J Cardiovasc Electrophysiol: 17 Oct 2019; epub ahead of print | PMID: 31626353
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Abstract

Improving Communication in Heart Failure Patient Care.

Goldstein NE, Mather H, McKendrick K, Gelfman LP, ... Pinney S, Morrison RS
Background
Although implantable cardioverter-defibrillators (ICDs) reduce sudden death, these patients die of heart failure (HF) or other diseases. To prevent shocks at the end of life, clinicians should discuss deactivating the defibrillation function.
Objectives
The purpose of this study was to determine if a clinician-centered teaching intervention and automatic reminders increased ICD deactivation discussions and increased device deactivation.
Methods
In this 6-center, single-blinded, cluster-randomized, controlled trial, primary outcomes were proportion of patients: 1) having ICD deactivation discussions; and 2) having the shocking function deactivated. Secondary outcomes included goals of care conversations and advance directive completion.
Results
A total of 525 subjects were included with advanced HF who had an ICD: 301 intervention and 224 control. At baseline, 52% (n = 272) were not candidates for advanced therapies (i.e., cardiac transplant or mechanical circulatory support). There were no differences in discussions (41 [14%] vs. 26 [12%]) or deactivation (33 [11%] vs. 26 [12%]). In pre-specified subgroup analyses of patients who were not candidates for advanced therapies, the intervention increased deactivation discussions (32 [25%] vs. 16 [11%]; odds ratio: 2.90; p = 0.003). Overall, 99 patients died; there were no differences in conversations or deactivations among decedents.
Secondary outcomes
Among all participants, there was an increase in goals of care conversations (47% intervention vs. 38% control; odds ratio: 1.53; p = 0.04). There were no differences in completion of advance directives.
Conclusions
The intervention increased conversations about ICD deactivation and goals of care. HF clinicians were able to apply new communication techniques based on patients\' severity of illness. (An Intervention to Improve Implantable Cardioverter-Defibrillator Deactivation Conversations [WISDOM]; NCT01459744).

Published by Elsevier Inc.

J Am Coll Cardiol: 01 Oct 2019; 74:1682-1692
Goldstein NE, Mather H, McKendrick K, Gelfman LP, ... Pinney S, Morrison RS
J Am Coll Cardiol: 01 Oct 2019; 74:1682-1692 | PMID: 31558252
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Abstract

The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction.

Reddy YNV, Obokata M, Wiley B, Koepp KE, ... Carter RE, Borlaug BA
Aims
Increases in extravascular lung water (EVLW) during exercise contribute to symptoms, morbidity, and mortality in patients with heart failure and preserved ejection fraction (HFpEF), but the mechanisms leading to pulmonary congestion during exercise are not well-understood.
Methods and results
Compensated, ambulatory patients with HFpEF (n = 61) underwent invasive haemodynamic exercise testing using high-fidelity micromanometers with simultaneous lung ultrasound, echocardiography, and expired gas analysis at rest and during submaximal exercise. The presence or absence of EVLW was determined by lung ultrasound to evaluate for sonographic B-line artefacts. An increase in EVLW during exercise was observed in 33 patients (HFpEFLW+, 54%), while 28 (46%) did not develop EVLW (HFpEFLW-). Resting left ventricular function was similar in the groups, but right ventricular (RV) dysfunction was two-fold more common in HFpEFLW+ (64 vs. 31%), with lower RV systolic velocity and RV fractional area change. As compared to HFpEFLW-, the HFpEFLW+ group displayed higher pulmonary capillary wedge pressure (PCWP), higher pulmonary artery (PA) pressures, worse RV-PA coupling, and higher right atrial (RA) pressures during exercise, with increased haemoconcentration indicating greater loss of water from the vascular space. The development of lung congestion during exercise was significantly associated with elevations in PCWP and RA pressure as well as impairments in RV-PA coupling (area under the curve values 0.76-0.84).
Conclusion
Over half of stable outpatients with HFpEF develop increases in interstitial lung water, even during submaximal exercise. The acute development of lung congestion is correlated with increases in pulmonary capillary hydrostatic pressure that favours fluid filtration, and systemic venous hypertension due to altered RV-PA coupling, which may interfere with fluid clearance.
Clinical trial registration
NCT02885636.

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: 13 Oct 2019; epub ahead of print
Reddy YNV, Obokata M, Wiley B, Koepp KE, ... Carter RE, Borlaug BA
Eur Heart J: 13 Oct 2019; epub ahead of print | PMID: 31609443
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Abstract

KLF15-Wnt-Dependent Cardiac Reprogramming Up-Regulates SHISA3 in the Mammalian Heart.

Noack C, Iyer LM, Liaw NY, Schoger E, ... Zimmermann WH, Zelarayán LC
Background
The combination of cardiomyocyte (CM) and vascular cell (VC) fetal reprogramming upon stress culminates in end-stage heart failure (HF) by mechanisms that are not fully understood. Previous studies suggest KLF15 as a key regulator of CM hypertrophy.
Objectives
This study aimed to characterize the impact of KLF15-dependent cardiac transcriptional networks leading to HF progression, amenable to therapeutic intervention in the adult heart.
Methods
Transcriptomic bioinformatics, phenotyping of Klf15 knockout mice, Wnt-signaling-modulated hearts, and pressure overload and myocardial ischemia models were applied. Human KLF15 knockout embryonic stem cells and engineered human myocardium, and human samples were used to validate the relevance of the identified mechanisms.
Results
The authors identified a sequential, postnatal transcriptional repression mediated by KLF15 of pathways implicated in pathological tissue remodeling, including distinct Wnt-pathways that control CM fetal reprogramming and VC remodeling. The authors further uncovered a vascular program induced by a cellular crosstalk initiated by CM, characterized by a reduction of KLF15 and a concomitant activation of Wnt-dependent transcriptional signaling. Within this program, a so-far uncharacterized cardiac player, SHISA3, primarily expressed in VCs in fetal hearts and pathological remodeling was identified. Importantly, the KLF15 and Wnt codependent SHISA3 regulation was demonstrated to be conserved in mouse and human models.
Conclusions
The authors unraveled a network interplay defined by KLF15-Wnt dynamics controlling CM and VC homeostasis in the postnatal heart and demonstrated its potential as a cardiac-specific therapeutic target in HF. Within this network, they identified SHISA3 as a novel, evolutionarily conserved VC marker involved in pathological remodeling in HF.

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

J Am Coll Cardiol: 08 Oct 2019; 74:1804-1819
Noack C, Iyer LM, Liaw NY, Schoger E, ... Zimmermann WH, Zelarayán LC
J Am Coll Cardiol: 08 Oct 2019; 74:1804-1819 | PMID: 31582141
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Abstract

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

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



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

Clinical presentation, aetiology and outcome of infective endocarditis. Results of the ESC-EORP EURO-ENDO (European infective endocarditis) registry: a prospective cohort study.

Habib G, Erba PA, Iung B, Donal E, ... Lancellotti P,
Aims
The EURO-ENDO registry aimed to study the management and outcomes of patients with infective endocarditis (IE).
Methods and results
Prospective cohort of 3116 adult patients (2470 from Europe, 646 from non-ESC countries), admitted to 156 hospitals in 40 countries between January 2016 and March 2018 with a diagnosis of IE based on ESC 2015 diagnostic criteria. Clinical, biological, microbiological, and imaging [echocardiography, computed tomography (CT) scan, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)] data were collected. Infective endocarditis was native (NVE) in 1764 (56.6%) patients, prosthetic (PVIE) in 939 (30.1%), and device-related (CDRIE) in 308 (9.9%). Infective endocarditis was community-acquired in 2046 (65.66%) patients. Microorganisms involved were staphylococci in 1085 (44.1%) patients, oral streptococci in 304 (12.3%), enterococci in 390 (15.8%), and Streptococcus gallolyticus in 162 (6.6%). 18F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 518 (16.6%) patients and presented with cardiac uptake (major criterion) in 222 (42.9%) patients, with a better sensitivity in PVIE (66.8%) than in NVE (28.0%) and CDRIE (16.3%). Embolic events occurred in 20.6% of patients, and were significantly associated with tricuspid or pulmonary IE, presence of a vegetation and Staphylococcus aureus IE. According to ESC guidelines, cardiac surgery was indicated in 2160 (69.3%) patients, but finally performed in only 1596 (73.9%) of them. In-hospital death occurred in 532 (17.1%) patients and was more frequent in PVIE. Independent predictors of mortality were Charlson index, creatinine > 2 mg/dL, congestive heart failure, vegetation length > 10 mm, cerebral complications, abscess, and failure to undertake surgery when indicated.
Conclusion
Infective endocarditis is still a life-threatening disease with frequent lethal outcome despite profound changes in its clinical, microbiological, imaging, and therapeutic profiles.

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: 13 Oct 2019; 40:3222-3232
Habib G, Erba PA, Iung B, Donal E, ... Lancellotti P,
Eur Heart J: 13 Oct 2019; 40:3222-3232 | PMID: 31504413
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Abstract

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

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

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

Copyright © 2019. Published by Elsevier Inc.

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

Digoxin-mortality: randomized vs. observational comparison in the DIG trial.

Aguirre Dávila L, Weber K, Bavendiek U, Bauersachs J, ... Yusuf S, Koch A
Aims
The Digitalis Investigation Group (DIG) trial, the only large randomized trial of digoxin in heart failure, reported a neutral effect on mortality and a significant reduction in heart failure hospitalizations. Recent observational studies reported increased mortality with digoxin treatment. We present further analyses of the DIG trial displaying the inability to control bias in observational treatment comparisons despite extensive statistical adjustments.
Methods and results
Forty-four percent of the 6800 patients in the DIG trial had been treated with digoxin before randomization, and half of them were randomly withdrawn from digoxin treatment. We contrast the main randomization-based result of the DIG trial with the observational non-randomized comparison of patients pre-treated or not pre-treated with digoxin. Mortality [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.12-1.34; P < 0.001] and heart failure hospitalizations (HR 1.47, 95% CI 1.33-1.61; P < 0.001) were significantly higher in patients pre-treated with digoxin even after adjustment for baseline population differences. The higher risks for both outcomes in those who had previously received digoxin persisted even if they received placebo during the trial (HR 1.24, 95% CI 1.10-1.40; P < 0.001). This sharply contradicts the neutral effect on mortality and the significant reduction in heart failure hospitalizations observed in the randomized comparison.
Conclusion
Prescription of digoxin is an indicator of disease severity and worse prognosis, which cannot be fully accounted for by covariate adjustments in the DIG trial where patients were well-characterized. It is unlikely that weaker research approaches (observational studies of administrative data or registries) can provide more reliable estimates of the effects of cardiac glycosides.

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

Eur Heart J: 20 Oct 2019; 40:3336-3341
Aguirre Dávila L, Weber K, Bavendiek U, Bauersachs J, ... Yusuf S, Koch A
Eur Heart J: 20 Oct 2019; 40:3336-3341 | PMID: 31211324
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Impact:
Abstract

Emerging Drug Classes and Their Potential Use in Hypertension.

Azizi M, Rossignol P, Hulot JS

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



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

Cardiovascular Toxicities Associated With Ibrutinib.

Salem JE, Manouchehri A, Bretagne M, Lebrun-Vignes B, ... Roden DM, Moslehi JJ
Background
Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.
Objectives
The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.
Methods
This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC (lower end of the IC 95% credibility interval) >0 is significant.
Results
This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).
Conclusions
Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).

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

J Am Coll Cardiol: 01 Oct 2019; 74:1667-1678
Salem JE, Manouchehri A, Bretagne M, Lebrun-Vignes B, ... Roden DM, Moslehi JJ
J Am Coll Cardiol: 01 Oct 2019; 74:1667-1678 | PMID: 31558250
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Abstract

Cardiac resynchronization therapy reduces expression of inflammation-promoting genes related to interleukin-1β in heart failure.

Bilchick K, Kothari H, Narayan A, Garmey J, ... Capaldo B, McNamara C
Aims
In light of recent data regarding inflammatory signalling pathways in cardiovascular disease and the recently demonstrated impact of pharmacologic inhibition of interleukin-1β (IL-1β) in heart failure, the primary aim was to assess the physiologic effects of cardiac resynchronization therapy (CRT) on the expression of systemic inflammatory, immune-modulatory, metabolic, and apoptotic genes in peripheral blood mononuclear cells (PBMCs) of patients with heart failure.
Methods and results
We used RNA sequencing (RNA-Seq) and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to identify gene expression changes in PBMCs in response to CRT. In total, 27 patients were analysed: 12 with heart failure undergoing CRT, 6 with heart failure undergoing standard implanted cardioverter defibrillators, and 9 with coronary artery disease but not heart failure. In CRT patients (median age 65.5 years, interquartile range 63.0-66.8 years, 33% female), RNA-Seq analysis identified 40 genes, including multiple genes associated with the IL-1β pathway, with significant correlations (false discovery rate < 0.05) with four key CRT response measures. CRT was associated with suppression of PBMC expression of IL-1β (1.80-fold decrease, P = 0.047), FOS proto-oncogene (FOS) (3.25-fold decrease, P = 0.01), dual specificity phosphatase 1 (DUSP1) (2.05-fold decrease, P = 0.001), and early growth response 1 (EGR1) (7.38-fold decrease, P = 0.03), and suppression was greater in responders vs. non-responders (P = 0.03 for IL-1β, P = 0.02 for FOS, P = 0.02 for DUSP1, and P = 0.11 for EGR1). Baseline FOS and DUSP-1 levels were greater in responders vs. non-responders (6.15-fold higher, FOS, P = 0.002; 2.60-fold higher, DUSP1, P = 0.0001). CRT responders but not non-responders showed higher baseline gene expression of FOS (P = 0.04) and DUSP1 (P = 0.06) compared with control patients without heart failure. Baseline serum high-sensitivity C-reactive protein levels were 3.47-fold higher in CRT responders vs. non-responders (P = 0.008).
Conclusion
Treatment of heart failure with CRT resulted in decreased PBMC expression of genes linked to inflammation. Moreover, CRT responders had higher expression of these inflammatory genes prior to CRT and greater suppression of these genes after CRT compared with non-responders.

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

Cardiovasc Res: 14 Oct 2019; epub ahead of print
Bilchick K, Kothari H, Narayan A, Garmey J, ... Capaldo B, McNamara C
Cardiovasc Res: 14 Oct 2019; epub ahead of print | PMID: 31612215
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Abstract

Transcatheter versus medical treatment of symptomatic severe tricuspid regurgitation.

Taramasso M, Benfari G, van der Bijl P, Alessandrini H, ... Enriquez-Sarano M, Maisano F
Background
Tricuspid Regurgitation (TR) is associated with increased rates of heart failure (HF) and mortality. Transcatheter tricuspid valve interventions (TTVI) are promising, but the clinical benefit is unknown.
Objectives
To investigate the potential benefit of TTVI over medical therapy in a propensity score matched population.
Methods
The TriValve (Transcatheter Tricuspid Valve Therapies) registry collected 472 patients from 22 European and North American centers, who underwent TTVI from 2016 to 2018. A control cohort formed by two large retrospective registries enrolling medically managed patients with ≥moderate TR in Europe and North America (1179 pts) were propensity score 1:1 matched (distance ± 0.2 SD) using age, Euroscore II, and systolic pulmonary artery pressure. Survival was tested with Cox regression analysis. Primary endpoint was 1-year mortality or HF rehospitalization or the composite.
Results
After matching, 268 adequately matched pairs of patients were identified. Compared to controls, TTVI patients had lower 1-year mortality (23 ±3% vs 36 ±3%, p=0.001), rehospitalization (26 ±3% vs 47 ±3% p<0.0001), and composite endpoint (32 ±4% vs 49 ±3%; p=0.0003). TTVI was associated with greater survival and freedom from HF rehospitalization (HR 0.60 [0.46-0.79], p=0.003 unadjusted) which remained significant after adjusting for sex, NYHA class, right ventricular dysfunction and atrial fibrillation (HR 0.39 [0.26-0.59], p<0.0001) and after further adjustment for mitral regurgitation and pacemaker/defibrillator (HR 0.35 [0.23.54], p<0.0001).
Conclusions
In this propensity matched case-control study, TTVI is associated with greater survival and reduced HF rehospitalization compared with medical therapy alone. Randomized trials should be performed to confirm these results.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 24 Sep 2019; epub ahead of print
Taramasso M, Benfari G, van der Bijl P, Alessandrini H, ... Enriquez-Sarano M, Maisano F
J Am Coll Cardiol: 24 Sep 2019; epub ahead of print | PMID: 31568868
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Abstract

Novel Transcatheter Mitral Valve Prosthesis for Patients With Severe Mitral Annular Calcification.

Sorajja P, Gössl M, Babaliaros V, Rizik D, ... Cavalcante JL, Sun B
Background
Treatment of mitral regurgitation (MR) in the setting of severe mitral annular calcification (MAC) is challenging due to the high risk for fatal atrioventricular groove disruption and significant paravalvular leak.
Objectives
The objective of this study was to evaluate the potential for transcatheter mitral valve replacement in patients with severe MAC using an anatomically designed mitral prosthesis.
Methods
Nine patients (77 ± 6 years of age; 5 men) were treated with the valve, using transapical delivery performed under general anesthesia and with guidance from transesophageal echocardiography and fluoroscopy.
Results
Device implantation was successful with relief of MR in all 9 patients. There were no procedural deaths. In 1 patient, left ventricular outflow tract obstruction occurred due to malrotation of the prosthesis, and successful alcohol septal ablation was performed. During a median follow-up of 12 months (range 1 to 28 months), there was 1 cardiac death, 1 noncardiac death, no other mortality, and no prosthetic dysfunction, and MR remained absent in all treated patients. Rehospitalization for heart failure occurred in 2 patients who did not die subsequently. Clinical improvement with mild or no symptoms occurred in all patients alive at the end of follow-up.
Conclusions
Transcatheter mitral valve replacement in severe mitral annular calcification with a dedicated prosthesis is feasible and can result in MR relief with symptom improvement. Further evaluation of this approach for these high-risk patients is warranted.

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

J Am Coll Cardiol: 17 Sep 2019; 74:1431-1440
Sorajja P, Gössl M, Babaliaros V, Rizik D, ... Cavalcante JL, Sun B
J Am Coll Cardiol: 17 Sep 2019; 74:1431-1440 | PMID: 31514943
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Abstract

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

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

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

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

Transcatheter Mitral Valve Replacement in Patients with Heart Failure and Secondary Mitral Regurgitation: From COAPT Trial.

Asch FM, Grayburn PA, Siegel RJ, Kar S, ... Weissman NJ,
Background
In the COAPT trial among patients with heart failure (HF) and moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation (SMR), patients treated with the transcatheter mitral valve replacement (TMVR) had reduced rates of HF hospitalization and mortality compared with guideline-directed medical therapy (GDMT) alone.
Objectives
To describe the echocardiographic patient qualification process for COAPT, baseline echocardiographic characteristics, changes over time, and the interaction between treatment group and echocardiographic parameters on clinical outcomes.
Methods
A novel echocardiographic algorithm was implemented for grading MR severity during the screening process. Standardized echocardiograms were obtained at baseline and during regular follow-up intervals through 2 years, and analyzed by a core laboratory.
Results
A total of 614 patients were randomized to TMVR plus maximally- tolerated GDMT or GDMT alone. Mean baseline left ventricular ejection fraction (LVEF) was 31.3±9.3%, LV end-diastolic volume was 192.7±71 ml, and effective regurgitant orifice area was 0.41±0.15 cm. The beneficial effect of TMVR compared with GDMT alone was consistent in all echocardiographic subgroups, independent of the severity of LV dysfunction, LV dilatation, pulmonary hypertension, severity of tricuspid regurgitation or individual MR characteristics. The LVEF decreased and the LV volumes progressively increased in both groups during follow-up, although less after TMVR (P<0.05).
Conclusions
HF patients in the COAPT trial with 3+ or 4+ SMR, selected using strict echocardiographic criteria, benefitted from TMVR with reduced 2-year rates of death and HF hospitalization. Strict application of these echocardiographic criteria should enable the COAPT results to be translated to clinical practice.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 19 Sep 2019; epub ahead of print
Asch FM, Grayburn PA, Siegel RJ, Kar S, ... Weissman NJ,
J Am Coll Cardiol: 19 Sep 2019; epub ahead of print | PMID: 31574303
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Abstract

Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use.

van der Wal HH, Grote Beverborg N, Dickstein K, Anker SD, ... Voors AA, van der Meer P
Aims
Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort.
Methods and results
We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation <20%. Univariable and multivariable logistic regression models were constructed to identify determinants for ID. We measured 92 cardiovascular markers (Olink Cardiovascular III) to establish a biomarker profile of ID. The primary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard deviation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (+interquartile range) were 4305 (2360-8329) ng/L. Iron deficiency was present in 1453 patients (61.6%), with highest prevalence in females (71.1% vs. 58.3%; P < 0.001). Independent determinants of ID were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein levels, lower serum albumin levels, and P2Y12 inhibitor use (all P < 0.05). None of these determinants were sex-specific. The biomarker profile of ID largely consisted of pro-inflammatory markers, including paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase type 5. In multivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of predictors of ID (hazard ratio 1.25, 95% confidence interval 1.06-1.46; P = 0.007).
Conclusion
Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets).

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

Eur Heart J: 25 Sep 2019; epub ahead of print
van der Wal HH, Grote Beverborg N, Dickstein K, Anker SD, ... Voors AA, van der Meer P
Eur Heart J: 25 Sep 2019; epub ahead of print | PMID: 31556953
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Abstract

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

Goldenberg I, Huang DT, Nielsen JC

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

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

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

Sudden death in cardiac sarcoidosis: an analysis of nationwide clinical and cause-of-death registries.

Ekström K, Lehtonen J, Nordenswan HK, Mäyränpää MI, ... Kerola T, Kupari M
Aims
The present study was done to assess the role of sudden cardiac death (SCD) among the presenting manifestations of and fatalities from cardiac sarcoidosis (CS).
Methods and results
We analysed altogether 351 cases of CS presenting from year 1998 through 2015 in Finland. There were 262 patients with a clinical diagnosis and treatment of CS, 27 patients with an initial lifetime diagnosis of giant cell myocarditis that was later converted to CS, and 62 cases detected at autopsy and identified by screening >820 000 death certificates from the national cause-of-death registry. The total case series comprised 253 females and 98 males aged on average 52 years at presentation. High-grade atrioventricular block was the most common first sign of CS (n = 147, 42%) followed by heart failure (n = 58, 17%), unexpected fatal (n = 38) or aborted (n = 12) SCD (14%), and sustained ventricular tachycardia (n = 48, 14%). Severe coronary artery disease was found at autopsy concomitant with CS in four of the 38 cases presenting with fatal SCD. Of all deaths recorded till the end of 2015, 64% (n = 54/84) were unexpected SCDs from CS that had either been silent during life or defied all attempts at diagnosis. The Kaplan-Meier estimate (95% CI) of survival from symptom onset was 85% (80-90%) at 5 years and 76% (68-84%) at 10 years.
Conclusion
Together fatal and aborted SCD constitute 14% of the presenting manifestations of CS. Nearly two-thirds of all fatalities from CS are caused by undiagnosed granulomas in the heart.

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

Eur Heart J: 30 Sep 2019; 40:3121-3128
Ekström K, Lehtonen J, Nordenswan HK, Mäyränpää MI, ... Kerola T, Kupari M
Eur Heart J: 30 Sep 2019; 40:3121-3128 | PMID: 31230070
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Abstract

Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.

Gigli M, Merlo M, Graw SL, Barbati G, ... Sinagra G, Mestroni L
Background
Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood.
Objectives
The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients.
Methods
A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF).
Results
A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction.
Conclusions
Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.

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

J Am Coll Cardiol: 17 Sep 2019; 74:1480-1490
Gigli M, Merlo M, Graw SL, Barbati G, ... Sinagra G, Mestroni L
J Am Coll Cardiol: 17 Sep 2019; 74:1480-1490 | PMID: 31514951
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Abstract

Cardiogenic Shock Classification to Predict Mortality in the Cardiac Intensive Care Unit.

Jentzer JC, van Diepen S, Barsness GW, Henry TD, ... Naidu SS, Baran DA
Background
A new 5-stage cardiogenic shock (CS) classification scheme was recently proposed by the Society for Cardiovascular Angiography and Intervention (SCAI) for the purpose of risk stratification.
Objectives
This study sought to apply the SCAI shock classification in a cardiac intensive care unit (CICU) population.
Methods
The study retrospectively analyzed Mayo Clinic CICU patients admitted between 2007 and 2015. SCAI CS stages A through E were classified retrospectively using CICU admission data based on the presence of hypotension or tachycardia, hypoperfusion, deterioration, and refractory shock. Hospital mortality in each SCAI shock stage was stratified by cardiac arrest (CA).
Results
Among the 10,004 unique patients, 43.1% had acute coronary syndrome, 46.1% had heart failure, and 12.1% had CA. The proportion of patients in SCAI CS stages A through E was 46.0%, 30.0%, 15.7%, 7.3%, and 1.0% and unadjusted hospital mortality in these stages was 3.0%, 7.1%, 12.4%, 40.4%, and 67.0% (p < 0.001), respectively. After multivariable adjustment, each higher SCAI shock stage was associated with increased hospital mortality (adjusted odds ratio: 1.53 to 6.80; all p < 0.001) compared with SCAI shock stage A, as was CA (adjusted odds ratio: 3.99; 95% confidence interval: 3.27 to 4.86; p < 0.001). Results were consistent in the subset of patients with acute coronary syndrome or heart failure.
Conclusions
When assessed at the time of CICU admission, the SCAI CS classification, including presence or absence of CA, provided robust hospital mortality risk stratification. This classification system could be implemented as a clinical and research tool to identify, communicate, and predict the risk of death in patients with, and at risk for, CS.

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

J Am Coll Cardiol: 17 Sep 2019; epub ahead of print
Jentzer JC, van Diepen S, Barsness GW, Henry TD, ... Naidu SS, Baran DA
J Am Coll Cardiol: 17 Sep 2019; epub ahead of print | PMID: 31548097
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Abstract

Nurse-led vs. usual-care for atrial fibrillation.

Wijtvliet EPJP, Tieleman RG, van Gelder IC, Pluymaekers NAHA, ... Tijssen JG, Crijns HJGM
Background
Nurse-led integrated care is expected to improve outcome of patients with atrial fibrillation compared with usual-care provided by a medical specialist.
Methods and results
We randomized 1375 patients with atrial fibrillation (64 ± 10 years, 44% women, 57% had CHA2DS2-VASc ≥ 2) to receive nurse-led care or usual-care. Nurse-led care was provided by specialized nurses using a decision-support tool, in consultation with the cardiologist. The primary endpoint was a composite of cardiovascular death and cardiovascular hospital admissions. Of 671 nurse-led care patients, 543 (81%) received anticoagulation in full accordance with the guidelines against 559 of 683 (82%) usual-care patients. The cumulative adherence to guidelines-based recommendations was 61% under nurse-led care and 26% under usual-care. Over 37 months of follow-up, the primary endpoint occurred in 164 of 671 patients (9.7% per year) under nurse-led care and in 192 of 683 patients (11.6% per year) under usual-care [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.69 to 1.04, P = 0.12]. There were 124 vs. 161 hospitalizations for arrhythmia events (7.0% and 9.4% per year), and 14 vs. 22 for heart failure (0.7% and 1.1% per year), respectively. Results were not consistent in a pre-specified subgroup analysis by centre experience, with a HR of 0.52 (95% CI 0.37-to 0.71) in four experienced centres and of 1.24 (95% CI 0.94-1.63) in four less experienced centres (P for interaction <0.001).
Conclusion
Our trial failed to show that nurse-led care was superior to usual-care. The data suggest that nurse-led care by an experienced team could be clinically beneficial (ClinicalTrials.gov NCT01740037).
Trial registration number
ClinicalTrials.gov (NCT01740037).

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

Eur Heart J: 22 Sep 2019; epub ahead of print
Wijtvliet EPJP, Tieleman RG, van Gelder IC, Pluymaekers NAHA, ... Tijssen JG, Crijns HJGM
Eur Heart J: 22 Sep 2019; epub ahead of print | PMID: 31544925
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Abstract

The neurohormonal basis of pulmonary hypertension in heart failure with preserved ejection fraction.

Obokata M, Kane GC, Reddy YNV, Melenovsky V, ... Jarolim P, Borlaug BA
Aims
Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve.
Methods and results
Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s\' and e\' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e\', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001).
Conclusion
Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype.
Clinical trial registration
NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.

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

Eur Heart J: 11 Sep 2019; epub ahead of print
Obokata M, Kane GC, Reddy YNV, Melenovsky V, ... Jarolim P, Borlaug BA
Eur Heart J: 11 Sep 2019; epub ahead of print | PMID: 31513270
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Abstract

Quality of life predicting long-term outcomes in cardiac resynchronization therapy patients.

Nagy KV, Merkely B, Rosero S, Geller L, ... Zareba W, Kutyifa V
Aims
While improvement in quality of life (QoL) has been widely reported in cardiac resynchronization therapy (CRT) patients, its predictive value is not well-understood. We aimed to assess the predictive role of baseline QoL on long-term heart failure (HF) or death events in mild HF patients enrolled in Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT).
Methods and results
A total of 1791 of 1820 patients had their QoL evaluated at baseline, using the EuroQol-5 dimensions (EQ-5D) and the Kansas City Cardiomyopathy Questionnaires (KCCQ). Kaplan-Meier survival analyses and multivariate Cox models were utilized. Issues within any of the domains of the baseline EQ-5D questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were associated with long-term mortality (median follow-up 5.6 years) (all P < 0.05). Heart failure or death events were predicted by issues in baseline mobility [hazard ratio (HR) = 1.41, P < 0.001], usual activities (HR = 1.41, P < 0.001), and anxiety/depression (HR = 1.21, P = 0.035). The risk of HF events alone was significantly higher in patients with baseline mobility issues (HR = 1.42, P < 0.001) or usual activity (HR = 1.35, P = 0.003). Every 10% increase in the visual analogue scale (0-100) was associated with an 8% lower risk of all-cause mortality (P = 0.006), and a 6% lower risk of HF/death (P = 0.002). Mobility issues also predicted echocardiographic reverse remodelling (-33.08 mL vs. -31.17 mL, P = 0.043). Using the KCCQ, patients in the lower tertile of the clinical summary or physical limitations score had a significantly higher risk of long-term HF or death (P < 0.05).
Conclusion
In mild HF patients enrolled in MADIT-CRT, multiple baseline QoL questionnaire domains were predictors of echocardiographic remodelling, long-term all-cause mortality, and HF events.

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

Europace: 15 Oct 2019; epub ahead of print
Nagy KV, Merkely B, Rosero S, Geller L, ... Zareba W, Kutyifa V
Europace: 15 Oct 2019; epub ahead of print | PMID: 31617896
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Abstract

Natriuretic Peptide Response and Outcomes in Chronic Heart Failure With Reduced Ejection Fraction.

Januzzi JL, Ahmad T, Mulder H, Coles A, ... Felker GM, O\'Connor CM
Background
The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial demonstrated that a strategy to \"guide\" application of guideline-directed medical therapy (GDMT) by reducing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not superior to GDMT alone.
Objectives
The purpose of this study was to examine the prognostic meaning of NT-proBNP changes following heart failure (HF) therapy intensification relative to the goal NT-proBNP value of 1,000 pg/ml explored in the GUIDE-IT trial.
Methods
A total of 638 study participants were included who were alive and had available NT-proBNP results 90 days after randomization. Rates of subsequent cardiovascular (CV) death/HF hospitalization or all-cause mortality during follow-up and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores were analyzed.
Results
A total of 198 (31.0%) subjects had an NT-proBNP ≤1,000 pg/ml at 90 days with no difference in achievement of NT-proBNP goal between the biomarker-guided and usual care arms. NT-proBNP ≤1,000 pg/ml by 90 days was associated with longer freedom from CV/HF hospitalization or all-cause mortality (p < 0.001 for both) and lower adjusted hazard of subsequent HF hospitalization/CV death (hazard ratio: 0.26; 95% confidence interval: 0.15 to 0.46; p < 0.001) and all-cause mortality (hazard ratio: 0.34; 95% confidence interval: 0.15 to 0.77; p = 0.009). Regardless of elevated baseline concentration, an NT-proBNP ≤1,000 pg/ml at 90 days was associated with better outcomes and significantly better KCCQ overall scores (p = 0.02).
Conclusions
Patients with heart failure with reduced ejection fraction whose NT-proBNP levels decreased to ≤1,000 pg/ml during GDMT had better outcomes. These findings may help to understand the results of the GUIDE-IT trial. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

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

J Am Coll Cardiol: 03 Sep 2019; 74:1205-1217
Januzzi JL, Ahmad T, Mulder H, Coles A, ... Felker GM, O'Connor CM
J Am Coll Cardiol: 03 Sep 2019; 74:1205-1217 | PMID: 31466618
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Abstract

Prognostic Value of F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Infective Endocarditis.

San S, Ravis E, Tessonier L, Philip M, ... Drancourt M, Habib G
Background
F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) is commonly used for the diagnosis of infective endocarditis (IE), but its prognostic value remains unknown.
Objectives
This study sought to assess the prognostic value of F-FDG PET/CT in prosthetic valve endocarditis (PVE) and native valve endocarditis (NVE).
Methods
This study prospectively included 173 consecutive patients (109 PVE and 64 NVE) with definite left-sided IE who had an F-FDG PET/CT and were followed-up for 1 year. The primary endpoint was a composite of major cardiac events: death, recurrence of IE, acute cardiac failure, nonscheduled hospitalization for cardiovascular indication, and new embolic event.
Results
F-FDG PET/CT was positive in 100 (58%) patients, 83% (n = 90 of 109) in the PVE, and 16% (n = 10 of 64) in the NVE group. At a mean follow-up of 225 days (interquartile range: 199 to 251 days), the primary endpoint occurred in 94 (54%) patients: 63 (58%) in the PVE group and 31 (48%) in the NVE group. In the PVE group, positive F-FDG PET/CT was significantly associated with a higher rate of primary endpoint (hazard ratio [HR]: 2.7; 95% confidence interval [CI]: 1.1 to 6.7; p = 0.04). Moderate to intense F-FDG valvular uptake was also associated with worse outcome (HR: 2.3; 95% CI: 1.3 to 4.5; p = 0.03) and to new embolic events in PVE (HR: 7.5; 95% CI: 1.24 to 45.2; p = 0.03) and in NVE (HR: 8.8; 95% CI: 1.1 to 69.5; p = 0.02). In the NVE group, F-FDG PET/CT was not associated with occurrence of the primary endpoint Conclusions: In addition to its good diagnostic performance, F-FDG PET/CT is predictive of major cardiac events in PVE and new embolic events within the first year following IE.

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

J Am Coll Cardiol: 27 Aug 2019; 74:1031-1040
San S, Ravis E, Tessonier L, Philip M, ... Drancourt M, Habib G
J Am Coll Cardiol: 27 Aug 2019; 74:1031-1040 | PMID: 31439211
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Abstract

Biomarkers and Clinical Cardiovascular Outcomes With Ezetimibe in the IMPROVE-IT Trial.

Qamar A, Giugliano RP, Bohula EA, Park JG, ... Braunwald E, Morrow DA
Background
Addition of ezetimibe to statin therapy reduces the risk of recurrent cardiovascular (CV) events in patients with prior acute coronary syndrome (ACS). The role of biomarkers in identifying subsets of patients who may derive greater clinical benefit with ezetimibe is unknown.
Objectives
This study sought to evaluate the role of established CV biomarkers in assessing likely benefit with ezetimibe added to statin therapy in post-ACS patients.
Methods
In a pre-specified nested analysis within a randomized, double-blind trial of ezetimibe/simvastatin versus placebo/simvastatin (IMPROVE-IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, growth-differentiation factor-15, and high-sensitivity C-reactive protein was measured in 7,195 patients stabilized (1 month post-randomization) after ACS. A multimarker approach based on biomarker values was used to examine the risk of recurrent CV events and clinical benefit with ezetimibe.
Results
Elevated levels of each biomarker were independently associated with higher risks of CV death/myocardial infarction/stroke and CV death/heart failure (p < 0.001 for each). There was a pattern of greater absolute risk reduction in CV death/myocardial infarction/stroke with the addition of ezetimibe to statin therapy in patients at higher risk on the basis of biomarker levels. High-risk patients (≥3 biomarkers \"positive\"; n = 1,437) had an absolute risk difference of -7.3% (95% confidence interval: -13.8% to -0.8%; p = 0.02) with ezetimibe, and intermediate-risk patients (1 to 2 biomarkers positive; n = 3,842) had an absolute risk difference of -4.4% (95% confidence interval: -9.7% to 0.8%), translating into numbers needed to treat at 7 years of 14 and 23, respectively. Low-risk patients (0 biomarkers positive; n = 1,916) did not appear to benefit from the addition of ezetimibe to statin therapy.
Conclusions
A biomarker-based strategy identifies a gradient of risk among patients post-ACS, offering the potential to identify higher-risk patients with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy.

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

J Am Coll Cardiol: 27 Aug 2019; 74:1057-1068
Qamar A, Giugliano RP, Bohula EA, Park JG, ... Braunwald E, Morrow DA
J Am Coll Cardiol: 27 Aug 2019; 74:1057-1068 | PMID: 31439215
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Abstract

Cardiomyocyte HIPK2 Maintains Basal Cardiac Function via ERK Signaling.

Guo Y, Sui JY, Kim K, Zhang Z, ... Force T, Lal H

Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown.We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction-suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology.studies with neonatal rat ventricular cardiomyocytes corroborated thefindings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers,and , at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts.rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling.



Circulation: 03 Oct 2019; epub ahead of print
Guo Y, Sui JY, Kim K, Zhang Z, ... Force T, Lal H
Circulation: 03 Oct 2019; epub ahead of print | PMID: 31581792
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Abstract

How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Pieske B, Tschöpe C, de Boer RA, Fraser AG, ... Seferovic P, Filippatos G

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the \'HFA-PEFF diagnostic algorithm\'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e\'), left ventricular (LV) filling pressure estimated using E/e\', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

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

Eur Heart J: 30 Aug 2019; epub ahead of print
Pieske B, Tschöpe C, de Boer RA, Fraser AG, ... Seferovic P, Filippatos G
Eur Heart J: 30 Aug 2019; epub ahead of print | PMID: 31504452
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Impact:
Abstract

Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry.

Sorbets E, Fox KM, Elbez Y, Danchin N, ... Vidal-Petiot E, Steg PG
Aims
Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants.
Methods and results
Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7-8.3] overall [male 8.1% (7.8-8.5); female 7.6% (7.0-8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9-12.9) vs. 8.2% (95% CI 7.8-8.7) in patients with no angina, P < 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4-7.3)] or without angina [6.4% (95% CI 5.9-7.0)], P > 0.99. Prescription rates of evidence-based secondary prevention therapies were high.
Conclusion
This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment.
Clinical registry
ISRCTN43070564.

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

Eur Heart J: 02 Sep 2019; epub ahead of print
Sorbets E, Fox KM, Elbez Y, Danchin N, ... Vidal-Petiot E, Steg PG
Eur Heart J: 02 Sep 2019; epub ahead of print | PMID: 31504434
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Impact:
Abstract

Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME® trial.

Fitchett D, Inzucchi SE, Wanner C, Mattheus M, ... Zinman B, Johansen OE
Aims
Hypoglycaemia, in patients with Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular (CV) events. In EMPA-REG OUTCOME, the sodium-glucose co-transporter-2 inhibitor empagliflozin reduced the risk of CV death by 38% and heart failure hospitalization (HHF) by 35%, while decreasing glycated haemoglobin (HbA1c) without increasing hypoglycaemia. We investigated CV outcomes in patients with hypoglycaemia during the trial and the impact of hypoglycaemia on the treatment effect of empagliflozin.
Methods and results
About 7020 patients with T2D (HbA1c 7-10%) were treated with empagliflozin 10 or 25 mg, or placebo and followed for median 3.1 years. The relationship between on-trial hypoglycaemia and CV outcomes, and effects of empagliflozin on outcomes by incident hypoglycaemia [HYPO-broad: symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia, and HYPO-strict: hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia] was investigated using adjusted Cox regression models with time-varying covariates for hypoglycaemia and interaction with treatment. HYPO-broad occurred in 28% in each group and HYPO-strict in 19%. In the placebo group, hypoglycaemia was associated with an increased risk of HHF for both HYPO-broad [hazard ratio (HR, 95% confidence interval, CI) 1.91 (1.25-2.93)] and HYPO-strict [1.72 (1.06-2.78)]. HYPO-broad (but not HYPO-strict) was associated with an increased risk of myocardial infarction (MI) [HR 1.56 (1.06-2.29)]. Empagliflozin improved CV outcomes, regardless of occurrence of hypoglycaemia (P-for interactions >0.05).
Conclusion
In this post hoc exploratory analysis, hypoglycaemia was associated with an increased risk of HHF and MI. Hypoglycaemia risk was not increased with empagliflozin and incident hypoglycaemia did not attenuate its cardio-protective effects.

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

Eur Heart J: 30 Aug 2019; epub ahead of print
Fitchett D, Inzucchi SE, Wanner C, Mattheus M, ... Zinman B, Johansen OE
Eur Heart J: 30 Aug 2019; epub ahead of print | PMID: 31504427
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Impact:
Abstract

Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1β inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis.

Ridker PM, MacFadyen JG, Thuren T, Libby P
Aims
The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis.
Methods and results
Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6.
Conclusion
There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors).
Clinical trial registration
ClinicalTrials.gov NCT01327846.

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: 31 Aug 2019; epub ahead of print
Ridker PM, MacFadyen JG, Thuren T, Libby P
Eur Heart J: 31 Aug 2019; epub ahead of print | PMID: 31504417
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Impact:
Abstract

Incidence of heart failure after pacemaker implantation: a nationwide Danish Registry-based follow-up study.

Tayal B, Fruelund P, Sogaard P, Riahi S, ... Kober L, Kragholm KH
Aims
The objective of the current study is to investigate the risk of heart failure (HF) after implantation of a pacemaker (PM) with a right ventricular pacing (RVP) lead in comparison to a matched cohort without a PM and factors associated with this risk.
Methods and results
All patients without a known history of HF who had a PM implanted with an RVP lead between 2000 and 2014 (n = 27 704) were identified using Danish nationwide registries. An age- and gender-matched control cohort (matched 1:5, n = 138 520) without PM and HF was identified to compare the risk. Outcome was the cumulative incidence of HF including fatal HF within the first 2 years of PM implantation, with all-cause mortality and myocardial infarction (MI) as competing risks. Due to violation of proportional hazards, the follow-up period was divided into three time-intervals: <30 days, 30-180 days, and >180 days-2 years. The cumulative incidence of HF including fatal HF was observed in 2937 (10.6%) PM patients. Risks for the three time-intervals were <30 days [hazard ratio (HR) 5.98, 95% CI 5.19-6.90], 30-180 days (HR 1.84, 95% CI 1.71-1.98), and >180 days (HR 1.11, 95% CI 1.04-1.17). Among patients with a PM device, factors associated with increased risk of HF were male sex (HR 1.33, 95% CI 1.24-1.43), presence of chronic kidney disease (CKD) (HR 1.64, 95% CI 1.29-2.09), and prior MI (1.77, 95% 1.50-2.09).
Conclusions
Pacemaker with an RVP lead is strongly associated with risk of HF specifically within the first 6 months. Patients with antecedent history of MI and CKD had substantially increased 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: 25 Aug 2019; epub ahead of print
Tayal B, Fruelund P, Sogaard P, Riahi S, ... Kober L, Kragholm KH
Eur Heart J: 25 Aug 2019; epub ahead of print | PMID: 31504437
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Impact:
Abstract

Protein Kinase N Promotes Stress-Induced Cardiac Dysfunction Through Phosphorylation of Myocardin-Related Transcription Factor A and Disruption of its Interaction with Actin.

Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, ... Kaibuchi K, Murohara T

Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear.To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line withandmice and applied a mouse model of transverse aortic constriction (TAC)- and angiotensin II (AngII)-induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA.We demonstrated that RHOA activates two members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encodingand(cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload- and AngII-induced cardiac dysfunction. Further, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK . We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload- and AngII-induced cardiac dysfunction in wild type mice, while cmc-PKN1/2 DKO mice suppressed TAC- and AngII-induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with G-actin by phosphorylating MRTFA, causing increased serum response factor (SRF)-mediated expression of cardiac hypertrophy- and fibrosis-associated genes.Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.



Circulation: 29 Sep 2019; epub ahead of print
Sakaguchi T, Takefuji M, Wettschureck N, Hamaguchi T, ... Kaibuchi K, Murohara T
Circulation: 29 Sep 2019; epub ahead of print | PMID: 31564129
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Impact:
Abstract

miRNA-Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post-MI Remodeling by Sleep Breathing Disorders.

Du Y, Wang X, Li LY, Hao W, ... Wei YX, Ma XL

Obstructive sleep apnea (OSA), a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown.To determine whether CIH exposure at different periods of MI may exacerbate post-MI heart failure and to identify the mechanisms underlying CIH-exacerbated post-MI remodeling.Adult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH prior to MI (CIH+MI) had no significant effect upon post-MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathologic remodeling and reduced survival rate. Mechanistically, CIH activated TGF-beta/Smad signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post-MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI),(a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Rt-PCR/Western analysis confirmed that cardiomyocyteexpression was significantly reduced in MI+CIH mice. RNA-seq, Rt-PCR, and dual-luciferase reporter assays identified that miR-214-3p is a noveltargeting miRNA. Its upregulation is responsible forgene suppression in MI+CIH. Finally, AAV9-mediated cardiac-specificoverexpression or rCTRP9 administration inhibited TGF-beta/Smad and Wnt/β-catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals.This study provides the first evidence that MI+CIH upregulates miR-214-3p, suppresses cardiac CTRP9 expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in MI patients with OSA.



Circ Res: 06 Nov 2019; epub ahead of print
Du Y, Wang X, Li LY, Hao W, ... Wei YX, Ma XL
Circ Res: 06 Nov 2019; epub ahead of print | PMID: 31694459
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Impact:
Abstract

Mortality Assessment of Paclitaxel-Coated Balloons: Patient-Level Meta-Analysis of the ILLUMENATE Clinical Program at 3 Years.

Gray WA, Jaff MR, Parikh SA, Ansel GM, ... Adelman MA, Lyden SP
Background
A recent summary-level meta-analysis comprising randomized, controlled trials (RCTs) of femoropopliteal paclitaxel-coated balloon and stent intervention identified excess late mortality in the paclitaxel-treated patients.
Methods
We evaluated the safety of the Stellarex drug-coated balloon (DCB) for femoropopliteal artery disease with an independently performed meta-analysis of patient-level data from all patients in the Stellarex femoropopliteal clinical program. To compare mortality after DCB or uncoated percutaneous transluminal angioplasty (PTA), we aggregated data from 2 RCTs comprising 419 patients treated with DCB and 170 patients treated with PTA. In an additional analysis, data were aggregated from 6 poolable Stellarex DCB studies (2 RCTs, 3 single-arm studies, and 1 registry). All serious adverse events including deaths were adjudicated by a blinded, third-party, independent Clinical Events Committee. Kaplan-Meier estimates in the RCTs were compared with restricted mean survival time. Predictors of death were assessed with hazard ratios (HRs) and Cox proportional hazards modeling.
Results
Baseline characteristics were similar in the patients treated with DCB and PTA in the pooled RCT analysis, with the exception that the DCB cohort was younger (67.4±9.7 versus 69.4±9.4 years, =0.02), smoked more frequently (86.6% versus 78.8%, =0.02), and were less often treated for recurrent lesions (8.8% versus 14.7%, =0.04). In the RCTs, patients treated with DCB had all-cause mortality rates that were not different from those of patients treated with PTA (Kaplan-Meier estimates 1.8±0.7% versus 1.3±0.9%, 6.5±1.2% versus 5.9±1.9%, and 9.3±1.5% versus 9.9±2.4% at 1, 2, and 3 years, respectively, =0.86). All-cause mortality rates were similar in a 1906-patient pooled nonrandomized DCB data set (Kaplan-Meier estimates of 2.1%, 4.9%, and 7.0% at 1, 2, and 3 years, respectively). Clinical Events Committee-adjudicated causes of death were balanced between the DCB and PTA cohorts. Multivariable Cox modeling identified age (HR, 1.06; 95% CI, 1.04-1.08; <0.001), diabetes mellitus (HR, 1.42; 95% CI, 1.01-2.00; =0.04), congestive heart failure (HR, 1.88; 95% CI, 1.12-3.16; =0.02), and renal insufficiency (HR, 2.00; 95% CI, 1.33-3.01; <0.001) as predictors of mortality. Paclitaxel exposure was unrelated to mortality (HR, 1.04; 95% CI, 0.98-1.10; =0.23).
Conclusions
The mortality rates for patients treated with the DCB and uncoated PTA were indistinguishable over 3-year follow-up. Additional patient-level, adequately powered meta-analyses with larger RCT data sets will be needed to confirm the generalizability of these findings.
Clinical trial registration
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110524, NCT01858363, NCT01858428, NCT03421561, NCT01912937, NCT01927068, and NCT02769273.



Circulation: 29 Sep 2019; 140:1145-1155
Gray WA, Jaff MR, Parikh SA, Ansel GM, ... Adelman MA, Lyden SP
Circulation: 29 Sep 2019; 140:1145-1155 | PMID: 31567024
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Impact:
Abstract

Human Immunodeficiency Virus Infection and Risk of Heart Failure Rehospitalizations.

Brouch D, Tashtish N, Di Felice C, Longenecker CT, Al-Kindi SG

Human Immunodeficiency Infection (HIV) is associated with increased risk for heart failure (HF). Outcomes of HF in patients living with HIV (PWH) are poorly understood. We sought to identify the risk of HF rehospitalizations (30 and 90 days) among PWH versus uninfected controls admitted with HF. Using the 2016 Nationwide Readmissions Database, we identified all patients (≥18 years) who were discharged alive with a primary diagnosis of HF (ICD10 I50.xx) with or without secondary diagnosis of HIV (ICD 10 Z21, B20, O98.7, or B97.35). Propensity score matching was used to match PWH with controls (1:1) based on 45 patient characteristics (demographics, hospitalization characteristics, and co-morbidities). Cox regression models were used to compare rates of HF rehospitalization (primary ICD10 I50.xx) within 30 and 90 days after discharge from the index HF hospitalization. A total of 312,264 patients with HF were identified, of whom 1,112 (0.4%) had HIV. After propensity score matching, 1,112 PWH were matched with 1,112 uninfected controls. The standard mean difference for each variable was <10% postmatching. Overall, HF rehospitalization rates were 11.2% and 19.2% at 30 and 90 days, respectively. The 2 groups (PWH and controls) were not different statistically with respect to all 45 covariates. Compared with controls, PWH had a higher risk of HF rehospitalization within 30 days (hazard ratio 1.45, 95% confidence interval 1.13 to 1.87, p = 0.004) and 90 days (hazard ratio 1.41, 95% CI 1.16 to 1.71, p <0.001). This risk was consistent across age groups, gender, types of HF, presence or absence of coronary artery disease, or chronic kidney disease. In conclusion, in this propensity-matched national cohort of patients admitted with HF, patients with HIV had increased risk of HF rehospitalizations compared with uninfected controls at 30 days and 90 days.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Oct 2019; 124:1232-1238
Brouch D, Tashtish N, Di Felice C, Longenecker CT, Al-Kindi SG
Am J Cardiol: 14 Oct 2019; 124:1232-1238 | PMID: 31537297
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Impact:
Abstract

Short-term decrease of left atrial size predicts clinical outcome in patients with severe aortic stenosis undergoing TAVR.

De Rosa R, Murray MI, Schranz D, Mas-Peiro S, ... Fichtlscherer S, Vasa-Nicotera M
Objectives
We investigated whether transcatheter aortic valve replacement (TAVR) results in a short-term decrease in left atrium (LA) size and whether such decrease may predict patients\' clinical outcome.
Background
Increased LA size is a hallmark of severe aortic stenosis (AS) and is associated with adverse patients\' cardiovascular outcome. Whether TAVR may lead to a decrease in LA size is not known.
Methods and results
Hundred and four patients with severe symptomatic AS and dilated LA undergoing TAVR were enrolled. LA volume was assessed by echocardiography before and shortly after TAVR (median time: 7 days). Composite rate of death and hospitalization for acutely decompensated heart failure (HF) was recorded and clinical status was assessed through NYHA-class evaluation at 12 months median follow-up. After TAVR, 49 patients (47%) demonstrated a decrease in LA volume. Despite a similar baseline NYHA class, patients with decrease in LA size had significant better improvement in clinical status respect to patients with unvaried LA size (NYHA post: 1.2 ± 0.6 vs. 1.8 ± 1.1, p = .001; NYHA reduction: -1.6 ± 0.9 vs. -0.9 ± 1.0, p = .002, respectively). Moreover, these patients had a significantly reduced rate of death or HF-hospitalization (4 vs. 29%, p = .001) and a significantly longer event-free-survival from Kaplan-Meier curves (p = .003). COX regression analysis showed that, among echocardiographic parameters, decrease in LA size was an independent predictor of clinical outcome (HR: 0.149, CI: 0.034-0.654, p = .012).
Conclusions
The lack of decrease in LA size shortly after TAVR is associated with significantly higher rates of death and HF-hospitalization, as well as with impaired improvement in clinical status during long-term follow-up.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 20 Oct 2019; epub ahead of print
De Rosa R, Murray MI, Schranz D, Mas-Peiro S, ... Fichtlscherer S, Vasa-Nicotera M
Catheter Cardiovasc Interv: 20 Oct 2019; epub ahead of print | PMID: 31631509
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Impact:
Abstract

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β.

Padrón-Barthe L, Villalba-Orero M, Gómez-Salinero JM, Domínguez F, ... Garcia-Pavia P, Lara-Pezzi E
Background
Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5.
Methods
We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter.
Results
We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition.
Conclusions
Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.



Circulation: 29 Sep 2019; 140:1188-1204
Padrón-Barthe L, Villalba-Orero M, Gómez-Salinero JM, Domínguez F, ... Garcia-Pavia P, Lara-Pezzi E
Circulation: 29 Sep 2019; 140:1188-1204 | PMID: 31567019
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Impact:
Abstract

Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared with Valsartan in HFpEF.

Vaduganathan M, Claggett BL, Desai AS, Anker SD, ... McMurray JJV, Solomon SD
Background
The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death.
Objectives
To determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to HF hospitalization among patients with HF and preserved ejection fraction (HFpEF).
Methods
In this post hoc analysis of PARAGON-HF, we assessed risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). Primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed using a semiparametric proportional rates method, stratified by geographic region.
Results
Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31-90 days, 435 (9%) within 91-180 days, 694 (14%) after 180 days, and 2,490 (52%) were never previously hospitalized. Over median 35 months follow-up, risk of total HF hospitalizations and cardiovascular death was inversely and non-linearly associated with timing from prior HF hospitalization (P<0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio 0.73; 95% confidence interval 0.53-0.99) to patients never hospitalized (rate ratio 1.00; 95% confidence interval 0.80-1.24); trend in relative risk reduction P=0.15. With valsartan alone, rate of total primary events was 26.7 (≤30 days), 24.2 (31-90 days), 20.7 (91-180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31-90 days), 3.4% (91-180 days), while no risk reduction was observed in patients screened >180 days or who were never hospitalized; trend in absolute risk reduction P=0.050.
Conclusions
Recent hospitalization for HFpEF identifies patients at high-risk for near-term clinical progression. In the PARAGON-HF trial, relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrants prospective validation.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 05 Nov 2019; epub ahead of print
Vaduganathan M, Claggett BL, Desai AS, Anker SD, ... McMurray JJV, Solomon SD
J Am Coll Cardiol: 05 Nov 2019; epub ahead of print | PMID: 31726194
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Impact:
Abstract

Cost-Effectiveness of Transcatheter Mitral Valve Repair versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation: Results from the COAPT Trial.

Baron SJ, Wang K, Arnold SV, Magnuson EA, ... Cohen DJ,

The COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair (TMVr) using the MitraClip resulted in reduced mortality and heart-failure hospitalizations and improved quality of life when compared with maximally-tolerated guideline-directed medical therapy (GDMT) in heart-failure patients with 3-4+ secondary mitral regurgitation (SMR). Whether TMVr is cost-effective compared with GDMT in this population is unknown.We used data from the COAPT trial to perform a formal, patient-level economic analysis of TMVr + GDMT vs. GDMT alone for patients with heart failure and 3-4+ SMR from the perspective of the US health care system. Costs for the index TMVr hospitalization were assessed using a combination of resource-based accounting and hospital billing data (when available). Follow-up medical care costs were estimated based on medical resource use collected during the COAPT trial. Health utilities were estimated for all patients at baseline, 1, 6, 12 and 24 months using the SF-6D.Initial costs for the TMVr procedure and index hospitalization were $35,755 and $48,198, respectively. Although follow-up costs were significantly lower with TMVr compared with GDMT ($26,654 vs. $38,345; p=0.018), cumulative 2-year costs remained higher with TMVr due to the up-front cost of the index procedure ($73,416 vs. $38,345; p<0.001). When intrial survival, health utilities, and costs were modeled over a lifetime horizon, TMVr was projected to increase life-expectancy by 1.13 years and quality-adjusted life-years (QALYs) by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost-effectiveness ratio of $40,361/life-year gained and $55,600/QALY gained.For symptomatic heart-failure patients with 3-4+ SMR, TMVr increases lifeexpectancy and quality-adjusted life-expectancy compared with GDMT at an incremental cost per QALY gained that represents acceptable economic value based on current U.S. thresholds.URL: https://clinicaltrials.gov Unique Identifier: NCT01626079.



Circulation: 28 Sep 2019; epub ahead of print
Baron SJ, Wang K, Arnold SV, Magnuson EA, ... Cohen DJ,
Circulation: 28 Sep 2019; epub ahead of print | PMID: 31564137
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Impact:
Abstract

Transcatheter aspiration of large pacemaker and implantable cardioverter-defibrillator lead vegetations facilitating safe transvenous lead extraction.

Starck CT, Schaerf RHM, Breitenstein A, Najibi S, ... Dreizler T, Falk V
Aims
Treatment of patients with systemic cardiac implantable electronic device (CIED) infection with large lead vegetations is challenging and associated with relevant morbidity and mortality. To avoid complications from open surgical extraction, a novel approach with percutaneous aspiration of large vegetations prior to transvenous lead extraction was instituted. The results of this treatment concept were retrospectively analysed in this multicentre study.
Methods and results
One hundred and one patients [mean age 68.2 ± 13.1 (30-92) years] were treated in four centres for endovascular CIED infection with large lead vegetations. Mean lead vegetation size was 30.7 ± 13.5 mm. Two hundred and forty-seven leads were targeted for extraction (170 pacemaker leads, 77 implantable cardioverter-defibrillator leads). Mean lead implant duration was 81.7 (1-254) months. The transcatheter aspiration system with a specialized long venous drainage cannula and a funnel-shaped tip was based on a veno-venous extracorporeal circuit with an in-line filter. The aspiration of vegetations showed complete procedural success in 94.0% (n = 95), partial success in 5.0% (n = 5). Three major complications (3.0%) were encountered. Complete procedural success (per lead) of the subsequently performed transvenous lead extraction procedure was 99.2% (n = 245). Thirty-day mortality was 3.0% (n = 3). Five patients (5.0%) died in the further course on Days 51, 54, 68, 134, and 182 post-procedure (septic complications: n = 4; heart failure: n = 1).
Conclusion
The percutaneous aspiration procedure is highly effective and is associated with a low complication profile. The aspiration of vegetations immediately prior and during the lead extraction procedure may avoid septic embolization into the pulmonary circulation. This may potentially lead to a long-term survival benefit.

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

Europace: 21 Oct 2019; epub ahead of print
Starck CT, Schaerf RHM, Breitenstein A, Najibi S, ... Dreizler T, Falk V
Europace: 21 Oct 2019; epub ahead of print | PMID: 31638648
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Impact:
Abstract

Effect of Once-Weekly Exenatide in Patients With Type 2 Diabetes With and Without Heart Failure and Heart Failure-Related Outcomes: Insights From the EXSCEL Trial.

Fudim M, White J, Pagidipati NJ, Lokhnygina Y, ... Hernandez AF, Mentz RJ

Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (hHF) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), with no differential treatment effect on major adverse cardiac events (MACE) by baseline heart failure (HF) status. EQW\'s effects on secondary endpoints based on hHF status have not been reported. The objective was to explore the effects of EQW on secondary endpoints in patients with and without baseline HF and test the effects of EQW on recurrent hHF events.The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each MACE component, first hHF and repeat hHF by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed.Of 14,752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, more likely to be male and White, and with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (HR 0.86, 95%CI 0.77-0.97) and the composite outcome of all-cause death or hHF (HR 0.89, 95%CI 0.80-0.99). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR 1.05, 95%CI 0.85-1.29), while the risk of mortality was reduced with EQW in the no-HF group (HR 0.79, 95%CI 0.68-0.92) with an interaction p-value of 0.031. Reduction in all-cause death or hHF seen with EQW in patients without baseline HF (HR 0.81, 95%CI 0.71-0.93) was not seen in patients with baseline HF (HR 1.07, 95%CI 0.89-1.29) (interaction p=0.015). First plus recurrent hHF was reduced in the exenatide group versus placebo (HR 0.82, 95%CI 0.68-0.99; p=0.038).In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01144338.



Circulation: 22 Sep 2019; epub ahead of print
Fudim M, White J, Pagidipati NJ, Lokhnygina Y, ... Hernandez AF, Mentz RJ
Circulation: 22 Sep 2019; epub ahead of print | PMID: 31542942
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Impact:
Abstract

Meta-Analysis Comparing Transcatheter Aortic Valve Implantation With Balloon Versus Self-Expandable Valves.

Osman M, Ghaffar YA, Saleem M, Kheiri B, ... Munir MB, Alkhouli M

Two transcatheter aortic valve systems are currently in use in the United States; balloon-expandable valves (BEV) and the self-expanding valve (SEV). However, comparative data outcomes between the 2 systems are limited, as only one randomized trial (RCT) performed a head-to-head comparison between BEVs and SEVs. However, there are several RCTs comparing BEV or SEV to surgical valve replacement. In this analysis, we used Bayesian network meta-analysis techniques to compare BEVs and SEVs. The primary outcome was all-cause mortality at maximum follow-up. Secondary outcomes were cardiovascular mortality, stroke, pacemaker implantation, reintervention, heart failure hospitalization, and moderate-severe paravalvular leak (PVL.). Eight RCTs with 8,095 patients were included. With the exception of less pacemaker implantation in BEV versus SEV (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.11 to 0.77, I = 51%), there was no difference between BEV and SEV in 30-day outcomes. During long-term follow-up (mean 3 ± 2 years); there was no difference between BEV and SEV in all-cause mortality (hazard ratio [HR] 1.1, 95% CI 0.87 to 1.5, I = 19.6%), cardiovascular mortality (HR 1.1, 95% CI 0.73 to 1.6, I = 18.5%), stroke (HR 1.3, 95% CI 0.73 to 2.1, I = 16.9%), hospitalization (HR 0.87, 95% CI 0.41 to 1.6, I = 62%), and reintervention (HR 0.68, 95% CI 0.2 to 2.3, I = 62%). New pacemaker implantation and PVL were significantly less in BEV group (HR 0.45, 95% CI 0.24 to 0.80, I = 38.2%), and (HR 0.03, 95% CI 0.0004 to 0.28, I = 79%), respectively. In conclusion, similar outcomes were seen following transcatheter aortic valve implantation with BEV and SEV with the exception of higher rates of pacemaker implantation and PVL in SEV group.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Oct 2019; 124:1252-1256
Osman M, Ghaffar YA, Saleem M, Kheiri B, ... Munir MB, Alkhouli M
Am J Cardiol: 14 Oct 2019; 124:1252-1256 | PMID: 31470973
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Impact:
Abstract

Preeclampsia and Cardiovascular Disease in a Large UK Pregnancy Cohort of Linked Electronic Health Records: A CALIBER Study.

Leon LJ, McCarthy FP, Direk K, Gonzalez-Izquierdo A, ... Casas JP, Chappell L
Background
The associations between pregnancy hypertensive disorders and common cardiovascular disorders have not been investigated at scale in a contemporaneous population. We aimed to investigate the association between preeclampsia, hypertensive disorders of pregnancy, and subsequent diagnosis of 12 different cardiovascular disorders.
Methods
We used linked electronic health records from 1997 to 2016 to recreate a UK population-based cohort of 1.3 million women, mean age at delivery 28 years, with nearly 1.9 million completed pregnancies. We used multivariable Cox models to determine the associations between hypertensive disorders of pregnancy, and preeclampsia alone (term and preterm), with 12 cardiovascular disorders in addition to chronic hypertension. We estimated the cumulative incidence of a composite end point of any cardiovascular disorder according to preeclampsia exposure.
Results
During the 20-year study period, 18 624 incident cardiovascular disorders were observed, 65% of which had occurred in women under 40 years. Compared to women without hypertension in pregnancy, women who had 1 or more pregnancies affected by preeclampsia had a hazard ratio of 1.9 (95% confidence interval 1.53-2.35) for any stroke, 1.67 (1.54-1.81) for cardiac atherosclerotic events, 1.82 (1.34-2.46) for peripheral events, 2.13 (1.64-2.76) for heart failure, 1.73 (1.38-2.16) for atrial fibrillation, 2.12 (1.49-2.99) for cardiovascular deaths, and 4.47 (4.32-4.62) for chronic hypertension. Differences in cumulative incidence curves, according to preeclampsia status, were apparent within 1 year of the first index pregnancy. Similar patterns of association were observed for hypertensive disorders of pregnancy, while preterm preeclampsia conferred slightly further elevated risks.
Conclusions
Hypertensive disorders of pregnancy, including preeclampsia, have a similar pattern of increased risk across all 12 cardiovascular disorders and chronic hypertension, and the impact was evident soon after pregnancy. Hypertensive disorders of pregnancy should be considered as a natural screening tool for cardiovascular events, enabling cardiovascular risk prevention through national initiatives.



Circulation: 23 Sep 2019; 140:1050-1060
Leon LJ, McCarthy FP, Direk K, Gonzalez-Izquierdo A, ... Casas JP, Chappell L
Circulation: 23 Sep 2019; 140:1050-1060 | PMID: 31545680
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Impact:
Abstract

The Economic Impact of Mitral Regurgitation on Patients With Medically Managed Heart Failure.

McCullough PA, Mehta HS, Barker CM, Cork DP, ... Mollenkopf S, Verta P

The objective of this study was to quantify the financial healthcare burden of mitral regurgitation (MR) on medically managed heart failure (HF) patients. Data from the Truven Health MarketScan Commercial Claims and Medicare Supplemental Databases were analyzed. Included patients had a minimum of 1 inpatient or 2 outpatient claims for HF with a 6-month preperiod (baseline). A 6-month postperiod (landmark) after HF index was used to capture MR diagnosis and severity. Following the landmark period, patients had to have 12 months of continuous medical and prescription drug plan enrollment with at least 2 records of HF medication refills. A therapeutic intensity score was calculated based on HF medication usage. Medically managed HF patients were separated into 3 cohorts: without MR (no MR), insignificant MR (iMR), and significant MR (sMR). Healthcare utilization and all-cause expenditures were modeled to quantify the burden of MR. All models controlled for baseline demographics, co-morbid conditions, and HF therapeutic intensity. Medically managed incident HF patients with sMR had significantly more hospital days (1.91 vs 1.72 days; p = 0.0096) and annual expenditures ($23,988 vs $21,530; p < 0.0001) compared with no MR patients. No differences were identified when comparing iMR and no MR. When evaluating HF admissions, sMR patients had an estimated 50% greater HF admissions rate (0.036 vs 0.024; p < 0.0001) compared with no MR patients. Additionally, HF admits for iMR were 23% more than those with no MR (0.029 vs 0.024; p = 0.0064). In conclusion, evidence of MR in retrospective claims significantly increases the healthcare impact of medically managed HF patients. Both utilization and financial burden is more pronounced when MR is clinically significant.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Oct 2019; 124:1226-1231
McCullough PA, Mehta HS, Barker CM, Cork DP, ... Mollenkopf S, Verta P
Am J Cardiol: 14 Oct 2019; 124:1226-1231 | PMID: 31470974
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Impact:
Abstract

Catheter ablation of ventricular arrhythmias and in-hospital mortality: insights from the German-wide Helios hospital network of 5052 cases.

König S, Ueberham L, Müller-Röthing R, Wiedemann M, ... Hindricks G, Bollmann A
Aims
Catheter ablation (CA) of ventricular arrhythmias is one of the most challenging electrophysiological interventions with an increasing use over the last years. Several benefits must be weighed against the risk of potentially life-threatening complications which necessitates a steady reevaluation of safety endpoints. Therefore, the aims of this study were (i) to investigate overall in-hospital mortality in patients undergoing such procedures and (ii) to identify variables associated with in-hospital mortality in a German-wide hospital network.
Methods and results
Between January 2010 and September 2018, administrative data provided by 85 Helios hospitals were screened for patients with main or secondary discharge diagnosis of ventricular tachycardia (VT) or premature ventricular contractions (PVCs) in combination with an arrhythmia-related CA using ICD- and OPS codes. In 5052 cases (mean age 60.9 ± 14.3 years, 30.1% female) of 30 different hospitals, in-hospital mortality was 1.27% with a higher mortality in patients ablated for VT (1.99%, n = 2, 955) compared to PVC (0.24%, n = 2, 097, P < 0.01). Mortality rates were 2.06% in patients with ischaemic heart disease (IHD, n = 2, 137), 1.47% in patients with non-ischaemic structural heart disease (NIHD, n = 1, 224), and 0.12% in patients without structural heart disease (NSHD, n = 1, 691). Considering different types of hospital admission, mortality rates were 0.35% after elective (n = 2, 825), 1.60% after emergency admission/hospital transfer <24 h (n = 1, 314) and 3.72% following delayed hospital transfer >24 h after initial admission (n = 861, P < 0.01 vs. elective admission and emergency admission/hospital transfer <24 h). In multivariable analysis, a delayed hospital transfer >24 h [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.59-3.28, P < 0.01], the occurrence of procedure-related major adverse events (OR 6.81, 95% CI 2.90-16.0, P < 0.01), Charlson Comorbidity Index (CCI, OR 2.39, 95% CI 1.56-3.66, P < 0.01) and its components congestive heart failure (OR 8.04, 95% CI 1.71-37.8, P < 0.01), and diabetes mellitus (OR 1.59, 95% CI 1.13-2.22, P < 0.01) were significantly associated with in-hospital death.
Conclusions
We reported in-hospital mortality rates after CA of ventricular arrhythmias in the largest multicentre, administrative dataset in Germany which can be implemented in quality management programs. Aside from comorbidities, a delayed hospital transfer to a CA performing centre is associated with an increased in-hospital mortality. This deserves further studies to determine the optimal management strategy.

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

Europace: 21 Oct 2019; epub ahead of print
König S, Ueberham L, Müller-Röthing R, Wiedemann M, ... Hindricks G, Bollmann A
Europace: 21 Oct 2019; epub ahead of print | PMID: 31638643
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Impact:
Abstract

Safety and efficacy of a self-expanding versus a balloon-expandable bioprosthesis for transcatheter aortic valve replacement in patients with symptomatic severe aortic stenosis: a randomised non-inferiority trial.

Lanz J, Kim WK, Walther T, Burgdorf C, ... Pilgrim T,
Background
Transcatheter aortic valve replacement (TAVR) is the preferred treatment option for older patients with symptomatic severe aortic stenosis. Differences in the properties of available TAVR systems can affect clinical outcomes. Among patients undergoing TAVR, we compared the self-expanding ACURATE neo TAVR system with the balloon-expandable SAPIEN 3 TAVR system with regard to early safety and efficacy.
Methods
In this randomised non-inferiority trial, patients (aged ≥75 years) undergoing transfemoral TAVR for treatment of symptomatic severe aortic stenosis, and who were deemed to be at increased surgical risk, were recruited at 20 tertiary heart valve centres in Germany, the Netherlands, Switzerland, and the UK. Participants were randomly assigned (1:1) to receive treatment with the ACURATE neo or the SAPIEN 3 with a computer-based randomly permuted block scheme, stratified by study centre and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) category. The primary composite safety and efficacy endpoint comprised all-cause death, any stroke, life-threatening or disabling bleeding, major vascular complications, coronary artery obstruction requiring intervention, acute kidney injury (stage 2 or 3), rehospitalisation for valve-related symptoms or congestive heart failure, valve-related dysfunction requiring repeat procedure, moderate or severe prosthetic valve regurgitation, or prosthetic valve stenosis within 30 days of the procedure. Endpoint assessors were masked to treatment allocation. Non-inferiority of ACURATE neo compared with SAPIEN 3 was assessed in the intention-to-treat population on the basis of a risk-difference margin of 7·7% for the primary composite endpoint, with a one-sided α of 0·05. This trial is registered with ClinicalTrials.gov (number NCT03011346) and is ongoing but not recruiting.
Findings
Between Feb 8, 2017, and Feb 2, 2019, up to 5132 patients were screened and 739 (mean age 82·8 years [SD 4·1]; median STS-PROM score 3·5% [IQR 2·6-5·0]) were enrolled. 30-day follow-up was available for 367 (99%) of 372 patients allocated to the ACURATE neo group, and 364 (99%) of 367 allocated to the SAPIEN 3 group. Within 30 days, the primary endpoint occurred in 87 (24%) patients in the ACURATE neo and in 60 (16%) in the SAPIEN 3 group; thus, non-inferiority of the ACURATE neo was not met (absolute risk difference 7·1% [upper 95% confidence limit 12·0%], p=0·42). Secondary analysis of the primary endpoint suggested superiority of the SAPIEN 3 device over the ACURATE neo device (95% CI for risk difference -1·3 to -12·9, p=0·0156). The ACURATE neo and SAPIEN 3 groups did not differ in incidence of all-cause death (nine patients [2%] vs three [1%]) and stroke (seven [2%] vs 11 [3%]); whereas acute kidney injury (11 [3%] vs three [1%]) and moderate or severe prosthetic aortic regurgitation (34 [9%] vs ten [3%]) were more common in the ACURATE neo group.
Interpretation
TAVR with the self-expanding ACURATE neo did not meet non-inferiority compared to the balloon-expandable SAPIEN 3 device in terms of early safety and clinical efficacy outcomes. An early composite safety and efficacy endpoint was useful in discriminating the performance of different TAVR systems.
Funding
Boston Scientific (USA).

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 25 Sep 2019; epub ahead of print
Lanz J, Kim WK, Walther T, Burgdorf C, ... Pilgrim T,
Lancet: 25 Sep 2019; epub ahead of print | PMID: 31570258
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Impact:
Abstract

Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis.

Suchard MA, Schuemie MJ, Krumholz HM, You SC, ... Hripcsak G, Ryan PB
Background
Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice.
Methods
We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested.
Findings
Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes.
Interpretation
This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers.
Funding
US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 23 Oct 2019; epub ahead of print
Suchard MA, Schuemie MJ, Krumholz HM, You SC, ... Hripcsak G, Ryan PB
Lancet: 23 Oct 2019; epub ahead of print | PMID: 31668726
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Abstract

Single Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation.

Martini E, Kunderfranco P, Peano C, Carullo P, ... Condorelli G, Kallikourdis M

Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure (HF). Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response.Here we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine non-ischemic, pressure-overload HF model. By focusing our analysis on CD45 cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multi-parameter flow cytometry, immunohistochemistry and tissue clarification immunofluorescence, in mouse and human.We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells (Treg), dendritic cells, NK cells, neutrophils and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whilst mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as Osm in pro-inflammatory macrophages and PD-1 in Treg, that may help explain clinical findings such as the refractivity of HF patients to anti-TNF therapy and cardiac toxicity during anti-PD-1 cancer immunotherapy, respectively.Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, NK cells and mast cells. This opens up the field of cardio-immunology to further investigation using toolkits that have already been developed to study the immune subsets above. The subset-specific molecules that mediate their activation may thus become useful targets for diagnostics or therapy of HF.



Circulation: 29 Oct 2019; epub ahead of print
Martini E, Kunderfranco P, Peano C, Carullo P, ... Condorelli G, Kallikourdis M
Circulation: 29 Oct 2019; epub ahead of print | PMID: 31661975
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Impact:
Abstract

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

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

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



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

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

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

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



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

Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.

Yusuf S, Joseph P, Rangarajan S, Islam S, ... McKee M, Dagenais G
Background
Global estimates of the effect of common modifiable risk factors on cardiovascular disease and mortality are largely based on data from separate studies, using different methodologies. The Prospective Urban Rural Epidemiology (PURE) study overcomes these limitations by using similar methods to prospectively measure the effect of modifiable risk factors on cardiovascular disease and mortality across 21 countries (spanning five continents) grouped by different economic levels.
Methods
In this multinational, prospective cohort study, we examined associations for 14 potentially modifiable risk factors with mortality and cardiovascular disease in 155 722 participants without a prior history of cardiovascular disease from 21 high-income, middle-income, or low-income countries (HICs, MICs, or LICs). The primary outcomes for this paper were composites of cardiovascular disease events (defined as cardiovascular death, myocardial infarction, stroke, and heart failure) and mortality. We describe the prevalence, hazard ratios (HRs), and population-attributable fractions (PAFs) for cardiovascular disease and mortality associated with a cluster of behavioural factors (ie, tobacco use, alcohol, diet, physical activity, and sodium intake), metabolic factors (ie, lipids, blood pressure, diabetes, obesity), socioeconomic and psychosocial factors (ie, education, symptoms of depression), grip strength, and household and ambient pollution. Associations between risk factors and the outcomes were established using multivariable Cox frailty models and using PAFs for the entire cohort, and also by countries grouped by income level. Associations are presented as HRs and PAFs with 95% CIs.
Findings
Between Jan 6, 2005, and Dec 4, 2016, 155 722 participants were enrolled and followed up for measurement of risk factors. 17 249 (11·1%) participants were from HICs, 102 680 (65·9%) were from MICs, and 35 793 (23·0%) from LICs. Approximately 70% of cardiovascular disease cases and deaths in the overall study population were attributed to modifiable risk factors. Metabolic factors were the predominant risk factors for cardiovascular disease (41·2% of the PAF), with hypertension being the largest (22·3% of the PAF). As a cluster, behavioural risk factors contributed most to deaths (26·3% of the PAF), although the single largest risk factor was a low education level (12·5% of the PAF). Ambient air pollution was associated with 13·9% of the PAF for cardiovascular disease, although different statistical methods were used for this analysis. In MICs and LICs, household air pollution, poor diet, low education, and low grip strength had stronger effects on cardiovascular disease or mortality than in HICs.
Interpretation
Most cardiovascular disease cases and deaths can be attributed to a small number of common, modifiable risk factors. While some factors have extensive global effects (eg, hypertension and education), others (eg, household air pollution and poor diet) vary by a country\'s economic level. Health policies should focus on risk factors that have the greatest effects on averting cardiovascular disease and death globally, with additional emphasis on risk factors of greatest importance in specific groups of countries.
Funding
Full funding sources are listed at the end of the paper (see Acknowledgments).

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 02 Sep 2019; epub ahead of print
Yusuf S, Joseph P, Rangarajan S, Islam S, ... McKee M, Dagenais G
Lancet: 02 Sep 2019; epub ahead of print | PMID: 31492503
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Impact:
Abstract

Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients with Heart Failure and Reduced Ejection Fraction:PARADIGM-HF.

Selvaraj S, Claggett B, Pozzi A, McMurray JJV, ... Swedberg K, Solomon SD

The contemporary prognostic value of the physical examination, beyond traditional risk factors including natriuretic peptides (NPs), risk scores, and symptoms, in heart failure with reduced ejection fraction (HFrEF) is unknown. We sought to determine the association between physical signs of congestion at baseline and during study follow up with quality of life (QoL) and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion.We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and S3) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up, and whether improvement in congestion is related to changes in clinical outcomes and QoL, assessed by Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-OSS).Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2%. Patients with baseline congestion were older, more often female, had higher Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores and lower KCCQ-OSS (p<0.05). After adjusting for baseline NPs, time-updated MAGGIC score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (p<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (p=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than enalapril (p=0.011). Each 1-sign reduction was independently associated with a 5.1 (95%CI: 4.7-5.5) point improvement in KCCQ-OSS. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (p<0.001).In HFrEF, the physical exam continues to provide significant, independent prognostic value even beyond symptoms, NPs, and MAGGIC risk score. Sacubitril/valsartan improved congestion to a greater extent than enalapril. Reducing congestion in the outpatient setting is independently associated with improved QoL and reduced cardiovascular events, including mortality.URL: https://clinicaltrials.gov Unique Identifier: NCT01035255.



Circulation: 11 Sep 2019; epub ahead of print
Selvaraj S, Claggett B, Pozzi A, McMurray JJV, ... Swedberg K, Solomon SD
Circulation: 11 Sep 2019; epub ahead of print | PMID: 31510768
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Impact:
Abstract

An artificial intelligence-enabled ECG algorithm for the identification of patients with atrial fibrillation during sinus rhythm: a retrospective analysis of outcome prediction.

Attia ZI, Noseworthy PA, Lopez-Jimenez F, Asirvatham SJ, ... Kapa S, Friedman PA
Background
Atrial fibrillation is frequently asymptomatic and thus underdetected but is associated with stroke, heart failure, and death. Existing screening methods require prolonged monitoring and are limited by cost and low yield. We aimed to develop a rapid, inexpensive, point-of-care means of identifying patients with atrial fibrillation using machine learning.
Methods
We developed an artificial intelligence (AI)-enabled electrocardiograph (ECG) using a convolutional neural network to detect the electrocardiographic signature of atrial fibrillation present during normal sinus rhythm using standard 10-second, 12-lead ECGs. We included all patients aged 18 years or older with at least one digital, normal sinus rhythm, standard 10-second, 12-lead ECG acquired in the supine position at the Mayo Clinic ECG laboratory between Dec 31, 1993, and July 21, 2017, with rhythm labels validated by trained personnel under cardiologist supervision. We classified patients with at least one ECG with a rhythm of atrial fibrillation or atrial flutter as positive for atrial fibrillation. We allocated ECGs to the training, internal validation, and testing datasets in a 7:1:2 ratio. We calculated the area under the curve (AUC) of the receiver operatoring characteristic curve for the internal validation dataset to select a probability threshold, which we applied to the testing dataset. We evaluated model performance on the testing dataset by calculating the AUC and the accuracy, sensitivity, specificity, and F1 score with two-sided 95% CIs.
Findings
We included 180 922 patients with 649 931 normal sinus rhythm ECGs for analysis: 454 789 ECGs recorded from 126 526 patients in the training dataset, 64 340 ECGs from 18 116 patients in the internal validation dataset, and 130 802 ECGs from 36 280 patients in the testing dataset. 3051 (8·4%) patients in the testing dataset had verified atrial fibrillation before the normal sinus rhythm ECG tested by the model. A single AI-enabled ECG identified atrial fibrillation with an AUC of 0·87 (95% CI 0·86-0·88), sensitivity of 79·0% (77·5-80·4), specificity of 79·5% (79·0-79·9), F1 score of 39·2% (38·1-40·3), and overall accuracy of 79·4% (79·0-79·9). Including all ECGs acquired during the first month of each patient\'s window of interest (ie, the study start date or 31 days before the first recorded atrial fibrillation ECG) increased the AUC to 0·90 (0·90-0·91), sensitivity to 82·3% (80·9-83·6), specificity to 83·4% (83·0-83·8), F1 score to 45·4% (44·2-46·5), and overall accuracy to 83·3% (83·0-83·7).
Interpretation
An AI-enabled ECG acquired during normal sinus rhythm permits identification at point of care of individuals with atrial fibrillation.
Funding
None.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 06 Sep 2019; 394:861-867
Attia ZI, Noseworthy PA, Lopez-Jimenez F, Asirvatham SJ, ... Kapa S, Friedman PA
Lancet: 06 Sep 2019; 394:861-867 | PMID: 31378392
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Impact:
Abstract

Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction: Observations From the SAVOR-TIMI 53 Trial.

Bergmark BA, Bhatt DL, McGuire DK, Cahn A, ... Scirica BM,
Background
Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved.
Methods
In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models.
Results
Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min·1.73 m). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease.
Conclusions
In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886.



Circulation: 16 Sep 2019; 140:1004-1014
Bergmark BA, Bhatt DL, McGuire DK, Cahn A, ... Scirica BM,
Circulation: 16 Sep 2019; 140:1004-1014 | PMID: 31362530
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Abstract

Widespread Translational Control of Fibrosis in the Human Heart by RNA-Binding Proteins.

Chothani S, Schäfer S, Adami E, Viswanathan S, ... Cook SA, Rackham OJL
Background
Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global posttranscriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored.
Methods
Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. The integration with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients demonstrates that these posttranscriptional mechanisms are also active in the diseased fibrotic human heart.
Results
We generated nucleotide-resolution translatome data during the transforming growth factor β1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation, and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in posttranscriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested the same posttranscriptional regulatory network was underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as Pumilio RNA binding family member 2 (PUM2) and Quaking (QKI) that work in concert to regulate the translation of target transcripts in human diseased hearts. Furthermore, silencing of both PUM2 and QKI inhibits the transition of fibroblasts toward profibrotic myofibroblasts in response to transforming growth factor β1.
Conclusions
We reveal widespread translational effects of transforming growth factor β1 and define novel posttranscriptional regulatory networks that control the fibroblast-to-myofibroblast transition. These networks are active in human heart disease, and silencing of hub genes limits fibroblast activation. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.



Circulation: 09 Sep 2019; 140:937-951
Chothani S, Schäfer S, Adami E, Viswanathan S, ... Cook SA, Rackham OJL
Circulation: 09 Sep 2019; 140:937-951 | PMID: 31284728
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Abstract

Conserved NPPB+ Border Zone Switches From MEF2- to AP-1-Driven Gene Program.

van Duijvenboden K, de Bakker DEM, Man JCK, Janssen R, ... Bakkers J, Christoffels VM
Background
Surviving cells in the postinfarction border zone are subjected to intense fluctuations of their microenvironment. Recently, border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here, we defined their unique transcriptional and regulatory properties, and comprehensively validated new molecular markers, including Nppb, encoding B-type natriuretic peptide, after infarction.
Methods
Transgenic reporter mice were used to identify the Nppb-positive border zone after myocardial infarction. Transcriptome analysis of remote, border, and infarct zones and of purified cardiomyocyte nuclei was performed using RNA-sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. Mice in which Nppb was deleted by genome editing were subjected to myocardial infarction. Chromatin accessibility landscapes of border zone and control cardiomyocyte nuclei were assessed by using assay for transposase-accessible chromatin using sequencing.
Results
We identified the border zone as a spatially confined region transcriptionally distinct from the remote myocardium. The transcriptional response of the border zone was much stronger than that of the remote ventricular wall, involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling, and sarcomere function, and the activation of a stress-response program. Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans, and led to the identification of novel conserved border zone markers including NPPB, ANKRD1, DES, UCHL1, JUN, and FOXP1. Homozygous Nppb mutant mice developed acute and lethal heart failure after myocardial infarction, indicating that B-type natriuretic peptide is required to preserve postinfarct heart function. Assay for transposase-accessible chromatin using sequencing revealed thousands of cardiomyocyte lineage-specific MEF2-occupied regulatory elements that lost accessibility in the border zone. Putative injury-responsive enhancers that gained accessibility were highly associated with AP-1 (activator protein 1) binding sites. Nuclear c-Jun, a component of AP-1, was observed specifically in border zone cardiomyocytes.
Conclusions
Cardiomyocytes in a discrete zone bordering the infarct switch from a MEF2-driven homeostatic lineage-specific to an AP-1-driven injury-induced gene expression program. This program is conserved between mouse and human, and includes Nppb expression, which is required to prevent acute heart failure after infarction.



Circulation: 08 Sep 2019; 140:864-879
van Duijvenboden K, de Bakker DEM, Man JCK, Janssen R, ... Bakkers J, Christoffels VM
Circulation: 08 Sep 2019; 140:864-879 | PMID: 31259610
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Abstract

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

Hausenloy DJ, Kharbanda RK, Møller UK, Ramlall M, ... Bøtker HE,
Background
Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months.
Methods
We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed.
Findings
Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed.
Interpretation
Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI.
Funding
British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 05 Sep 2019; epub ahead of print
Hausenloy DJ, Kharbanda RK, Møller UK, Ramlall M, ... Bøtker HE,
Lancet: 05 Sep 2019; epub ahead of print | PMID: 31500849
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Abstract

Exercise-Induced Cardiac Troponin I Increase and Incident Mortality and Cardiovascular Events.

Aengevaeren VL, Hopman MTE, Thompson PD, Bakker EA, ... Thijssen DHJ, Eijsvogels TMH
Background
Blood concentrations of cardiac troponin above the 99 percentile are a key criterion for the diagnosis of acute myocardial injury and infarction. Troponin concentrations, even below the 99 percentile, predict adverse outcomes in patients and the general population. Elevated troponin concentrations are commonly observed after endurance exercise, but the clinical significance of this increase is unknown. We examined the association between postexercise troponin I concentrations and clinical outcomes in long-distance walkers.
Methods
We measured cardiac troponin I concentrations in 725 participants (61 [54-69] yrs) before and immediately after 30 to 55 km of walking. We tested for an association between postexercise troponin I concentrations above the 99 percentile (>0.040 µg/L) and a composite end point of all-cause mortality and major adverse cardiovascular events (myocardial infarction, stroke, heart failure, revascularization, or sudden cardiac arrest). Continuous variables were reported as mean ± standard deviation when normally distributed or median [interquartile range] when not normally distributed.
Results
Participants walked 8.3 [7.3-9.3] hours at 68±10% of their maximum heart rate. Baseline troponin I concentrations were >0.040 µg/L in 9 participants (1%). Troponin I concentrations increased after walking (P<.001), with 63 participants (9%) demonstrating a postexercise troponin concentration >0.040 µg/L. During 43 [23-77] months of follow-up, 62 participants (9%) experienced an end point; 29 died and 33 had major adverse cardiovascular events. Compared with 7% with postexercise troponin I ≤0.040 µg/L (log-rank P<.001), 27% of participants with postexercise troponin I concentrations >0.040 µg/L experienced an end point. The hazard ratio was 2.48 (95% CI, 1.29-4.78) after adjusting for age, sex, cardiovascular risk factors (hypertension, hypercholesterolemia or diabetes mellitus), cardiovascular diseases (myocardial infarction, stroke, or heart failure), and baseline troponin I concentrations.
Conclusions
Exercise-induced troponin I elevations above the 99 percentile after 30 to 55 km of walking independently predicted higher mortality and cardiovascular events in a cohort of older long-distance walkers. Exercise-induced increases in troponin may not be a benign physiological response to exercise, but an early marker of future mortality and cardiovascular events.



Circulation: 08 Sep 2019; 140:804-814
Aengevaeren VL, Hopman MTE, Thompson PD, Bakker EA, ... Thijssen DHJ, Eijsvogels TMH
Circulation: 08 Sep 2019; 140:804-814 | PMID: 31401842
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Abstract

Glucose 6-Phosphate Accumulates via Phosphoglucose Isomerase Inhibition in Heart Muscle.

Karlstaedt A, Khanna R, Thangam M, Taegtmeyer H

Metabolic and structural remodeling is a hallmark of heart failure. This remodeling involves activation of the mammalian target of rapamycin (mTOR) signaling pathway, but little is known on how intermediary metabolites are integrated as metabolic signals.We investigated the metabolic control of cardiac glycolysis and explored the potential of glucose 6-phosphate to regulate glycolytic flux and mTOR activation.We developed a kinetic model of cardiomyocyte carbohydrate metabolism, CardioGlyco, to study the metabolic control of myocardial glycolysis and glucose 6-phosphate levels. Metabolic control analysis revealed that glucose 6-phosphate concentration is dependent on phosphoglucose isomerase activity. Next, we integrated ex vivo tracer studies with mathematical simulations to test how changes in glucose supply and glycolytic flux affect mTOR activation. Nutrient deprivation promoted a tight coupling between glucose uptake and oxidation, glucose 6-phosphate reduction, and increased protein-protein interaction between hexokinase II and mTOR. We validated the in silico modeling in cultured adult mouse ventricular cardiomyocytes by modulating phosphoglucose isomerase activity using erythrose 4-phosphate. Inhibition of glycolytic flux at the level of phosphoglucose isomerase caused glucose 6-phosphate accumulation, which correlated with increased mTOR activation. Using click chemistry, we labeled newly synthesized proteins and confirmed that inhibition of phosphoglucose isomerase increases protein synthesis.The reduction of phosphoglucose isomerase activity directly affects myocyte growth by regulating mTOR activation.



Circ Res: 07 Nov 2019; epub ahead of print
Karlstaedt A, Khanna R, Thangam M, Taegtmeyer H
Circ Res: 07 Nov 2019; epub ahead of print | PMID: 31698999
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Abstract

Association Between Use of Primary Prevention Implantable Cardioverter-Defibrillators and Mortality in Patients with Heart Failure: A Prospective Propensity-Score Matched Analysis from the Swedish Heart Failure Registry.

Schrage B, Uijl A, Benson L, Westermann D, ... Braunschweig F, Savarese G
Background
Most randomized trials on implantable cardioverter-defibrillator (ICD) use for primary prevention of sudden cardiac death in heart failure with reduced ejection fraction (HFrEF) enrolled patients >20 years ago. We investigated the association between ICD use and all-cause mortality in a contemporary HFrEF cohort and examined relevant subgroups.
Methods
Patients from the Swedish HF Registry (SwedeHF) fulfilling the European Society of Cardiology criteria for primary prevention ICD were included. The association between ICD use and 1-year and 5-year all-cause and cardiovascular (CV) mortality was assessed by Cox Regression models in a 1:1 propensity score matched cohort and in prespecified subgroups.
Results
Of 16,702 eligible patients, only 1,599 (10%) had an ICD. After matching, 1,305 ICD recipients were compared to 1,305 non-recipients. ICD use was associated with a reduction in all-cause mortality risk within 1 year [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.60-0.90] and 5 years (HR: 0.88, 95%CI: 0.78-0.99). Results were consistent in all subgroups including patients with vs. without ischemic heart disease, males vs. females, in those aged <75 vs. ≥75 years, in those with earlier vs. later enrollment in SwedeHF and in patients with vs. without cardiac resynchronization therapy.
Conclusions
In a contemporary HFrEF population, ICD for primary prevention was underused although it was associated with reduced short- and long-term all-cause mortality. This association was consistent across all the investigated subgroups. These results call for better implementation of ICD therapy.



Circulation: 02 Sep 2019; epub ahead of print
Schrage B, Uijl A, Benson L, Westermann D, ... Braunschweig F, Savarese G
Circulation: 02 Sep 2019; epub ahead of print | PMID: 31476893
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Abstract

Contrasting Effects of Pharmacological, Procedural, and Surgical Interventions on Proportionate and Disproportionate Functional Mitral Regurgitation in Chronic Heart Failure.

Packer M, Grayburn PA

Two distinct pathways can lead to functional mitral regurgitation (MR) in patients with chronic heart failure and a reduced ejection fraction. When remodeling and enlargement of the left ventricle (LV) cause annular dilatation and tethering of the mitral valve leaflets, there is a linear relationship between LV end-diastolic volume and the effective regurgitant orifice area of the mitral valve. These patients, designated as having proportionate MR, respond favorably to treatments that lead to reversal of LV remodeling and a decrease in LV volumes (eg, neurohormonal antagonists and LV assist devices), but they may not benefit from interventions that are directed only at the mitral valve leaflets (eg, transcatheter mitral valve repair). In contrast, when ventricular dyssynchrony causes functional MR attributable to unequal contraction of the papillary muscles, the magnitude of regurgitation is greater than that predicted by LV volumes. These patients, designated as having severe but disproportionate MR, respond favorably to treatments that are directed to the mitral valve leaflets or their supporting structures (eg, cardiac resynchronization or transcatheter mitral valve repair), but they may derive little benefit from interventions that act only to reduce LV cavity size (eg, pharmacological treatments). This novel conceptual framework reflects the important interplay between LV geometry and mitral valve function in determining the clinical presentation of patients, and it allows characterization of the determinants of functional MR to guide the most appropriate therapy in the clinical setting.



Circulation: 26 Aug 2019; 140:779-789
Packer M, Grayburn PA
Circulation: 26 Aug 2019; 140:779-789 | PMID: 31070944
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Abstract

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups.

Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, ... Brenner BM, Perkovic V
Background
Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention).
Methods
In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care.
Results
Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome).
Conclusions
Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.



Circulation: 26 Aug 2019; 140:739-750
Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, ... Brenner BM, Perkovic V
Circulation: 26 Aug 2019; 140:739-750 | PMID: 31291786
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Abstract

Heart Failure Risk Stratification and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Type 2 Diabetes Mellitus.

Berg DD, Wiviott SD, Scirica BM, Gurmu Y, ... Braunwald E, Sabatine MS
Background
Patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing heart failure. Sodium-glucose cotransporter-2 inhibitors reduce the risk of hospitalization for heart failure (HHF) in patients with T2DM. We aimed to develop and validate a practical clinical risk score for HHF in patients with T2DM and assess whether this score can identify high-risk patients with T2DM who have the greatest reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor.
Methods
We developed a clinical risk score for HHF in 8212 patients with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using multivariable Cox regression, and independent clinical risk indicators achieving statistical significance of <0.001 were included in the risk score. We externally validated the score in 8578 patients with T2DM in the placebo arm of DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58). The relative and absolute risk reductions in HHF with the sodium-glucose cotransporter-2 inhibitor dapagliflozin were assessed by baseline HHF risk.
Results
Five clinical variables were independent risk predictors of HHF: prior heart failure, history of atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. A simple integer-based score (0-7 points) using these predictors identified a >20-fold gradient of HHF risk ( for trend <0.001) in both the derivation and validation cohorts, with C indices of 0.81 and 0.78, respectively. Although relative risk reductions with dapagliflozin were similar for patients across the risk scores (25%-34%), absolute risk reductions were greater in those at higher baseline risk (1-sidedfor trend=0.04), with high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5% and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4 years, respectively.
Conclusions
Risk stratification using a novel clinical risk score for HHF in patients with T2DM identifies patients at higher risk for HHF who derive greater absolute benefit from sodium-glucose cotransporter-2 inhibition.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01107886 and NCT01730534.



Circulation: 04 Nov 2019; 140:1569-1577
Berg DD, Wiviott SD, Scirica BM, Gurmu Y, ... Braunwald E, Sabatine MS
Circulation: 04 Nov 2019; 140:1569-1577 | PMID: 31474116
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Abstract

Underuse of ECG monitoring in oncology patients receiving QT-interval prolonging drugs.

Pezo RC, Yan AT, Earle C, Chan KK
Objective
We examined use of ECG monitoring in oncology patients prescribed QT-prolonging drugs.
Methods
Patients ≥66 years diagnosed with cancer between 2005 and 2011 were identified through the Ontario Cancer Registry and linked to multiple population-based administrative databases to ascertain demographics, comorbidities, prescription drug use, systemic therapy and ECG. QT-prolonging drugs were identified as per drug lists developed by the Arizona Center for Education and Research on Therapeutics. Univariable and multivariable analyses were used to examine factors associated with ECG use in patients on first-line systemic therapy.
Results
A total of 48 236 patients (median age 74; 49% women) received one or more drugs associated with a risk of QT-interval prolongation but only 27% of patients had an ECG performed. Factors associated with more ECG use on multivariable analysis included recent cancer diagnosis (p for trend <0.001 between 2005 and 2011), use of concurrent QT-prolonging drugs (OR=1.15 per each additional QT-prolonging drug, 95% CI 1.12 to 1.17) and the presence of coronary artery disease (OR 1.31; 95% CI 1.25 to 1.38) and heart failure (OR 1.25; 95% CI 1.17 to 1.35). Use of anticancer (OR 0.74; 95% CI 0.70 to 0.79) and antiemetic (OR 0.93; 95% CI 0.88 to 0.99) QT-prolonging drugs was paradoxically associated with less ECG use.
Conclusions
Our study highlights common use of QT-prolonging drugs and underuse of ECG in oncology patients. Since ECG is an inexpensive, non-invasive and widely available test, it may be readily incorporated in the monitoring of patients for toxicities in routine clinical practice.

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

Heart: 30 Oct 2019; 105:1649-1655
Pezo RC, Yan AT, Earle C, Chan KK
Heart: 30 Oct 2019; 105:1649-1655 | PMID: 31129611
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Abstract

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

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

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



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

This program is still in alpha version.