Topic: Heart Failure

Abstract

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

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

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

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

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

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

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

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

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

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

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

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

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

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

Zelniker TA, Braunwald E

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

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

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

A Contemporary Picture of Enterococcal Endocarditis.

Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
Background
Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking.
Objectives
The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort.
Methods
This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses.
Results
Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p = 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p = 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs. 45.9%; p = 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p = 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse.
Conclusions
Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.

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

J Am Coll Cardiol: 10 Feb 2020; 75:482-494
Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
J Am Coll Cardiol: 10 Feb 2020; 75:482-494 | PMID: 32029130
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Abstract

Cardiometabolic-Based Chronic Disease, Addressing Knowledge and Clinical Practice Gaps: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

In the second part of this JACC State-of-the-Art Review, an early and sustainable preventive care plan is described for cardiometabolic-based chronic disease. This plan can improve cardiometabolic health by targeting early mechanistic events to decrease the risk for certain cardiovascular diseases (e.g., coronary heart disease, heart failure, and atrial fibrillation). Included are various prevention modalities, intensive lifestyle interventions, pharmacotherapy and cardiovascular outcome trial evidence, and bariatric/metabolic procedures. A tactical approach of implementing published clinical practice guidelines/algorithms for early behavioral, adiposity, and dysglycemia targeting is emphasized, as well as relevant educational and research implications.

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

J Am Coll Cardiol: 10 Feb 2020; 75:539-555
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:539-555 | PMID: 32029137
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Abstract

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

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

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

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

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

Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies.

Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
Background
Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.
Objectives
The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.
Methods
From the [email protected], clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.
Results
Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).
Conclusions
Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 17 Feb 2020; 75:620-628
Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
J Am Coll Cardiol: 17 Feb 2020; 75:620-628 | PMID: 32057377
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Abstract

Clinical impact of conduction disturbances in transcatheter aortic valve replacement recipients: a systematic review and meta-analysis.

Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Aims
The clinical impact of new-onset persistent left bundle branch block (NOP-LBBB) and permanent pacemaker implantation (PPI) on transcatheter aortic valve replacement (TAVR) recipients remains controversial. We aimed to evaluate the impact of (i) periprocedural NOP-LBBB and PPI post-TAVR on 1-year all-cause death, cardiac death, and heart failure hospitalization and (ii) NOP-LBBB on the need for PPI at 1-year follow-up.
Methods and results
We performed a systematic search from PubMed and EMBASE databases for studies reporting raw data on 1-year clinical impact of NOP-LBBB or periprocedural PPI post-TAVR. Data from 30 studies, including 7792 patients (12 studies) and 42 927 patients (21 studies) for the evaluation of the impact of NOP-LBBB and PPI after TAVR were sourced, respectively. NOP-LBBB was associated with an increased risk of all-cause death [risk ratio (RR) 1.32, 95% confidence interval (CI) 1.17-1.49; P < 0.001], cardiac death (RR 1.46, 95% CI 1.20-1.78; P < 0.001), heart failure hospitalization (RR 1.35, 95% CI 1.05-1.72; P = 0.02), and PPI (RR 1.89, 95% CI 1.58-2.27; P < 0.001) at 1-year follow-up. Periprocedural PPI after TAVR was associated with a higher risk of all-cause death (RR 1.17, 95% CI 1.11-1.25; P < 0.001) and heart failure hospitalization (RR 1.18, 95% CI 1.03-1.36; P = 0.02). Permanent pacemaker implantation was not associated with an increased risk of cardiac death (RR 0.84, 95% CI 0.67-1.05; P = 0.13).
Conclusion
NOP-LBBB and PPI after TAVR are associated with an increased risk of all-cause death and heart failure hospitalization at 1-year follow-up. Periprocedural NOP-LBBB also increased the risk of cardiac death and PPI within the year following the procedure. Further studies are urgently warranted to enhance preventive measures and optimize the management of conduction disturbances post-TAVR.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 02 Jan 2020; epub ahead of print
Faroux L, Chen S, Muntané-Carol G, Regueiro A, ... Nazif T, Rodés-Cabau J
Eur Heart J: 02 Jan 2020; epub ahead of print | PMID: 31899484
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Abstract

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis.

Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Aims
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis.
Methods and results
We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e\' were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001).
Conclusion
The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 16 Jan 2020; epub ahead of print
Chacko L, Martone R, Bandera F, Lane T, ... Gillmore JD, Fontana M
Eur Heart J: 16 Jan 2020; epub ahead of print | PMID: 31950987
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Abstract

Trends in U.S. Ambulatory Cardiovascular Care 2013 to 2017: JACC Review Topic of the Week.

Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA

The National Cardiovascular Data Registry PINNACLE (Practice Innovation and Clinical Excellence) Registry is the largest outpatient cardiovascular practice registry in the world. It tracks real-world management and quality of 4 common cardiovascular conditions: heart failure, coronary artery disease, atrial fibrillation, and hypertension. In 2013, the PINNACLE Registry contained information on 2,898,505 patients, cared for by 4,859 providers in 431 practices. By 2017, the registry contained information on 6,040,996 patients, cared for by 8,853 providers in 724 practices. During this time period, care processes for PINNACLE patients generally improved. Among patients with heart failure, combined beta-blocker and renin-angiotensin antagonist medication rates increased from 60.7% to 72.8%. Among patients with coronary artery disease, statin medication rates increased from 66% to 80.1%. Among patients with atrial fibrillation, oral anticoagulation rates increased from 52.7% to 65.2%. In contrast, blood pressure control rates among patients with hypertension were largely stable. PINNACLE data also fueled a variety of quality measurement programs and 51 peer-reviewed publications.

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

J Am Coll Cardiol: 06 Jan 2020; 75:93-112
Maddox TM, Song Y, Allen J, Chan PS, ... Virani SS, Masoudi FA
J Am Coll Cardiol: 06 Jan 2020; 75:93-112 | PMID: 31918838
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Abstract

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Aims
Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.
Methods and results
One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson\'s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].
Conclusion
Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 11 Feb 2020; epub ahead of print
Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049275
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Abstract

S-Nitrosylation of Muscle LIM Protein Facilitates Myocardial Hypertrophy Through Toll-Like Receptor 3-Mediated Receptor-Interacting Protein Kinase 3 and NLRP3 Inflammasome Activation.

Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of S-nitrosylation of muscle LIM protein (MLP) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. S-nitrosylation sites were further identified through liquid chromatography-tandem mass spectrometry (LCMS/MS). Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase (GSNOR) was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry (MS) and confirmed by co-immunoprecipitation. Recruitment of toll-like receptor 3 (TLR3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA (siRNA)-transfected neonatal rat cardiomyocytes (NRCMs) and in TLR3 knockout mouse model.SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction (TAC). The level of SNO-MLP also increased in angiotensin II (Ang II) or phenylephrine (PE)-treated NRCMs. S-nitrosylated site of MLP at cysteine (Cys) 79 was identified by LCMS/MS and further confirmed in NRCMs. Mutation of Cys79 significantly reduced hypertrophic growth in Ang II or PE-treated NRCMs and TAC mice. Reducing MLP Snitrosylation level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, MLP S-nitrosylation stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupting this interaction by downregulating TLR3 attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and receptor-interacting protein kinase 3 (RIP3). This interaction in turn induced NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a novel therapeutic target for myocardial hypertrophy and heart failure.



Circulation: 05 Jan 2020; epub ahead of print
Tang X, Pan L, Zhao S, Dai F, ... Han Y, Ji Y
Circulation: 05 Jan 2020; epub ahead of print | PMID: 31902237
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Abstract

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Aim
Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking.
Methods and results
We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001).
Conclusions
The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Feb 2020; epub ahead of print
López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Eur Heart J: 03 Feb 2020; epub ahead of print | PMID: 32016393
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Abstract

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J

Orai1 is a critical ion channel subunit, best recognized as a mediator of storeoperated Ca entry (SOCE) in non-excitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop JPIII, a small-molecule Orai1 channel inhibitor suitable fordelivery.Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. 5 weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and pro-hypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca signaling alterations (increased SOCE, decreased [Ca]i transients amplitude and decay rate, lower SR Ca load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from CdnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult.The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.



Circulation: 06 Jan 2020; epub ahead of print
Bartoli F, Bailey MA, Rode B, Mateo P, ... Benitah JP, Sabourin J
Circulation: 06 Jan 2020; epub ahead of print | PMID: 31906693
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Abstract

Cytokine mRNA Degradation in Cardiomyocytes Restrains Sterile Inflammation in Pressure Overloaded Hearts.

Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K

Proinflammatory cytokines play an important role in the pathogenesis of heart failure. However, the mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of the mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in non-immune cells such as cardiomyocytes remains to be elucidated.To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction (TAC) to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Furthermore, interleukin-6 (IL-6) signaling was inhibited by the administration with its receptor antibody. Finally, overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer.Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared to the control littermates. Four weeks after TAC, themRNA level was upregulated, but not other cytokine mRNAs including tumor necrosis factor-α in Regnase-1-deficient hearts. Although themRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-IL-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction ofmRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9- mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-IL-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice.The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.



Circulation: 13 Jan 2020; epub ahead of print
Omiya S, Omori Y, Taneike M, Murakawa T, ... Akira S, Otsu K
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931613
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Abstract

OUTSMART HF: A Randomized Controlled Trial of Routine Versus Selective Cardiac Magnetic Resonance for Patients with Non-Ischemic Heart Failure (IMAGE-HF 1B).

Paterson DI, Wells G, Erthal F, Mielniczuk L, ... Chan KL,

Cardiac magnetic resonance (CMR) is a recommended imaging test for patients with heart failure (HF), however there is a lack of evidence showing incremental benefit over transthoracic echocardiography. Hypothesis: Routine use of CMR will yield more specific diagnoses in non-ischemic HF. Secondary hypothesis: Routine use of CMR will improve patient outcomes.Patients with non-ischemic HF were randomized to Routine versus Selective CMR. Patients in the Routine strategy underwent echo and CMR whereas those assigned to Selective use underwent echo with or without CMR according to the clinical presentation. HF etiology was classified from the imaging data as well as by the treating physician at 3 months (primary outcome). Clinical events were collected for 12 months.500 patients (344 male), mean age 59±13, were randomized. The Routine and Selective CMR strategies had similar rates of specific HF etiologies at 3 months clinical follow-up, 44% vs. 50% respectively, p=0.22. At image interpretation, rates of specific HF etiology were also not different between Routine and Selective CMR, 34% vs. 30% respectively, p=0.34. However, 24% of patients in the Selective group underwent a non-protocol CMR. Patients with specific HF etiologies had more clinical events than those with non-specific etiologies based on imaging classification, 19% vs. 12% respectively, p=0.02, but not on clinical assessment, 15% vs. 14%, p=0.49.In patients with non-ischemic HF, Routine CMR does not yield more specific HF etiologies on clinical assessment. Patients with specific HF etiologies from imaging had worse outcomes whereas HF etiologies defined clinically did not.URL: https://clinicaltrials.gov. Unique Identifier: NCT01281384.



Circulation: 07 Jan 2020; epub ahead of print
Paterson DI, Wells G, Erthal F, Mielniczuk L, ... Chan KL,
Circulation: 07 Jan 2020; epub ahead of print | PMID: 31910649
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Abstract

Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

Schimmel K, Jung M, Foinquinos A, San José G, ... González A, Thum T

Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure (HF) development, a leading cause of deaths worldwide. Clinically there is no therapeutic strategy available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, we aimed at the development of novel anti-fibrotic therapeutics based on natural-derived substance library screens for the treatment of cardiac fibrosis.Anti-fibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts (HCFs), subsequent validation and mechanisticandstudies. Hits were analyzed for dose-dependent inhibition of proliferation of HCFs, for modulation of apoptosis and extracellular matrix expression.findings were confirmed , using an angiotensin II (Ang II)-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt sensitive rat model. To investigate the mechanism underlying the anti-fibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary HCFs were analyzed by RNA-deep sequencing.High-throughput natural compound library screening identified 15 substances with antiproliferative effects in HCFs. Using multiple in vitro fibrosis assays and stringent selection algorithms we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (fromspecies) to be effective anti-fibrotic molecules bothandleading to improvement in diastolic function in two hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers nor the morphology of kidney and liver, providing first toxicological safety data. By next-generation sequencing we identified the conserved microRNA (miR) miR-671-5p and downstream the antifibrotic selenoprotein P1 (SEPP1) as common effectors of the anti-fibrotic compounds.We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.



Circulation: 16 Jan 2020; epub ahead of print
Schimmel K, Jung M, Foinquinos A, San José G, ... González A, Thum T
Circulation: 16 Jan 2020; epub ahead of print | PMID: 31948273
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Abstract

Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association.

Kociol RD, Cooper LT, Fang JC, Moslehi JJ, ... Vardeny O,

Fulminant myocarditis (FM) is an uncommon syndrome characterized by sudden and severe diffuse cardiac inflammation often leading to death resulting from cardiogenic shock, ventricular arrhythmias, or multiorgan system failure. Historically, FM was almost exclusively diagnosed at autopsy. By definition, all patients with FM will need some form of inotropic or mechanical circulatory support to maintain end-organ perfusion until transplantation or recovery. Specific subtypes of FM may respond to immunomodulatory therapy in addition to guideline-directed medical care. Despite the increasing availability of circulatory support, orthotopic heart transplantation, and disease-specific treatments, patients with FM experience significant morbidity and mortality as a result of a delay in diagnosis and initiation of circulatory support and lack of appropriately trained specialists to manage the condition. This scientific statement outlines the resources necessary to manage the spectrum of FM, including extracorporeal life support, percutaneous and durable ventricular assist devices, transplantation capabilities, and specialists in advanced heart failure, cardiothoracic surgery, cardiac pathology, immunology, and infectious disease. Education of frontline providers who are most likely to encounter FM first is essential to increase timely access to appropriately resourced facilities, to prevent multiorgan system failure, and to tailor disease-specific therapy as early as possible in the disease process.



Circulation: 05 Jan 2020:CIR0000000000000745; epub ahead of print
Kociol RD, Cooper LT, Fang JC, Moslehi JJ, ... Vardeny O,
Circulation: 05 Jan 2020:CIR0000000000000745; epub ahead of print | PMID: 31902242
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Abstract

Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial.

Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL.DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms (\"atrial fibrillation\", \"atrial flutter\").Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005).Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients\' prior history of AF, ASCVD, or HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 26 Jan 2020; epub ahead of print
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983236
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Abstract

Regulatory RNAs in Heart Failure.

Gomes CPDC, Schroen B, Kuster GM, Robinson EL, ... Devaux Y,

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.



Circulation: 27 Jan 2020; 141:313-328
Gomes CPDC, Schroen B, Kuster GM, Robinson EL, ... Devaux Y,
Circulation: 27 Jan 2020; 141:313-328 | PMID: 31986093
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Abstract

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multi-Cohort Study.

Lewis AA, Ayers CR, Selvin E, Neeland I, ... deFilippi CR, de Lemos JA

A \"malignant\" subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk.Participants (n=15, 710) without prevalent cardiovascular disease were pooled from three population-based cohort studies, the Atherosclerosis Risk in Communities Study (ARIC), the Dallas Heart Study (DHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were classified into three groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT < 6 ng/L and NT-proBNP < 100 pg/mL), and those with ECGLVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF.Over the 10 year follow up period, HF occurred in 512 (3.3%) participants, with rates 5.2% among black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women vs white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI 2.1 to 3.5) in those with malignant LVH and 0.9 (95% CI 0.6 to 1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction (PAF) of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding PAF, were intermediate and similar among black women and white men and lowest among white women.A higher prevalence of malignant LVH may in part explain the higher risk of heart failure among blacks vs whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower heart failure risk and mitigate racial disparities.



Circulation: 13 Jan 2020; epub ahead of print
Lewis AA, Ayers CR, Selvin E, Neeland I, ... deFilippi CR, de Lemos JA
Circulation: 13 Jan 2020; epub ahead of print | PMID: 31931608
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Abstract

First in Human Experience with Peritoneal Direct Sodium Removal Using a Zero Sodium Solution: A New Candidate Therapy for Volume Overload.

Rao VS, Turner JM, Griffin M, Mahoney D, ... Finkelstein F, Testani JM

Loop diuretics have well described toxicities and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Non-renal removal of sodium directly across the peritoneal membrane (direct sodium removal, DSR) using a sodium free osmotic solution should result in extraction of large quantities of sodium with limited off target solute removal.This report describes the pre-clinical development and first-in-human proof of concept for DSR. Sodium free 10% dextrose was utilized as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, scalability, and to determine the effect of experimental HF. In the human study, participants with end stage renal disease (ESRD) on peritoneal dialysis (PD) underwent randomization and crossover to either a two-hour dwell with one liter of DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary endpoint was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary endpoint was difference in sodium removal between DSR and standard PD solution.Porcine experiments revealed that one liter of DSR solution removed 4.1±0.4 grams of sodium in 2 hours with negligible off target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (p=0.005). In the setting of experimental HF with elevated right atrial pressure, sodium removal was ~4 times greater than in healthy animals (p<0.001). In the human proof of concept study, DSR solution was well-tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable and off target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 grams) compared to standard PD solution (1.0±0.3 grams, p<0.0001).DSR was well-tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in HF is warranted.URL: https://clinicaltrials.gov Unique identifier: NCT03801226.



Circulation: 07 Jan 2020; epub ahead of print
Rao VS, Turner JM, Griffin M, Mahoney D, ... Finkelstein F, Testani JM
Circulation: 07 Jan 2020; epub ahead of print | PMID: 31910658
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Abstract

Readmission and Mortality After Hospitalization for Myocardial Infarction and Heart Failure.

Ko DT, Khera R, Lau G, Qiu F, ... Wijeysundera HC, Krumholz HM
Background
Readmission rates after acute myocardial infarction (AMI) and heart failure (HF) hospitalizations have decreased in the United States since the implementation of the Hospital Readmissions Reduction Program.
Objectives
This study was designed to examine the temporal trends of readmission and mortality after AMI and HF in Ontario, Canada, where reducing hospital readmissions has not had a policy incentive.
Methods
The cohort was comprised of AMI or HF patients 65 years of age or older who had been hospitalized from 2006 to 2017. Primary outcomes were 30-day readmission and post-discharge mortality. Secondary outcomes included in-hospital mortality, 30-day mortality from admission, and in-hospital mortality or 30-day mortality post-discharge. Adjusted monthly trends for each outcome were examined over the study period.
Results
Our cohorts included 152,808 AMI and 223,283 HF patients. Age- and sex-standardized AMI hospitalization rates in Ontario declined 32% from 2006 to 2017 while HF hospitalization rates declined slightly (9.1%). For AMI, risk-adjusted 30-day readmission rates declined from 17.4% in 2006 to 14.7% in 2017. All AMI risk-adjusted mortality rates also declined from 2006 to 2017 with 30-day post-discharge mortality from 5.1% to 4.4%. For HF, overall risk-adjusted 30-day readmission was largely unchanged from 2006 to 2014 at 21.9%, followed by a decline to 20.8% in 2017. Risk-adjusted 30-day post-discharge mortality declined from 7.1% in 2006 to 6.6% in 2017.
Conclusions
The patterns of outcomes in Ontario are consistent with the United States for AMI, but diverge for HF. For AMI and HF, admissions, readmissions, and mortality rates declined over this period. The reasons for the country-specific patterns for HF need further exploration.

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

J Am Coll Cardiol: 24 Feb 2020; 75:736-746
Ko DT, Khera R, Lau G, Qiu F, ... Wijeysundera HC, Krumholz HM
J Am Coll Cardiol: 24 Feb 2020; 75:736-746 | PMID: 32081282
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Abstract

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.We assayed myosin ATP binding to define the proportions of myosin in SRX or DRX conformations in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants with unknown clinical significance (VUS) that were identified in HCM patients, predicted functional consequences and associations with heart failure and arrhythmias.Myosins undergo physiologic shifts between SRX conformations that maximized energy-conservation and active states (DRX) that enable cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacologic modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased SRX conformations while pathogenic variants destabilized these and increased the proportion of DRX myosins, which enhanced cardiomyocyte contractility but impaired relaxation, and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify VUS, we showed that variants that unbalanced myosin conformations were associated with higher rates of heart failure and arrhythmias in HCM patients.Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy conserving states promotes contractile abnormalities, morphological and metabolic remodeling and adverse clinical outcomes in HCM patients. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in HCM patients.



Circulation: 26 Jan 2020; epub ahead of print
Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983222
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Abstract

Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium.

Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL

Diastolic dysfunction is a prevalent and therapeutically intractable feature of heart failure (HF). Increasing ventricular compliance can improve diastolic performance, but the viscoelastic forces that resist diastolic filling and become elevated in human HF are poorly defined. Having recently identified post-translationally detyrosinated microtubules as a source of viscoelasticity in cardiomyocytes, we sought to test whether microtubules contribute meaningful viscoelastic resistance to diastolic stretch in human myocardium.Experiments were conducted in isolated human cardiomyocytes and trabeculae. First, slow and rapid (diastolic) stretch was applied to intact cardiomyocytes from non-failing and HF hearts, and viscoelasticity was characterized following interventions targeting microtubules. Next, intact left-ventricular trabeculae from HF patient hearts were incubated with colchicine or vehicle and subject to pre- and post-treatment mechanical testing, which consisted of a staircase protocol and rapid stretches from slack length to increasing strains.Viscoelasticity was increased during diastolic stretch of HF cardiomyocytes compared to non-failing counterparts. Reducing either microtubule density or detyrosination reduced myocyte stiffness, particularly at diastolic strain rates, indicating reduced viscous forces. In myocardial tissue, we found microtubule depolymerization reduced myocardial viscoelasticity, with an effect that decreased with increasing strain. Colchicine reduced viscoelasticity at strains below, but not above, 15%, with a two-fold reduction in energy dissipation upon microtubule depolymerization. Post-hoc sub-group analysis revealed that myocardium from patients with HF with reduced ejection fraction (HFrEF) were more fibrotic and elastic than myocardium from patients with HF with preserved ejection fraction (HFpEF), which were relatively more viscous. Colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium.Failing cardiomyocytes exhibit elevated viscosity, and reducing microtubule density or detyrosination lowers viscoelastic resistance to diastolic stretch in human myocytes and myocardium. In failing myocardium, microtubules elevate stiffness over the typical working range of strains and strain rates, but exhibited diminishing effects with increasing length, consistent with an increasing contribution of the extracellular matrix and/or myofilament proteins at larger excursions. These studies indicate that a stabilized microtubule network provides a viscous impediment to diastolic stretch, particularly in HF.



Circulation: 15 Jan 2020; epub ahead of print
Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL
Circulation: 15 Jan 2020; epub ahead of print | PMID: 31941365
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Abstract

Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.

Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Background
The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).
Methods
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year\'s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year\'s edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association\'s 2020 Impact Goals.
Results
Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.
Conclusions
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.



Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print
Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print | PMID: 31992061
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Abstract

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Sharma A, Pagidipati NJ, Califf RM, McGuire DK, ... McMurray JJV, Granger CB

Responding to concerns about the potential for increased risk of adverse cardiovascular (CV) outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the U.S. Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were primarily granted regulatory approval from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on CV outcomes. The 2008 guidance aimed to ensure CV safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new CV outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated CV benefits of the newer agents, resulting in the first-ever CV protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed CV outcome trials. The group made several recommendations for future regulatory guidance and for CV outcome trials regarding glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.



Circulation: 28 Jan 2020; epub ahead of print
Sharma A, Pagidipati NJ, Califf RM, McGuire DK, ... McMurray JJV, Granger CB
Circulation: 28 Jan 2020; epub ahead of print | PMID: 31992065
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Abstract

Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials.

Marsico F, Paolillo S, Gargiulo P, Bruzzese D, ... Iesu I, Perrone Filardi P
Aims 
Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD.
Methods and results 
In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo.
Conclusion 
Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 19 Feb 2020; epub ahead of print
Marsico F, Paolillo S, Gargiulo P, Bruzzese D, ... Iesu I, Perrone Filardi P
Eur Heart J: 19 Feb 2020; epub ahead of print | PMID: 32077924
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Abstract

2020 Focused Update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation.

Bonow RO, O\'Gara PT, Adams DH, Badhwar V, ... Whisenant B, Woo YJ

Mitral regurgitation (MR) is a complex valve lesion that can pose significant management challenges. This Expert Consensus Decision Pathway emphasizes that recognition of MR should prompt an assessment of its etiology, mechanism, and severity, as well as consideration of the indications for treatment. The document is a focused update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation, with some sections updated and others added in light of the publication of new trial data related to secondary MR, among other developments. A structured approach to evaluation based on clinical findings, accurate echocardiographic imaging, and, when necessary, adjunctive testing, can help clarify decision making. Treatment goals include timely intervention by an experienced multidisciplinary heart team to prevent left ventricular dysfunction, heart failure, reduced quality of life, and premature death.

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

J Am Coll Cardiol: 09 Feb 2020; epub ahead of print
Bonow RO, O'Gara PT, Adams DH, Badhwar V, ... Whisenant B, Woo YJ
J Am Coll Cardiol: 09 Feb 2020; epub ahead of print | PMID: 32068084
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Abstract

Preventive or Deferred Ablation of Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial.

Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,

Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implanted cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation in order to prevent ICD shocks for VT) and deferred ablation after three ICD shocks for VT.The Preventive Ablation of Ventricular Tachycardia in Patients with Myocardial Infarction (BERLIN VT) study was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population.During a mean follow-up of 396{plus minus}284 days, the primary endpoint occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09; 95% CI, 0.62-1.92; P=0.77). Using prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, six versus two patients died (7.9% vs. 2.4%; P=0.18), eight versus two patients were admitted for worsening heart failure (10.4% vs. 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% vs. 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% vs. 48.2%; P=0.050) and appropriate ICD therapy (34.2% vs. 47.0%; P=0.030) were numerically reduced in the preventive ablation group.Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up when compared to the deferred ablation strategy.URL: https://www.clinicaltrials.gov. Unique identifier: NCT02501005.



Circulation: 30 Jan 2020; epub ahead of print
Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,
Circulation: 30 Jan 2020; epub ahead of print | PMID: 32000514
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Abstract

Women\'s Participation in Cardiovascular Clinical Trials From 2010 to 2017.

Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Background
Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials.
Methods
We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation).
Results
We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (=0.007) and heart failure (=0.01) trials compared with previous periods.
Conclusions
Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials.



Circulation: 17 Feb 2020; 141:540-548
Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Circulation: 17 Feb 2020; 141:540-548 | PMID: 32065763
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Abstract

Myocardial reperfusion reverses the J-curve association of cardiovascular risk and diastolic blood pressure in patients with left ventricular dysfunction and heart failure after myocardial infarction: insights from the EPHESUS trial.

Böhm M, Ferreira JP, Mahfoud F, Duarte K, ... Zannad F, Rossignol P
Aims
The described association of low diastolic blood pressure (DBP) with increased cardiovascular outcomes could be due to reduced coronary perfusion or is simply due to reverse causation. If DBP is physiologically relevant, coronary reperfusion after myocardial infarction (MI) might influence DBP-risk association.
Methods and results
The relation of achieved DBP with cardiovascular death or cardiovascular hospitalization, cardiovascular death, and all-cause death was explored in 5929 patients after acute myocardial infarction (AMI) with impaired left ventricular function, signs and symptoms of heart failure, or diabetes in the EPHESUS trial according to their reperfusion status. Cox regression models were used to assess the impact of reperfusion status on the association of DBP and systolic blood pressure (SBP) with outcomes in an adjusted fashion. In patients without reperfusion, lower DBP <70 mmHg was associated with increased risk for all-cause death [adjusted hazard ratios (HRs) 1.80, 95% confidence interval (CI) 1.41-2.30; P < 0.001], cardiovascular death (HR 1.70, 95% CI 1.3-3.22; P < 0.001), cardiovascular death or cardiovascular hospitalization (HR 1.54, 95% CI 1.26-1.87; P < 0.001). In patients with reperfusion, the risk increase at low DBP was not observed. At low SBP, risk increased independently of reperfusion. A sensitivity analysis in the subgroup of patients with optimal SBP of 120-130 mmHg showed again risk reduction of reperfusion at low DBP. Adding the treatment allocation to eplerenone or placebo into the models had no effects on the results.
Conclusion
Patients after AMIs with a low DBP had an increased risk, which was sensitive to reperfusion therapy. Low blood pressure after MI identifies in patients with particular higher risk. These data support the hypothesis that low DBP in patients with stenotic coronary lesions is associated with risk, potentially involving coronary perfusion pressure and the recommendations provided by guidelines suggesting lower DBP boundaries for these high-risk patients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 01 Mar 2020; epub ahead of print
Böhm M, Ferreira JP, Mahfoud F, Duarte K, ... Zannad F, Rossignol P
Eur Heart J: 01 Mar 2020; epub ahead of print | PMID: 32118256
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Abstract

Heart failure can affect everyone: the ESC Geoffrey Rose lecture.

Sliwa K

The principle of \'sick individuals vs. sick population\', a concept pioneered by Geoffrey Rose 35 years ago, is particularly applicable to heart failure (HF). This perspective article summarizes and expands on the Geoffrey Rose lecture given at the European Society of Cardiology meeting held in conjunction with the World Congress of Cardiology, in Paris, 2019. This article focuses on the fact that, clearly, HF not only affects a large spectrum of the population globally, but it occurs in all ages and equally in both genders. Heart failure, in most parts of the world, is clearly not a disease of the elderly. There are multiple and complex pathways leading to HF which include various risk factors (including communicable diseases and exposure to indoor and environmental pollutants), poverty and overcrowding, as well as sub-optimal access to health care systems due to socioeconomic inequities. Reflecting on Geoffrey Rose\'s concept 35 years later motivates us to confront our global responsibility to address the population distribution of risk factors more effectively, instead of focusing solely on interventions that target high-risk individuals.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 01 Mar 2020; epub ahead of print
Sliwa K
Eur Heart J: 01 Mar 2020; epub ahead of print | PMID: 32118263
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Abstract

Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer: A Population-Based Cohort Study.

Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L
Background
The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern.
Methods
We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality).
Results
The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14-3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11-2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88-2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82-1.72]).
Conclusions
In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.



Circulation: 17 Feb 2020; 141:549-559
Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L
Circulation: 17 Feb 2020; 141:549-559 | PMID: 32065766
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Abstract

The association of long-term outcome and biological sex in patients with acute heart failure from different geographic regions.

Motiejūnaitė J, Akiyama E, Cohen-Solal A, Maggioni AP, ... Regitz-Zagrosek V, Mebazaa A
Aims
Recent data from national registries suggest that acute heart failure (AHF) outcomes might vary in men and women, however, it is not known whether this observation is universal. The aim of this study was to evaluate the association of biological sex and 1-year all-cause mortality in patients with AHF in various regions of the world.
Methods and results
We analysed several AHF cohorts including GREAT registry (22 523 patients, mostly from Europe and Asia) and OPTIMIZE-HF (26 376 patients from the USA). Clinical characteristics and medication use at discharge were collected. Hazard ratios (HRs) for 1-year mortality according to biological sex were calculated using a Cox proportional hazards regression model with adjustment for baseline characteristics (e.g. age, comorbidities, clinical and laboratory parameters at admission, left ventricular ejection fraction). In the GREAT registry, women had a lower risk of death in the year following AHF [HR 0.86 (0.79-0.94), P < 0.001 after adjustment]. This was mostly driven by northeast Asia [n = 9135, HR 0.76 (0.67-0.87), P < 0.001], while no significant differences were seen in other countries. In the OPTIMIZE-HF registry, women also had a lower risk of 1-year death [HR 0.93 (0.89-0.97), P < 0.001]. In the GREAT registry, women were less often prescribed with a combination of angiotensin-converting enzyme inhibitors and beta-blockers at discharge (50% vs. 57%, P = 0.001).
Conclusion
Globally women with AHF have a lower 1-year mortality and less evidenced-based treatment than men. Differences among countries need further investigation. Our findings merit consideration when designing future global clinical trials in AHF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 02 Mar 2020; epub ahead of print
Motiejūnaitė J, Akiyama E, Cohen-Solal A, Maggioni AP, ... Regitz-Zagrosek V, Mebazaa A
Eur Heart J: 02 Mar 2020; epub ahead of print | PMID: 32125360
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Abstract

Body Mass Index in Young Women and Risk of Cardiomyopathy: A Long-Term Follow-Up Study in Sweden.

Robertson J, Lindgren M, Schaufelberger M, Adiels M, ... Rosengren A, Åberg M
Background
Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy.
Methods
This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18-45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers.
Results
In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81-7.89) was found for severely obese subjects (BMI ≥35 kg/m), as compared with BMI 20 to <22.5.
Conclusions
Elevated BMI among young women was associated with an increased risk of being diagnosed with a subsequent cardiomyopathy, especially dilated cardiomyopathy, starting already at mildly elevated body weight, whereas severe obesity entailed an almost 5-fold increase in risk. With the increasing numbers of persons who are overweight or obese, higher rates of cardiomyopathy can be expected in the future, along with an altered disease burden related to adiposity.



Circulation: 17 Feb 2020; 141:520-529
Robertson J, Lindgren M, Schaufelberger M, Adiels M, ... Rosengren A, Åberg M
Circulation: 17 Feb 2020; 141:520-529 | PMID: 32065765
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Abstract

Emerging Techniques for Risk Stratification in Nonischemic Dilated Cardiomyopathy: JACC Review Topic of the Week.

Marrow BA, Cook SA, Prasad SK, McCann GP

Dilated cardiomyopathy (DCM) is a common condition, which carries significant mortality from sudden cardiac death and pump failure. Left ventricular ejection fraction has conventionally been used as a risk marker for sudden cardiac death, but has performed poorly in trials. There have been significant advances in the areas of cardiac magnetic resonance imaging and genetics, which are able to provide useful rick prediction in DCM. Biomarkers and cardiopulmonary exercise testing are well validated in the prediction of risk in heart failure; however, they have been tested less specifically in the DCM setting. This review will discuss these methods with a view toward multiparametric risk assessment in DCM with the hope of creating parametric risk models to predict sudden cardiac death and pump failure in the DCM population.

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

J Am Coll Cardiol: 16 Mar 2020; 75:1196-1207
Marrow BA, Cook SA, Prasad SK, McCann GP
J Am Coll Cardiol: 16 Mar 2020; 75:1196-1207 | PMID: 32164893
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Abstract

Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review.

Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM

Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics.

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

J Am Coll Cardiol: 16 Mar 2020; 75:1178-1195
Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM
J Am Coll Cardiol: 16 Mar 2020; 75:1178-1195 | PMID: 32164892
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Abstract

Effects of Liraglutide on Cardiovascular Outcomes in Patients With Diabetes With or Without Heart Failure.

Marso SP, Baeres FMM, Bain SC, Goldman B, ... Buse JB,
Background
More data regarding effects of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes (T2D) and heart failure (HF) are required.
Objectives
The purpose of this study was to investigate the effects of liraglutide on cardiovascular events and mortality in LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) participants, by HF history.
Methods
In the multinational, double-blind, randomized LEADER trial, 9,340 patients with T2D and high cardiovascular risk were assigned 1:1 to liraglutide (1.8 mg daily or maximum tolerated dose up to 1.8 mg daily) or placebo plus standard care, and followed for 3.5 to 5 years. New York Heart Association (NYHA) functional class IV HF was an exclusion criterion. The primary composite major adverse cardiovascular events outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Post hoc Cox regression analyses of outcomes by baseline HF history were conducted.
Results
At baseline, 18% of patients had a history of NYHA functional class I to III HF (liraglutide: n = 835 of 4,668; placebo: n = 832 of 4,672). Effects of liraglutide versus placebo on major adverse cardiovascular events were consistent in patients with (hazard ratio [HR]: 0.81 [95% confidence interval (CI): 0.65 to 1.02]) and without (HR: 0.88 [95% CI: 0.78 to 1.00]) a history of HF (p interaction = 0.53). In both subgroups, fewer deaths were observed with liraglutide (HR: 0.89 [95% CI: 0.70 to 1.14] with HF; HR: 0.83 [95% CI: 0.70 to 0.97] without HF; p interaction = 0.63) versus placebo. No increased risk of HF hospitalization was observed with liraglutide, regardless of HF history (HR: 0.98 [95% CI: 0.75 to 1.28] with HF; HR: 0.78 [95% CI: 0.61 to 1.00] without HF; p interaction = 0.22). Effects of liraglutide on the composite of HF hospitalization or cardiovascular death were consistent in patients with (HR: 0.92 [95% CI: 0.74 to 1.15]) and without (HR: 0.77 [95% CI: 0.65 to 0.91]) a history of HF (p interaction = 0.19).
Conclusions
Based on these findings, liraglutide should be considered suitable for patients with T2D with or without a history of NYHA functional class I to III HF. (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER]; NCT01179048).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 16 Mar 2020; 75:1128-1141
Marso SP, Baeres FMM, Bain SC, Goldman B, ... Buse JB,
J Am Coll Cardiol: 16 Mar 2020; 75:1128-1141 | PMID: 32164886
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Abstract

Stem Cell-Derived Cardiomyocytes and Beta-Adrenergic Receptor Blockade in Duchenne Muscular Dystrophy Cardiomyopathy.

Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
Background
Although cardiomyopathy has emerged as a leading cause of death in Duchenne muscular dystrophy (DMD), limited studies and therapies have emerged for dystrophic heart failure.
Objectives
The purpose of this study was to model DMD cardiomyopathy using DMD patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and to identify physiological changes and future drug therapies.
Methods
To explore and define therapies for DMD cardiomyopathy, the authors used DMD patient-specific hiPSC-derived cardiomyocytes to examine the physiological response to adrenergic agonists and β-blocker treatment. The authors further examined these agents in vivo using wild-type and mdx mouse models.
Results
At baseline and following adrenergic stimulation, DMD hiPSC-derived cardiomyocytes had a significant increase in arrhythmic calcium traces compared to isogenic controls. Furthermore, these arrhythmias were significantly decreased with propranolol treatment. Using telemetry monitoring, the authors observed that mdx mice, which lack dystrophin, had an arrhythmic death when stimulated with isoproterenol; the lethal arrhythmias were rescued, in part, by propranolol pre-treatment. Using single-cell and bulk RNA sequencing (RNA-seq), the authors compared DMD and control hiPSC-derived cardiomyocytes, mdx mice, and control mice (in the presence or absence of propranolol and isoproterenol) and defined pathways that were perturbed under baseline conditions and pathways that were normalized after propranolol treatment in the mdx model. The authors also undertook transcriptome analysis of human DMD left ventricle samples and found that DMD hiPSC-derived cardiomyocytes have dysregulated pathways similar to the human DMD heart. The authors further determined that relatively few patients with DMD see a cardiovascular specialist or receive β-blocker therapy.
Conclusions
The results highlight mechanisms and therapeutic interventions from human to animal and back to human in the dystrophic heart. These results may serve as a prelude for an adequately powered clinical study that examines the impact of β-blocker therapy in patients with dystrophinopathies.

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

J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174
Kamdar F, Das S, Gong W, Klaassen Kamdar A, ... Zhang J, Garry DJ
J Am Coll Cardiol: 16 Mar 2020; 75:1159-1174 | PMID: 32164890
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Abstract

Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac Hypertrophy.

Ren Z, Yu P, Li D, Li Z, ... Zhou B, Wang L

Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart\'s workload after the onset of heart failure. Thus, more etiology-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular level.By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and non-cardiomyocytes, based on their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay amongst cell types, and tested potential pharmacologic treatment strategies to retard its progression .We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific non-cardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose co-transporter 2 inhibitor in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Importantly, similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy, but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.



Circulation: 25 Feb 2020; epub ahead of print
Ren Z, Yu P, Li D, Li Z, ... Zhou B, Wang L
Circulation: 25 Feb 2020; epub ahead of print | PMID: 32098504
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Abstract

Clinical characteristics, diagnosis, and risk stratification of pulmonary hypertension in severe tricuspid regurgitation and implications for transcatheter tricuspid valve repair.

Lurz P, Orban M, Besler C, Braun D, ... Hausleiter J, Rommel KP
Aims
Patients with pulmonary hypertension (PHT) are often excluded from surgical therapies for tricuspid regurgitation (TR). Transcatheter tricuspid valve repair (TTVR) with the MitraClip™ technique is a novel treatment option for these patients. We aimed to assess the role of PHT in severe TR and its implications for TTVR.
Methods and results
A total of 243 patients underwent TTVR at two centres. One hundred twenty-one patients were grouped as iPHT+ [invasive systolic pulmonary artery pressures (PAPs) ≥50 mmHg]. Patients were similarly stratified according to echocardiographic PAPs (ePHT). The occurrence of the combined clinical endpoint (death, heart failure hospitalization, and reintervention) was investigated during a follow-up of 330 (interquartile range 175-402) days. iPHT+ patients were at higher preoperative risk (P < 0.01), had more severe symptoms (P = 0.01), higher N-terminal pro-B-type natriuretic peptide levels (P < 0.01), more impaired right ventricular (RV) function (P < 0.01), and afterload corrected RV function (P < 0.01). Procedural TTVR success was similar in iPHT+ and iPHT- patients (84 vs. 84%, P = 0.99). The echocardiographic diagnostic accuracy to detect iPHT was only 55%. During follow-up, 35% of patients reached the combined clinical endpoint. The discordant diagnosis of iPHT+/ePHT- carried the highest risk for the combined clinical endpoint [HR 3.76 (CI 2.25-6.37), P < 0.01], while iPHT+/ePHT+ patients had a similar survival-free time from the combined endpoint compared to iPHT- patients (P = 0.48). In patients with isolated tricuspid procedure (n = 131) a discordant iPHT+/ePHT- diagnosis and an impaired afterload corrected RV function (P < 0.01 for both) were independent predictors for the occurrence of the combined endpoint.
Conclusion
The discordant echocardiographic and invasive diagnosis of PHT in severe TR predicts outcomes after TTVR.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 15 Mar 2020; epub ahead of print
Lurz P, Orban M, Besler C, Braun D, ... Hausleiter J, Rommel KP
Eur Heart J: 15 Mar 2020; epub ahead of print | PMID: 32176280
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Abstract

Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure.

Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM

Pulmonary hypertension (PH) is a feature of a variety of diseases and continues to harbor high morbidity and mortality. The main consequence of PH is right-sided heart failure which causes a complex clinical syndrome affecting multiple organ systems including left heart, brain, kidneys, liver, gastrointestinal tract, skeletal muscle, as well as the endocrine, immune, and autonomic systems. Interorgan crosstalk and interdependent mechanisms include hemodynamic consequences such as reduced organ perfusion and congestion as well as maladaptive neurohormonal activation, oxidative stress, hormonal imbalance, and abnormal immune cell signaling. These mechanisms, which may occur in acute, chronic, or acute-on-chronic settings, are common and precipitate adverse functional and structural changes in multiple organs which contribute to increased morbidity and mortality. While the systemic character of PH and right-sided heart failure is often neglected or underestimated, such consequences place additional burden on patients and may represent treatable traits in addition to targeted therapy of PH and underlying causes. Here, we highlight the current state-of-the-art understanding of the systemic consequences of PH and right-sided heart failure on multiple organ systems, focusing on self-perpetuating pathophysiological mechanisms, aspects of increased susceptibility of organ damage, and their reciprocal impact on the course of the disease.



Circulation: 24 Feb 2020; 141:678-693
Rosenkranz S, Howard LS, Gomberg-Maitland M, Hoeper MM
Circulation: 24 Feb 2020; 141:678-693 | PMID: 32091921
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Abstract

Effect of bariatric surgery on long-term cardiovascular outcomes: a nationwide nested cohort study.

Moussa O, Ardissino M, Heaton T, Tang A, ... Collins P, Purkayastha S
Aims
This study aims to evaluate the long-term effect of bariatric surgery on cardiovascular outcomes of patients with obesity.
Methods and results
A nested cohort study was carried out within the Clinical Practice Research Datalink. The study cohort included the 3701 patients on the database who had undergone bariatric surgery and 3701 age, gender, and body mass index-matched controls. The primary endpoint was the composite of fatal or non-fatal myocardial infarction and fatal or non-fatal ischaemic stroke. Secondary endpoints included fatal or non-fatal myocardial infarction alone, fatal or non-fatal ischaemic stroke alone, incident heart failure, and mortality. The median follow-up achieved was 11.2 years. Patients who had undergone bariatric surgery had a significantly lower occurrence of major adverse cardiovascular events [hazard ratio (HR) 0.410, 95% confidence interval (CI) 0.274-0.615; P < 0.001]. This was mainly driven by a reduction in myocardial infarction (HR 0.412, 95% CI 0.280-0.606; P < 0.001) and not in acute ischaemic stroke (HR 0.536, 95% CI 0.164-1.748; P = 0.301). A reduction was also observed in new diagnoses of heart failure (HR 0.403, 95% CI 0.181-0.897; P = 0.026) and mortality (HR 0.254, 95% CI 0.183-0.353; P < 0.001).
Conclusion
The results of this large, nationwide cohort study support the association of bariatric surgery with lower long-term risk of major cardiovascular events and incident heart failure in patients with obesity.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 18 Mar 2020; epub ahead of print
Moussa O, Ardissino M, Heaton T, Tang A, ... Collins P, Purkayastha S
Eur Heart J: 18 Mar 2020; epub ahead of print | PMID: 32188981
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Abstract

Evidence from Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy: Associations of Circulating Anti-Heart and Anti-Intercalated Disk Autoantibodies with Disease Severity and Family History.

Caforio ALP, Re F, Avella A, Marcolongo R, ... Iliceto S, Zachara E

Serum anti-heart autoantibodies (AHA) and anti-intercalated disk autoantibodies (AIDA) are autoimmune markers in myocarditis. In arrhythmogenic right ventricular cardiomyopathy (ARVC) myocarditis has been reported. To provide evidence for autoimmunity, we searched for AHA and AIDA in ARVC.We studied: 42 ARVC probands, 23 male, aged 42, interquartile range (IQR) 33;49, 20 from familial and 22 non-familial pedigrees; 37 clinically affected relatives (AR), 24 male aged 35, IQR 18;46; 96 healthy relatives (HR), 49 male, aged 27, IQR 17;45. Serum AHA and AIDA were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with: non-inflammatory cardiac disease (NICD) (n=160), ischemic heart failure (IHF) (n=141), normal blood donors (NBD) (n=270). Screening of five desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunological results.AHA frequency was higher (36.8%) in probands, AR (37.8%) and HR (25%) than in NICD (1%), IHF (1%) or NBD (2.5%) (p=0.0001). AIDA frequency was higher in probands (8%, p=0.006), in AR (21.6%, p=0.00001) and in HR (14.6% p=0.00001) than in NICD (3.75%), IHF (2%) or NBD (0.3%). AHA positive status was associated with higher frequency of palpitation (p=0.004), ICD implantation (p=0.021), lower left ventricular ejection fraction (LVEF) (p=0.004), AIDA positive status with both lower RV and LVEF (p=0.027 and p=0.027 respectively). AHA and/or AIDA positive status in the proband and/or at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees (p=0.007).Presence of AHA and AIDA provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in AR these antibodies were associated with disease severity features; longitudinal studies are needed to clarify whether they may predict ARVC development in HR or if they be a result of manifest ARVC.



Circulation: 01 Mar 2020; epub ahead of print
Caforio ALP, Re F, Avella A, Marcolongo R, ... Iliceto S, Zachara E
Circulation: 01 Mar 2020; epub ahead of print | PMID: 32114801
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Abstract

The Prognostic Significance of Quantitative Myocardial Perfusion: An Artificial Intelligence Based Approach Using Perfusion Mapping.

Knott KD, Seraphim A, Augusto JB, Xue H, ... Kellman P, Moon JC

Myocardial perfusion reflects the macro- and microvascular coronary circulation. Recent quantitation developments using cardiovascular magnetic resonance (CMR) perfusion permit automated measurement clinically. We explored the prognostic significance of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR, the ratio of stress to rest MBF).A two center study of patients with both suspected and known coronary artery disease referred clinically for perfusion assessment. Image analysis was performed automatically using a novel artificial intelligence approach deriving global and regional stress and rest MBF and MPR. Cox proportional hazard models adjusting for co-morbidities and CMR parameters sought associations of stress MBF and MPR with death and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, heart failure hospitalization, late (>90 day) revascularization and death.1049 patients were included with median follow-up 605 (interquartile range 464-814) days. There were 42 (4.0%) deaths and 188 MACE in 174 (16.6%) patients. Stress MBF and MPR were independently associated with both death and MACE. For each 1ml/g/min decrease in stress MBF the adjusted hazard ratio (HR) for death and MACE were 1.93 (95% CI 1.08-3.48, P=0.028) and 2.14 (95% CI 1.58-2.90, P<0.0001) respectively, even after adjusting for age and co-morbidity. For each 1 unit decrease in MPR the adjusted HR for death and MACE were 2.45 (95% CI 1.42-4.24, P=0.001) and 1.74 (95% CI 1.36-2.22, P<0.0001) respectively. In patients without regional perfusion defects on clinical read and no known macrovascular coronary artery disease (n=783), MPR remained independently associated with death and MACE, with stress MBF remaining associated with MACE only.In patients with known or suspected coronary artery disease, reduced MBF and MPR measured automatically inline using artificial intelligence quantification of CMR perfusion mapping provides a strong, independent predictor of adverse cardiovascular outcomes.



Circulation: 13 Feb 2020; epub ahead of print
Knott KD, Seraphim A, Augusto JB, Xue H, ... Kellman P, Moon JC
Circulation: 13 Feb 2020; epub ahead of print | PMID: 32078380
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Abstract

Inflammation in Heart Failure: JACC State-of-the-Art Review.

Murphy SP, Kakkar R, McCarthy CP, Januzzi JL

It has long been observed that heart failure (HF) is associated with measures of systemic inflammation. In recent years, there have been significant advancements in our understanding of how inflammation contributes to the pathogenesis and progression of HF. However, although numerous studies have validated the association between measures of inflammation and HF severity and prognosis, clinical trials of anti-inflammatory therapies have proven mostly unsuccessful. On this backdrop emerges the yet unmet goal of targeting precise phenotypes within the syndrome of HF; if such precise definitions can be realized, and with better understanding of the roles played by specific inflammatory mediators, the expectation is that targeted anti-inflammatory therapies may improve prognosis in patients whose HF is driven by inflammatory pathobiology. Here, the authors describe mechanistic links between inflammation and HF, discuss traditional and novel inflammatory biomarkers, and summarize the latest evidence from clinical trials of anti-inflammatory therapies.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1324-1340
Murphy SP, Kakkar R, McCarthy CP, Januzzi JL
J Am Coll Cardiol: 23 Mar 2020; 75:1324-1340 | PMID: 32192660
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Abstract

Multiple Plasma Biomarkers for Risk Stratification in Patients With Heart Failure and Preserved Ejection Fraction.

Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
Background
Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).
Objectives
The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.
Methods
In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).
Results
Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.
Conclusions
Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.

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

J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295
Chirinos JA, Orlenko A, Zhao L, Basso MD, ... Moore JH, Cappola TP
J Am Coll Cardiol: 23 Mar 2020; 75:1281-1295 | PMID: 32192654
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Abstract

Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort.

Mulrooney DA, Hyun G, Ness KK, Ehrhardt MJ, ... Hudson MM, Armstrong GT
Objective
To investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer.
Design
Retrospective cohort study.
Setting
27 institutions participating in the Childhood Cancer Survivor Study.
Participants
23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included.
Main outcome measures
Cumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute\'s Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments.
Results
The 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10).
Conclusions
Historical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes.
Trial registration
ClinicalTrials.gov NCT01120353.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 14 Jan 2020; 368:l6794
Mulrooney DA, Hyun G, Ness KK, Ehrhardt MJ, ... Hudson MM, Armstrong GT
BMJ: 14 Jan 2020; 368:l6794 | PMID: 31941657
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Abstract

Cellular Adhesion Molecules in Young Adulthood and Cardiac Function in Later Life.

Patel RB, Colangelo LA, Reiner AP, Gross MD, ... Lloyd-Jones DM, Shah SJ
Background
E-selectin and intercellular adhesion molecule-1 (ICAM-1) are biomarkers of endothelial activation, which has been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF). However, the temporal associations between E-selectin and ICAM-1 with subclinical cardiac dysfunction are unclear.
Objectives
To assess the longitudinal associations of E-selectin and ICAM-1 with subclinical alterations in cardiac function.
Methods
In the Coronary Artery Disease Risk Development in Young Adults study, a cohort of black and white young adults, we evaluated the associations of E-selectin and ICAM-1, obtained at year 7 (Y7) and Y15 examinations, with cardiac function assessed at Y30 after adjustment for key covariates.
Results
Higher E-selectin (n=1,810) and ICAM-1 (n=1,548) at Y7 were associated with black race, smoking, hypertension, and higher BMI. After multivariable adjustment, higher E-selectin at Y7 (β-coefficient per 1-SD higher: 0.22, SE: 0.06, P<0.001) and Y15 (β-coefficient per 1-SD higher: 0.19, SE: 0.06, P=0.002) was associated with worse left ventricular (LV) global longitudinal strain (GLS). Additionally, higher Y15 ICAM-1 (β-coefficient per 1-SD higher: 0.18, SE: 0.06, P=0.004) and its increase from Y7 to Y15 (β-coefficient per 1-SD higher: 0.16, SE: 0.07, P=0.03) were also independently associated with worse LV GLS. E-selectin and ICAM-1 partially mediated the associations between higher BMI and black race with worse GLS. Neither E-selectin nor ICAM-1 were associated with measures of LV diastolic function after multivariable adjustment.
Conclusion
Circulating levels of E-selectin and ICAM-1 and increases in ICAM-1 over the course of young adulthood are associated with worse indices of LV systolic function in midlife. These findings suggest associations of endothelial activation with subclinical HFpEF.

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

J Am Coll Cardiol: 10 Mar 2020; epub ahead of print
Patel RB, Colangelo LA, Reiner AP, Gross MD, ... Lloyd-Jones DM, Shah SJ
J Am Coll Cardiol: 10 Mar 2020; epub ahead of print | PMID: 32194198
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Abstract

Post-discharge acute care and outcomes following readmission reduction initiatives: national retrospective cohort study of Medicare beneficiaries in the United States.

Khera R, Wang Y, Bernheim SM, Lin Z, Krumholz HM
Objectives
To determine whether patients discharged after hospital admissions for conditions covered by national readmission programs who received care in emergency departments or observation units but were not readmitted within 30 days had an increased risk of death and to evaluate temporal trends in post-discharge acute care utilization in inpatient units, emergency departments, and observation units for these patients.
Design
Retrospective cohort study.
Setting
Medicare claims data for 2008-16 in the United States.
Participants
Patients aged 65 or older admitted to hospital with heart failure, acute myocardial infarction, or pneumonia-conditions included in the US Hospital Readmissions Reduction Program.
Main outcome measures
Post-discharge 30 day mortality according to patients\' 30 day acute care utilization; acute care utilization in inpatient and observation units and the emergency department during the 30 day and 31-90 day post-discharge period.
Results
3 772 924 hospital admissions for heart failure, 1 570 113 for acute myocardial infarction, and 3 131 162 for pneumonia occurred. The overall post-discharge 30 day mortality was 8.7% for heart failure, 7.3% for acute myocardial infarction, and 8.4% for pneumonia. Risk adjusted mortality increased annually by 0.05% (95% confidence interval 0.02% to 0.08%) for heart failure, decreased by 0.06% (-0.09% to -0.04%) for acute myocardial infarction, and did not significantly change for pneumonia. Specifically, mortality increased for patients with heart failure who did not utilize any post-discharge acute care, increasing at a rate of 0.08% (0.05% to 0.12%) per year, exceeding the overall absolute annual increase in post-discharge mortality in heart failure, without an increase in mortality in observation units or the emergency department. Concurrent with a reduction in 30 day readmission rates, stays for observation and visits to the emergency department increased across all three conditions during and beyond the 30 day post-discharge period. Overall 30 day post-acute care utilization did not change significantly.
Conclusions
The only condition with increasing mortality through the study period was heart failure; the increase preceded the policy and was not present among patients who received emergency department or observation unit care without admission to hospital. During this period, the overall acute care utilization in the 30 days after discharge significantly decreased for heart failure and pneumonia, but not for acute myocardial infarction.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 14 Jan 2020; 368:l6831
Khera R, Wang Y, Bernheim SM, Lin Z, Krumholz HM
BMJ: 14 Jan 2020; 368:l6831 | PMID: 31941686
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Abstract

Systolic Blood Pressure in Heart Failure With Preserved Ejection Fraction Treated With Sacubitril/Valsartan.

Selvaraj S, Claggett BL, Böhm M, Anker SD, ... McMurray JJV, Solomon SD
Background
Guidelines recommend targeting systolic blood pressure (SBP) <130 mm Hg in heart failure with preserved ejection fraction (HFpEF) with limited data.
Objectives
This study sought to determine the optimal achieved SBP and whether the treatment effects of sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from sacubitril/valsartan.
Methods
Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles (<120, 120 to 129, 130 to 139, ≥140 mm Hg) to the primary outcome (cardiovascular death and total heart failure hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 16-week visit, the study assessed the relationship between SBP change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). The study analyzed whether the BP-lowering effects of sacubitril/valsartan accounted for its treatment effects.
Results
Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p < 0.001) but not KCCQ-OSS (p = 0.40). The association between sacubitril/valsartan and the primary outcome was not modified by baseline SBP (interaction p = 0.50) and was similar when adjusting for time-updated SBP, regardless of sex.
Conclusions
Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of sacubitril/valsartan, and the BP-lowering effects of sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

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

J Am Coll Cardiol: 10 Mar 2020; epub ahead of print
Selvaraj S, Claggett BL, Böhm M, Anker SD, ... McMurray JJV, Solomon SD
J Am Coll Cardiol: 10 Mar 2020; epub ahead of print | PMID: 32192799
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Abstract

Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy.

Kazi DS, Bellows BK, Baron SJ, Shen C, ... Maurer MS, Shah SJ

In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), tafamidis reduces all-cause mortality and cardiovascular hospitalizations, and slows decline in quality-oflife compared with placebo. In May 2019, tafamidis received expedited approval from the US FDA as a breakthrough drug for a rare disease. However, at $225,000 per year, it is the most expensive cardiovascular drug ever launched in the US, and its long-term cost-effectiveness and budget impact are uncertain. We therefore sought to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending.We developed a Markov model of patients with wild-type or variant ATTR-CM and heart failure (mean age 74.5 years) using inputs from the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. We compared no disease-specific treatment (\"usual care\") with tafamidis therapy. The model reproduced 30-month survival, quality-of-life, and cardiovascular hospitalization rates observed in ATTR-ACT; future projections used a parametric survival model in the control arm, with constant hazards reduction in the tafamidis arm. We discounted future costs and quality-adjusted life years (QALYs) by 3% annually, and examined key parameter uncertainty using deterministic and probabilistic sensitivity analyses. The main outcomes were lifetime incremental costeffectiveness ratio (ICER) and annual budget impact, assessed from the US healthcare sector perspective. This study was independent of the ATTR-ACT trial sponsor.Compared with usual care, tafamidis was projected to add 1.29 (95% uncertainty interval, 0.47-1.75) QALYs at an incremental cost of $1,135,000 (872,000-1,377,000), resulting in an ICER of $880,000 (697,000-1,564,000) per QALY gained. Assuming a threshold of $100,000 per QALY gained and current drug price, tafamidis was cost-effective in 0% of 10,000 probabilistic simulations. A 92.6% price reduction from $225,000 to $16,563 would be necessary to make tafamidis cost-effective at $100,000/QALY. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with ATTR-CM in the US with tafamidis (n = 120,000) was estimated to increase annual healthcare spending by $32.3 billion.Treatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. Based on recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.



Circulation: 11 Feb 2020; epub ahead of print
Kazi DS, Bellows BK, Baron SJ, Shen C, ... Maurer MS, Shah SJ
Circulation: 11 Feb 2020; epub ahead of print | PMID: 32078382
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Abstract

Association of Intensive Lifestyle Intervention, Fitness and Body Mass Index with Risk of Heart Failure in Overweight or Obese Adults with Type 2 Diabetes Mellitus: An Analysis from the Look AHEAD Trial.

Pandey A, Patel KV, Bahnson JL, Gaussoin SA, ... Berry JD,

Type 2 diabetes mellitus (T2DM) is associated with higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF), and body mass index (BMI) on risk for HF is not well-established.Participants from the Look AHEAD (Action for Health in Diabetes) trial without prevalent HF were included. Time to event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention (ILI) vs. diabetes support and education (DSE) groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, BMI, and longitudinal changes in these parameters with risk of HF were evaluated using multivariable adjusted Cox models.Among the 5,109 trial participants, there was no significant difference in the risk of incident HF (n = 257) between the ILI vs. DSE groups [HR (95% CI) = 0.96 (0.75 to 1.23)] over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit [Tertile 2: HR (95% CI) = 0.61 (0.44 to 0.83)] and high fit [Tertile 3: HR (95% CI) = 0.38 (0.24 to 0.59)] groups, respectively (referent group: low fit, Tertile 1). Among HF subtypes, after adjustment for traditional CV risk factors and interval incidence of MI, baseline CRF was not significantly associated with risk of incident HFrEF. In contrast, the risk of incident HFpEF was 40% lower in moderate fit and 77% lower in the high fit groups. Baseline BMI was also not associated with risk of incident HF, HFpEF, or HFrEF after adjustment for CRF and traditional CV risk factors. Among participants with repeat CRF assessments (n = 3,902), improvements in CRF and weight loss over 4-year follow-up was significantly associated with lower risk of HF [HR (95% CI) per 10% increase in CRF = 0.90 (0.82 to 0.99), per 10% decrease in BMI = 0.80 (0.69 to 0.94)].Among participants with T2DM in the Look AHEAD trial, the ILI did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF.URL: https://www.clinicaltrials.gov Unique identifier: NCT00017953.



Circulation: 04 Mar 2020; epub ahead of print
Pandey A, Patel KV, Bahnson JL, Gaussoin SA, ... Berry JD,
Circulation: 04 Mar 2020; epub ahead of print | PMID: 32134326
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Abstract

Health Status Changes and Outcomes in Patients with Heart Failure and Mitral Regurgitation: From COAPT.

Arnold SV, Stone GW, Mack MJ, Chhatriwalla AK, ... Cohen DJ,
Background
In the COAPT trial, transcatheter mitral valve repair (TMVr) with the MitraClip rapidly improved health status and reduced the long-term risks of death and heart failure (HF) hospitalization in patients with HF and severe secondary mitral regurgitation (SMR) who remained symptomatic despite maximally-tolerated guideline directed medical therapy (GDMT).
Objective
To examine if early health status changes were associated with long-term clinical outcomes in the COAPT population.
Methods
We evaluated the association between change in health status (KCCQ-OS) from baseline to 1 month and the composite rate of death or HF hospitalization between 1 month and 2 years in the COAPT trial and tested whether treatment (TMVr or GDMT alone) modified this association.
Results
Among 551 patients with HF and severe SMR who were alive at 1 month, those randomized to TMVr were more likely than GDMT alone to achieve a ≥10-point improvement in KCCQ-OS from baseline to 1 month (TMVr 58%, GDMT alone 26%). Early improvement in KCCQ-OS was inversely associated with the risk of death or HF hospitalization between 1 month and 2 years (p<0.001). When analyzed as a continuous variable, a 10-point increase in KCCQ-OS was associated with a 14% lower risk of death or HF hospitalization (HR 0.86, 95% CI 0.81-0.92, p<0.001), with no significant interaction with treatment group (p=0.17). After adjusting for demographic and clinical factors, the association between change in KCCQ-OS and outcomes was strengthened (HR 0.79, 95% CI 0.73-0.86, p<0.001).
Conclusion
In patients with HF and severe SMR, a short-term change in disease-specific health status was strongly associated with the subsequent long-term risk of death or HF hospitalization. These findings reinforce the prognostic utility of serial KCCQ-OS assessments to identify patients at risk for poor long-term clinical outcomes in this population.

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

J Am Coll Cardiol: 03 Mar 2020; epub ahead of print
Arnold SV, Stone GW, Mack MJ, Chhatriwalla AK, ... Cohen DJ,
J Am Coll Cardiol: 03 Mar 2020; epub ahead of print | PMID: 32194195
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Impact:
Abstract

Cost-Effectiveness of Transitional Care Services After Hospitalization With Heart Failure.

Blum MR, Øien H, Carmichael HL, Heidenreich P, Owens DK, Goldhaber-Fiebert JD
Background
Patients with heart failure (HF) discharged from the hospital are at high risk for death and rehospitalization. Transitional care service interventions attempt to mitigate these risks.
Objective
To assess the cost-effectiveness of 3 types of postdischarge HF transitional care services and standard care.
Design
Decision analytic microsimulation model.
Data sources
Randomized controlled trials, clinical registries, cohort studies, Centers for Disease Control and Prevention life tables, Centers for Medicare & Medicaid Services data, and National Inpatient Sample (Healthcare Cost and Utilization Project) data.
Target population
Patients with HF who were aged 75 years at hospital discharge.
Time horizon
Lifetime.
Perspective
Health care sector.
Intervention
Disease management clinics, nurse home visits (NHVs), and nurse case management.
Outcome measures
Quality-adjusted life-years (QALYs), costs, net monetary benefits, and incremental cost-effectiveness ratios (ICERs).
Results of base-case analysis
All 3 transitional care interventions examined were more costly and effective than standard care, with NHVs dominating the other 2 interventions. Compared with standard care, NHVs increased QALYs (2.49 vs. 2.25) and costs ($81 327 vs. $76 705), resulting in an ICER of $19 570 per QALY gained.
Results of sensitivity analysis
Results were largely insensitive to variations in in-hospital mortality, age at baseline, or costs of rehospitalization. Probabilistic sensitivity analysis confirmed that transitional care services were preferred over standard care in nearly all 10 000 samples, at willingness-to-pay thresholds of $50 000 or more per QALY gained.
Limitation
Transitional care service designs and implementations are heterogeneous, leading to uncertainty about intervention effectiveness and costs when applied in particular settings.
Conclusion
In older patients with HF, transitional care services are economically attractive, with NHVs being the most cost-effective strategy in many situations. Transitional care services should become the standard of care for postdischarge management of patients with HF.
Primary funding source
Swiss National Science Foundation, Research Council of Norway, and an Intermountain-Stanford collaboration.



Ann Intern Med: 27 Jan 2020; epub ahead of print
Blum MR, Øien H, Carmichael HL, Heidenreich P, Owens DK, Goldhaber-Fiebert JD
Ann Intern Med: 27 Jan 2020; epub ahead of print | PMID: 31986526
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Impact:
Abstract

Myocardial Energetics in Obesity: Enhanced ATP Delivery Through Creatine Kinase with Blunted Stress Response.

Rayner JJ, Peterzan MA, Watson WD, Clarke WT, ... Rodgers CT, Rider OJ

Obesity is strongly associated with exercise intolerance and development of heart failure. While myocardial energetics and diastolic function are impaired in obesity, systolic function is usually preserved. This suggests that the rate of ATP delivery is maintained, but this has never been explored in human obesity. We hypothesised that ATP transfer rate through creatine kinase (CK) () would be increased, compensating for depleted energy stores (PCr/ATP), but potentially limiting greater ATP delivery during increased workload. We hypothesised these changes would normalise with weight loss.We recruited 80 volunteers (35 controls (BMI 24±3kg/m), 45 obese (BMI 35±5m/kg)) without co-existing cardiovascular disease. Participants underwent body composition analysis, MRI of abdominal, liver and myocardial fat content, left ventricular function and P-magnetic resonance spectroscopy to assess PCr/ATP and CK kinetics, at rest and during dobutamine stress. Obese volunteers were assigned to a dietary weight loss intervention, before re-examination.At rest, although myocardial PCr/ATP was 14% lower in obesity (1.9±0.3 vs 2.2±0.2, p<0.001),was 33% higher (0.23±0.07s vs 0.16±0.08s, p=0.002), yielding no difference in overall resting ATP delivery (obese 2.5±0.9µmol/g/sec vs control 2.2±1.1µmol/g/sec, p=0.232). In controls, increasing cardiac workload led to an increase in both(+86%, p<0.001) and ATP delivery (+80%, p<0.001). However, in obesity, similar stress led to no significant increase in either(p=0.117), or ATP delivery (p=0.608). This was accompanied by reduced systolic augmentation (absolute increase in LVEF obese +16±7% vs control +21±4%, p=0.031). Successful weight loss (-11±5% body weight) was associated with improvement of these energetic changes such that there was no significant difference compared to controls.In the obese resting heart, the myocardial CK reaction rate is increased, maintaining ATP delivery despite reduced PCr/ATP. During increased workload, whilst the non-obese heart increases ATP delivery through CK, the obese heart does not; this is associated with reduced systolic augmentation and exercise tolerance. Weight loss reverses these energetic changes. This highlights myocardial energy delivery via CK as a potential therapeutic target to improve symptoms in obesity-related heart disease, as well as a fascinating modifiable pathway involved in the progression to heart failure.



Circulation: 05 Mar 2020; epub ahead of print
Rayner JJ, Peterzan MA, Watson WD, Clarke WT, ... Rodgers CT, Rider OJ
Circulation: 05 Mar 2020; epub ahead of print | PMID: 32138541
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Abstract

Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses.

Wallach JD, Wang K, Zhang AD, Cheng D, ... Krumholz HM, Ross JS
Objectives
To conduct a systematic review and meta-analysis of the effects of rosiglitazone treatment on cardiovascular risk and mortality using multiple data sources and varying analytical approaches with three aims in mind: to clarify uncertainties about the cardiovascular risk of rosiglitazone; to determine whether different analytical approaches are likely to alter the conclusions of adverse event meta-analyses; and to inform efforts to promote clinical trial transparency and data sharing.
Design
Systematic review and meta-analysis of randomized controlled trials.
Data sources
GlaxoSmithKline\'s (GSK\'s) ClinicalStudyDataRequest.com for individual patient level data (IPD) and GSK\'s Study Register platforms, MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Registry of Controlled Trials, Scopus, and ClinicalTrials.gov from inception to January 2019 for summary level data.
Eligibility criteria for selecting studies
Randomized, controlled, phase II-IV clinical trials that compared rosiglitazone with any control for at least 24 weeks in adults.
Data extraction and synthesis
For analyses of trials for which IPD were available, a composite outcome of acute myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death was examined. These four events were examined independently as secondary analyses. For analyses including trials for which IPD were not available, myocardial infarction and cardiovascular related death were examined, which were determined from summary level data. Multiple meta-analyses were conducted that accounted for trials with zero events in one or both arms with two different continuity corrections (0.5 constant and treatment arm) to calculate odds ratios and risk ratios with 95% confidence intervals.
Results
33 eligible trials were identified from ClinicalStudyDataRequest.com for which IPD were available (21 156 patients). Additionally, 103 trials for which IPD were not available were included in the meta-analyses for myocardial infarction (23 683 patients), and 103 trials for which IPD were not available contributed to the meta-analyses for cardiovascular related death (22 772 patients). Among 29 trials for which IPD were available and that were included in previous meta-analyses using GSK\'s summary level data, more myocardial infarction events were identified by using IPD instead of summary level data for 26 trials, and fewer cardiovascular related deaths for five trials. When analyses were limited to trials for which IPD were available, and a constant continuity correction of 0.5 and a random effects model were used to account for trials with zero events in only one arm, patients treated with rosiglitazone had a 33% increased risk of a composite event compared with controls (odds ratio 1.33, 95% confidence interval 1.09 to 1.61; rosiglitazone population: 274 events among 11 837 patients; control population: 219 events among 9319 patients). The odds ratios for myocardial infarction, heart failure, cardiovascular related death, and non-cardiovascular related death were 1.17 (0.92 to 1.51), 1.54 (1.14 to 2.09), 1.15 (0.55 to 2.41), and 1.18 (0.60 to 2.30), respectively. For analyses including trials for which IPD were not available, odds ratios for myocardial infarction and cardiovascular related death were attenuated (1.09, 0.88 to 1.35, and 1.12, 0.72 to 1.74, respectively). Results were broadly consistent when analyses were repeated using trials with zero events across both arms and either of the two continuity corrections was used.
Conclusions
The results suggest that rosiglitazone is associated with an increased cardiovascular risk, especially for heart failure events. Although increased risk of myocardial infarction was observed across analyses, the strength of the evidence varied and effect estimates were attenuated when summary level data were used in addition to IPD. Because more myocardial infarctions and fewer cardiovascular related deaths were reported in the IPD than in the summary level data, sharing IPD might be necessary when performing meta-analyses focused on safety.
Systematic review registration
OSF Home https://osf.io/4yvp2/.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 04 Feb 2020; 368:l7078
Wallach JD, Wang K, Zhang AD, Cheng D, ... Krumholz HM, Ross JS
BMJ: 04 Feb 2020; 368:l7078 | PMID: 32024657
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Abstract

How Do SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors and GLP-1 (Glucagon-Like Peptide-1) Receptor Agonists Reduce Cardiovascular Outcomes?: Completed and Ongoing Mechanistic Trials.

Lee MMY, Petrie MC, McMurray JJV, Sattar N
Objective
There is substantial interest in how glucagon-like peptide-1 receptor agonists (GLP-1RA) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated.
Conclusions
We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.



Arterioscler Thromb Vasc Biol: 29 Jan 2020:ATVBAHA119311904; epub ahead of print
Lee MMY, Petrie MC, McMurray JJV, Sattar N
Arterioscler Thromb Vasc Biol: 29 Jan 2020:ATVBAHA119311904; epub ahead of print | PMID: 31996025
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Impact:
Abstract

Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.

Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; ≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, =0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.



Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914028; epub ahead of print
Zanetti D, Bergman H, Burgess S, Assimes TL, Bhalla V, Ingelsson E
Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914028; epub ahead of print | PMID: 32008434
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Impact:
Abstract

Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance.

Packer M

Sodium-glucose cotransporter 2 inhibitors reduce the risk of serious heart failure and adverse renal events, but the mechanisms that underlie this benefit are not understood. Treatment with SGLT2 inhibitors is distinguished by two intriguing features - ketogenesis and erythrocytosis. Both reflect the induction of a fasting-like and hypoxia-like transcriptional paradigm that is capable of restoring and maintaining cellular homeostasis and survival. In the face of perceived nutrient and oxygen deprivation, cells activate low-energy sensors, which include sirtuin-1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and hypoxia inducible factors (especially HIF-2α); these enzymes and transcription factors are master regulators of hundreds of genes and proteins that maintain cellular homeostasis. The activation of SIRT1 (through its effects to promote gluconeo-genesis and fatty acid oxidation) drives ketogenesis, and working in concert with AMPK, it can directly inhibit inflammasome activation and maintain mitochondrial capacity and stability. Hypoxia inducible factors act to promote oxygen delivery (by stimulating erythropoietin and erythrocytosis) and decrease oxygen consumption. Most importantly, the activation of SIRT1, AMPK and HIF-2α enhances autophagy, a lysosome-dependent degradative pathway that removes dangerous constituents, particularly damaged mitochondria and peroxisomes, which are major sources of oxidative stress and triggers of cellular dysfunction and death. SIRT1 and AMPK also act on sodium transport mechanisms to reduce intracellular sodium concentrations. Interestingly, type 2 diabetes, obesity, chronic heart failure and chronic kidney failure are characterized by the accumulation of intracellular glucose and lipid intermediates that are perceived by cells as indicators of energy overabundance. The cells respond by down-regulating SIRT1, AMPK and HIF-2α, thus leading to an impairment of autophagic flux and acceleration of cardiomyopathy and nephropathy. SGLT2 inhibitors reverse this maladaptive signaling by triggering a state of fasting and hypoxia mimicry, which includes activation of SIRT1, AMPK and HIF-2α, enhanced autophagic flux, reduced cellular stress, decreased sodium influx into cells, and restoration of mitochondrial homeostasis. This mechanistic framework clarifies the findings of large-scale randomized trials and the close association of ketogenesis and erythrocytosis with the cardioprotective and renoprotective benefits of these drugs.



Circulation: 12 Mar 2020; epub ahead of print
Packer M
Circulation: 12 Mar 2020; epub ahead of print | PMID: 32164457
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Impact:
Abstract

Screening Rates for Primary Aldosteronism in Resistant Hypertension: A Cohort Study.

Jaffe G, Gray Z, Krishnan G, Stedman M, ... Leppert JT, Bhalla V

Resistant hypertension is associated with higher rates of cardiovascular disease, kidney disease, and death than primary hypertension. Although clinical practice guidelines recommend screening for primary aldosteronism among persons with resistant hypertension, rates of screening are unknown. We identified 145 670 persons with hypertension and excluded persons with congestive heart failure or advanced chronic kidney disease. Among this cohort, we studied 4660 persons ages 18 to <90 from the years 2008 to 2014 with resistant hypertension and available laboratory tests within the following 24 months. The screening rate for primary aldosteronism in persons with resistant hypertension was 2.1%. Screened persons were younger (55.9±13.3 versus 65.5±11.6 years; <0.0001) and had higher systolic (145.1±24.3 versus 139.6±20.5 mm Hg; =0.04) and diastolic blood pressure (81.8±13.6 versus 74.4±13.8 mm Hg; <0.0001), lower rates of coronary artery disease (5.2% versus 14.2%; =0.01), and lower serum potassium concentrations (3.9±0.6 versus 4.1±0.5 mmol/L; =0.04) than unscreened persons. Screened persons had significantly higher rates of prescription for calcium channel blockers, mixed α/β-adrenergic receptor antagonists, sympatholytics, and vasodilators, and lower rates of prescription for loop, thiazide, and thiazide-type diuretics. The prescription of mineralocorticoid receptor antagonists or other potassium-sparing diuretics was not significantly different between groups (=0.20). In conclusion, only 2.1% of eligible persons received a screening test within 2 years of meeting criteria for resistant hypertension. Low rates of screening were not due to the prescription of antihypertensive medications that may potentially interfere with interpretation of the screening test. Efforts to highlight guideline-recommended screening and targeted therapy are warranted.



Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914359; epub ahead of print
Jaffe G, Gray Z, Krishnan G, Stedman M, ... Leppert JT, Bhalla V
Hypertension: 02 Feb 2020:HYPERTENSIONAHA11914359; epub ahead of print | PMID: 32008436
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Impact:
Abstract

Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial.

Deodhar A, Helliwell PS, Boehncke WH, Kollmeier AP, ... Ritchlin CT,
Background
Many patients with psoriatic arthritis have an inadequate response to tumor necrosis factor (TNF) inhibitors. Guselkumab, a specific inhibitor of interleukin-23 (IL-23) via IL-23 p19 subunit binding, significantly improved psoriatic arthritis signs and symptoms with an acceptable safety profile in a phase 2 trial.
Methods
This multicentre, double-blind, randomised, placebo-controlled, phase 3 trial was done at 86 sites in 13 countries across Asia, Australasia, Europe, and North America and enrolled adults with active psoriatic arthritis (at least three swollen and three tender joints; and C-reactive protein ≥0·3 mg/dL) despite standard therapies. Eligibility criteria included inadequate response to or intolerance of standard treatment, including at least 4 months of apremilast, at least 3 months of non-biologic disease-modifying antirheumatic drugs (DMARDs), or at least 4 weeks of non-steroidal anti-inflammatory drugs for psoriatic arthritis. About 30% of study participants could have previously received one or two TNF inhibitors. Patients were randomly assigned (1:1:1, computer-generated permuted blocks; stratified by baseline DMARD and previous TNF inhibitor use) to subcutaneous guselkumab 100 mg every 4 weeks; guselkumab 100 mg at weeks 0, 4, then every 8 weeks; or matching placebo. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 24 in all patients per assigned treatment group using non-responder imputation. Safety was assessed in all patients per treatment received. This trial is registered at ClinicalTrials.gov, NCT03162796 (active, not recruiting).
Findings
From Aug 28, 2017, to Aug 17, 2018, we screened 624 patients, of whom 381 were randomly assigned and treated with guselkumab every 4 weeks (n=128), guselkumab every 8 weeks (n=127), or placebo (n=126). 362 patients continued study treatment up to week 24. The primary endpoint was met: ACR20 at week 24 was achieved by significantly greater proportions of patients in the guselkumab every 4 weeks group (76 [59%] of 128 [95% CI 50-68]) and every 8 weeks group (66 [52%] of 127 [43-61]) than in the placebo group (28 [22%] of 126 [15-30]), with percentage differences versus placebo of 37% (95% CI 26-48) for the every 4 weeks group and 30% (19-41) for the every 8 weeks group (both p<0·0001). Serious adverse events up to week 24 occurred in no patients receiving guselkumab every 4 weeks, four (3%) patients receiving guselkumab every 8 weeks, and five (4%) patients receiving placebo. Up to week 24, one patient in the placebo group died from cardiac failure and two had serious infections; no guselkumab-treated patient died or had serious infections.
Interpretation
Guselkumab demonstrated a favourable benefit-risk profile and might be an effective treatment option for patients with active psoriatic arthritis.
Funding
Janssen Research and Development.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 12 Mar 2020; epub ahead of print
Deodhar A, Helliwell PS, Boehncke WH, Kollmeier AP, ... Ritchlin CT,
Lancet: 12 Mar 2020; epub ahead of print | PMID: 32178765
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Impact:
Abstract

Identification of novel pheno-groups in heart failure with preserved ejection fraction using machine learning.

Hedman ÅK, Hage C, Sharma A, Brosnan MJ, ... Ziemek D, Lund L
Objective
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. We aimed to derive HFpEF phenotype-based groups (\'phenogroups\') based on clinical and echocardiogram data using machine learning, and to compare clinical characteristics, proteomics and outcomes across the phenogroups.
Methods
We applied model-based clustering to 32 echocardiogram and 11 clinical and laboratory variables collected in stable condition from 320 HFpEF outpatients in the Karolinska-Rennes cohort study (56% female, median 78 years (IQR: 71-83)). Baseline proteomics and the composite end point of all-cause mortality or heart failure (HF) hospitalisation were used in secondary analyses.
Results
We identified six phenogroups, for which significant differences in the prevalence of concomitant atrial fibrillation (AF), anaemia and kidney disease were observed (p<0.05). Fifteen out of 86 plasma proteins differed between phenogroups (false discovery rate, FDR<0.05), including biomarkers of HF, AF and kidney function. The composite end point was significantly different between phenogroups (log-rank p<0.001), at short-term (100 days), mid-term (18 months) and longer-term follow-up (1000 days). Phenogroup 2 was older, with poorer diastolic and right ventricular function and higher burden of risk factors as AF (85%), hypertension (83%) and chronic obstructive pulmonary disease (30%). In this group a third experienced the primary outcome to 100 days, and two-thirds to 18 months (HR (95% CI) versus phenogroups 1, 3, 4, 5, 6: 1.5 (0.8-2.9); 5.7 (2.6-12.8); 2.9 (1.5-5.6); 2.7 (1.6-4.6); 2.1 (1.2-3.9)).
Conclusions
Using machine learning we identified distinct HFpEF phenogroups with differential characteristics and outcomes, as well as differential levels of inflammatory and cardiovascular proteins.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 06 Jan 2020; epub ahead of print
Hedman ÅK, Hage C, Sharma A, Brosnan MJ, ... Ziemek D, Lund L
Heart: 06 Jan 2020; epub ahead of print | PMID: 31911501
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Impact:
Abstract

Characteristics and Outcomes of Retinal Artery Occlusion: Nationally Representative Data.

Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS

Background and Purpose- There are few large studies examining comorbidities, outcomes, and acute interventions for patients with retinal artery occlusion (RAO). RAO shares pathophysiology with acute ischemic stroke (AIS); direct comparison may inform emergent treatment, evaluation, and secondary prevention. Methods- The National Readmissions Database contains data on ≈50% of US hospitalizations from 2013 to 2015. We used , , codes to identify and compare index RAO and AIS admissions, comorbidities, and interventions and Clinical Comorbidity Software codes to identify readmissions causes, using survey-weighted methods when possible. Cumulative risk of all-cause readmission after RAO ≤1 year was estimated by Kaplan-Meier analysis. Results- Among 4871 RAO and 1 239 963 AIS admissions, patients with RAO were less likely (<0.0001) than patients with AIS to have diabetes mellitus (RAO, 24.3% versus AIS, 36.8%), congestive heart failure (9.1% versus 14.8%), atrial fibrillation (15.5% versus 25.2%), or hypertension (62.2% versus 67.6%) but more likely to have valvular disease (13.3% versus 10.5%) and tobacco usage (38.6% versus 32.9%). In RAO admissions, thrombolysis was administered in 2.9% (5.8% in central RAO subgroup, versus 8.0% of AIS), therapeutic anterior chamber paracentesis in 1.0%, thrombectomy in none; 1.4% received carotid endarterectomy during index admission, 1.6% within 30 days. Nearly 1 in 10 patients with RAO were readmitted within 30 days and were more than twice as likely as patients with AIS to be readmitted for dysrhythmia or endocarditis. Readmission for stroke after RAO was the highest within the first 150 days after index admission, and risk was higher in central RAO than in branch RAO. Conclusions- Patients with RAO had high prevalence of many stroke risk factors, particularly valvular disease and smoking, which can be addressed to minimize subsequent risk. Despite less baseline atrial fibrillation, RAO patients were more likely to be readmitted for atrial fibrillation/dysrhythmias. A variety of interventions was administered. AIS risk is the highest shortly after RAO, emphasizing the importance of urgent, thorough neurovascular evaluation.



Stroke: 16 Jan 2020:STROKEAHA119027034; epub ahead of print
Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS
Stroke: 16 Jan 2020:STROKEAHA119027034; epub ahead of print | PMID: 31951154
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Impact:
Abstract

Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy beyond ejection fraction.

Cannatà A, De Angelis G, Boscutti A, Normand C, ... Merlo M, Sinagra G

Sudden cardiac death and arrhythmia-related events in patients with non-ischaemic dilated cardiomyopathy (NICM) have been significantly reduced over the last couple of decades as a result of evidence-based pharmacological and non-pharmacological therapeutic strategies. Nevertheless, the arrhythmic stratification in patients with NICM remains extremely challenging, and the simple indication based on left ventricular ejection fraction appears to be insufficient. Therefore, clinicians need to go beyond the current criteria for implantable cardioverter-defibrillator implantation in the direction of a multiparametric evaluation of arrhythmic risk. Several parameters for arrhythmic risk stratification, ranging from electrocardiographic, echocardiographic, imaging-derived and genetic markers, are crucial for proper arrhythmic risk stratification and a multiparametric evaluation of risk in patients with NICM. In particular, integration of cardiac magnetic resonance parameters (mostly late gadolinium enhancement) and specific genetic information (ie, presence ofmutations) appears fundamental for proper implementation of the current arrhythmic risk stratification. Finally, a novel approach focused on both arrhythmic risk and prediction of left ventricular reverse remodelling during follow-up might be useful for effective multiparametric and dynamic arrhythmic risk stratification in NICM. In the future, a complete and integrated evaluation might be mandatory to implement arrhythmic risk prediction in patients with NICM and to discriminate the competing risk between heart failure-related events and life-threatening arrhythmias.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 20 Jan 2020; epub ahead of print
Cannatà A, De Angelis G, Boscutti A, Normand C, ... Merlo M, Sinagra G
Heart: 20 Jan 2020; epub ahead of print | PMID: 31964657
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Impact:
Abstract

Angiocrine FSTL1 (Follistatin-Like Protein 1) Insufficiency Leads to Atrial and Venous Wall Fibrosis via SMAD3 Activation.

Jiang H, Zhang L, Liu X, Sun W, ... Gao X, He Y
Objective
Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells () led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice withdeletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers ofmutants. The SMAD3 phosphorylation was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells ofmice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels inmutant mice.
Conclusions
The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.



Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313901; epub ahead of print
Jiang H, Zhang L, Liu X, Sun W, ... Gao X, He Y
Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313901; epub ahead of print | PMID: 32078339
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Abstract

Association of Isolated Diastolic Hypertension as Defined by the 2017 ACC/AHA Blood Pressure Guideline With Incident Cardiovascular Outcomes.

McEvoy JW, Daya N, Rahman F, Hoogeveen RC, ... Coresh J, Selvin E
Importance
In the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, the definition of hypertension was lowered from a blood pressure (BP) of greater than or equal to 140/90 to greater than or equal to 130/80 mm Hg. The new diastolic BP threshold of 80 mm Hg was recommended based on expert opinion and changes the definition of isolated diastolic hypertension (IDH).
Objective
To compare the prevalence of IDH in the United States, by 2017 ACC/AHA and 2003 Joint National Committee (JNC7) definitions, and to characterize cross-sectional and longitudinal associations of IDH with outcomes.
Design, setting, and participants
Cross-sectional analyses of the National Health and Nutrition Examination Survey (NHANES 2013-2016) and longitudinal analyses of the Atherosclerosis Risk in Communities (ARIC) Study (baseline 1990-1992, with follow-up through December 31, 2017). Longitudinal results were validated in 2 external cohorts: (1) the NHANES III (1988-1994) and NHANES 1999-2014 and (2) the Give Us a Clue to Cancer and Heart Disease (CLUE) II cohort (baseline 1989).
Exposures
IDH, by 2017 ACC/AHA (systolic BP <130 mm Hg, diastolic BP ≥80 mm Hg) and by JNC7 (systolic BP <140 mm Hg, diastolic BP ≥90 mm Hg) definitions.
Main outcomes and measures
Weighted estimates for prevalence of IDH in US adults and prevalence of US adults recommended BP pharmacotherapy by the 2017 ACC/AHA guideline based solely on the presence of IDH. Risk of incident atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD) in the ARIC Study.
Results
The study population included 9590 adults from the NHANES (mean [SD] baseline age, 49.6 [17.6] years; 5016 women [52.3%]) and 8703 adults from the ARIC Study (mean [SD] baseline age, 56.0 [5.6] years; 4977 women [57.2%]). The estimated prevalence of IDH in the NHANES was 6.5% by the 2017 ACC/AHA definition and 1.3% by the JNC7 definition (absolute difference, 5.2% [95% CI, 4.7%-5.7%]). Among those newly classified as having IDH, an estimated 0.6% (95% CI, 0.5%-0.6%) also met the guideline threshold for antihypertensive therapy. Compared with normotensive ARIC participants, IDH by the 2017 ACC/AHA definition was not significantly associated with incident ASCVD (n = 1386 events; median follow-up, 25.2 years; hazard ratio [HR], 1.06 [95% CI, 0.89-1.26]), HF (n = 1396 events; HR, 0.91 [95% CI, 0.76-1.09]), or CKD (n = 2433 events; HR, 0.98 [95% CI, 0.65-1.11]). Results were also null for cardiovascular mortality in the 2 external cohorts (eg, HRs of IDH by the 2017 ACC/AHA definition were 1.17 [95% CI, 0.87-1.56] in the NHANES [n = 1012 events] and 1.02 [95% CI, 0.92-1.14] in CLUE II [n = 1497 events]).
Conclusions and relevance
In this analysis of US adults, the estimated prevalence of IDH was more common when defined by the 2017 ACC/AHA BP guideline compared with the JNC7 guideline. However, IDH was not significantly associated with increased risk for cardiovascular outcomes.



JAMA: 27 Jan 2020; 323:329-338
McEvoy JW, Daya N, Rahman F, Hoogeveen RC, ... Coresh J, Selvin E
JAMA: 27 Jan 2020; 323:329-338 | PMID: 31990314
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Abstract

Financial and resource costs of transvenous lead extraction in a high-volume lead extraction centre.

Gould J, Sidhu BS, Porter B, Sieniewicz BJ, ... Razavi R, Rinaldi CA
Objectives
Transvenous lead extraction (TLE) poses a significant economic and resource burden on healthcare systems; however, limited data exist on its true cost. We therefore estimate real-world healthcare reimbursement costs of TLE to the UK healthcare system at a single extraction centre.
Methods
Consecutive admissions entailing TLE at a high-volume UK centre between April 2013 and March 2018 were prospectively recorded in a computer registry. In the hospital\'s National Health Service (NHS) clinical coding/reimbursement database, 447 cases were identified. Mean reimbursement cost (n=445) and length of stay (n=447) were calculated. Ordinary least squares regressions estimated the relationship between cost (bed days) and clinical factors.
Results
Mean reimbursement cost per admission was £17 399.09±£13 966.49. Total reimbursement for all TLE admissions was £7 777 393.51. Mean length of stay was 16.3±15.16 days with a total of 7199 bed days. Implantable cardioverter-defibrillator and cardiac resynchronisation therapy defibrillator devices incurred higher reimbursement costs (70.5% and 68.7% higher, respectively, both p<0.001). Heart failure and prior valve surgery also incurred significantly higher reimbursement costs. Prior valve surgery and heart failure were associated with 8.3 (p=0.017) and 5.5 (p=0.021) additional days in hospital, respectively.
Conclusions
Financial costs to the NHS from TLE are substantial. Consideration should therefore be given to cost/resource-sparing potential of leadless/extravascular cardiac devices that negate the need for TLE particularly in patients with prior valve surgery and/or heart failure. Additionally, use of antibiotic envelopes and other interventions that reduce infection risk in patients receiving transvenous leads should be considered.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 12 Jan 2020; epub ahead of print
Gould J, Sidhu BS, Porter B, Sieniewicz BJ, ... Razavi R, Rinaldi CA
Heart: 12 Jan 2020; epub ahead of print | PMID: 31932286
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Abstract

Value of a Machine Learning Approach for Predicting Clinical Outcomes in Young Patients With Hypertension.

Wu X, Yuan X, Wang W, Liu K, ... Zhou S, Song L

Risk stratification of young patients with hypertension remains challenging. Generally, machine learning (ML) is considered a promising alternative to traditional methods for clinical predictions because it is capable of processing large amounts of complex data. We, therefore, explored the feasibility of an ML approach for predicting outcomes in young patients with hypertension and compared its performance with that of approaches now commonly used in clinical practice. Baseline clinical data and a composite end point-comprising all-cause death, acute myocardial infarction, coronary artery revascularization, new-onset heart failure, new-onset atrial fibrillation/atrial flutter, sustained ventricular tachycardia/ventricular fibrillation, peripheral artery revascularization, new-onset stroke, end-stage renal disease-were evaluated in 508 young patients with hypertension (30.83±6.17 years) who had been treated at a tertiary hospital. Construction of the ML model, which consisted of recursive feature elimination, extreme gradient boosting, and 10-fold cross-validation, was performed at the 33-month follow-up evaluation, and the model\'s performance was compared with that of the Cox regression and recalibrated Framingham Risk Score models. An 11-variable combination was considered most valuable for predicting outcomes using the ML approach. The C statistic for identifying patients with composite end points was 0.757 (95% CI, 0.660-0.854) for the ML model, whereas for Cox regression model and the recalibrated Framingham Risk Score model it was 0.723 (95% CI, 0.636-0.810) and 0.529 (95% CI, 0.403-0.655). The ML approach was comparable with Cox regression for determining the clinical prognosis of young patients with hypertension and was better than that of the recalibrated Framingham Risk Score model.



Hypertension: 15 Mar 2020:HYPERTENSIONAHA11913404; epub ahead of print
Wu X, Yuan X, Wang W, Liu K, ... Zhou S, Song L
Hypertension: 15 Mar 2020:HYPERTENSIONAHA11913404; epub ahead of print | PMID: 32172622
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Abstract

First-Ever Ischemic Stroke and Incident Major Adverse Cardiovascular Events in 93 627 Older Women and Men.

Sposato LA, Lam M, Allen B, Shariff SZ, Saposnik G

Background and Purpose- Stroke risk is sex-specific, but little is known about sex differences of poststroke major adverse cardiovascular events (MACEs). Stroke-related brain damage causes autonomic dysfunction and inflammation, sometimes resulting in cardiac complications. Sex-specific cardiovascular susceptibility to stroke without the confounding effect of preexisting heart disease constitutes an unexplored field because previous studies focusing on sex differences in poststroke MACE have not excluded patients with known cardiovascular comorbidities. We therefore investigated sex-specific risks of incident MACE in a heart disease-free population-based cohort of patients with first-ever ischemic stroke and propensity-matched individuals without stroke. Methods- We included Ontario residents ≥66 years, without known cardiovascular comorbidities, with first-ever ischemic stroke between 2002 and 2012 and propensity-matched individuals without stroke. We investigated the 1-year risk of incident MACE (acute coronary syndrome, myocardial infarction, incident coronary artery disease, coronary revascularization procedures, incident heart failure, or cardiovascular death) separately for females and males. For estimating cause-specific adjusted hazard ratios, we adjusted Cox models for variables with weighted standardized differences >0.10 or those known to influence MACE risk. Results- We included 93 627 subjects without known cardiovascular comorbidities; 21 931 with first-ever ischemic stroke and 71 696 propensity-matched subjects without stroke. Groups were well-balanced on propensity-matching variables. There were 53 476 women (12 421 with and 41 055 without ischemic stroke) and 40 151 men (9510 with and 30 641 without ischemic stroke). First-ever ischemic stroke was associated with increased risk of incident MACE in both sexes. The risk was time-dependent, highest within 30 days (women: adjusted hazard ratio, 25.1 [95% CI, 19.3-32.6]; men: aHR, 23.4 [95% CI, 17.2-31.9]) and decreasing but remaining significant between 31 and 90 days (women: aHR, 4.8 [95% CI, 3.8-6.0]; men: aHR, 4.2 [95% CI, 3.3-5.4]), and 91 to 365 days (aHR, 2.1 [95% CI, 1.8-2.3]; men: aHR, 2.0 [95% CI, 1.7-2.3]). Conclusions- In this large population-based study, ischemic stroke was independently associated with increased risk of incident MACE in both sexes.



Stroke: 08 Jan 2020:STROKEAHA119028066; epub ahead of print
Sposato LA, Lam M, Allen B, Shariff SZ, Saposnik G
Stroke: 08 Jan 2020:STROKEAHA119028066; epub ahead of print | PMID: 31914883
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Abstract

Enhanced CaMKII-Dependent Late I Induces Atrial Pro-Arrhythmic Activity in Patients with Sleep-Disordered Breathing.

Lebek S, Pichler K, Reuthner K, Trum M, ... Arzt M, Wagner S

Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased Ca/calmodulin-dependent protein kinase II (CaMKII) activity has been previously implicated in atrial arrhythmogenesis.We hypothesized that CaMKII-dependent dysregulation of Na current (I) may contribute to atrial pro-arrhythmic activity in SDB patients.We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index, AHI {greater than or equal to}15/h) was assessed with a portable SDB monitor the night before surgery. Compared to 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure I. There was a significantly enhanced late I but reduced peak I due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (Na1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions (PACs) in atrial trabeculae of SDB patients, which could be blocked by either AIP or KN93. In multivariable linear regression models incorporating age, gender, body mass index, existing AF, existing heart failure, diabetes and creatinine levels, AHI was independently associated with increased CaMKII activity, enhanced late I and correlated with PAC severity.In atrial myocardium of SDB patients, increased CaMKII-dependent phosphorylation of Na1.5 results in dysregulation of I with pro-arrhythmic activity that was independent from pre-existing co-morbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB.



Circ Res: 05 Jan 2020; epub ahead of print
Lebek S, Pichler K, Reuthner K, Trum M, ... Arzt M, Wagner S
Circ Res: 05 Jan 2020; epub ahead of print | PMID: 31902278
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Abstract

Characteristics and outcomes of patients with normal left atrial pressure undergoing transcatheter mitral valve repair.

Sims JR, Reeder GS, Guerrero M, Alkhouli M, ... Rihal CS, Eleid MF
Objective
A subset of patients at the time of transcatheter mitral valve repair (TMVR) will have normal left atrial pressure (LAP) (<13 mm Hg) despite having severe mitral regurgitation (MR). The goal of this study was to determine clinical characteristics and outcomes in patients with normal LAP undergoing TMVR.
Methods
A single-centre retrospective cohort of consecutive patients who underwent transcatheter edge-to-edge mitral valve clip and continuous LAP monitoring between 5/1/2014 and 5/1/2018 was analysed. One-year mortality was compared by Kaplan-Meier survival curves. Multivariable analysis was performed to identify predictors of normal LAP and 1 year mortality.
Results
Of the 204 patients undergoing TMVR, 65% were men and the mean age was 81. Of these patients, 31 (15%) had normal LAP (mean LAP 10.5 mm Hg, mean V wave 16.5 mm Hg) and 173 had elevated LAP (mean LAP 19 mm Hg, mean V wave 32.5 mm Hg). The prevalence of severe MR was not different between groups, although the normal LAP group had significantly lower effective regurgitant orifice area and regurgitant volume. Other notable baseline characteristics including prior cardiac surgery, atrial fibrillation, hypertension, diabetes, congestive heart failure, body mass index, mechanism of MR and ejection fraction were similar between groups. However, there was an increased prevalence of chronic lung disease (CLD) (45.2% vs 17.3%, p<0.001) in the normal LAP group. On multivariate analysis, the only significant predictor of normal LAP was the presence of CLD (OR 4.79 (1.83-12.36), p=0.001) and 1-year mortality was significantly higher in the normal LAP group (32.3% vs 12.7%, p=0.006). After adjustment for comorbidities, normal LAP was no longer a predictor of 1-year mortality (RR 1.62 (0.64-4.06), p=0.32); however, CLD (RR 3.44 (1.37-8.67), p=0.01) remained a statistically significant predictor.
Conclusion
Normal LAP at the time of TMVR is associated with a higher incidence of CLD which independently predicts increased 1-year mortality. In patients with CLD and apparently severe MR, measurement of LAP may help identify those with lower likelihood of benefit from TMVR.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 23 Jan 2020; epub ahead of print
Sims JR, Reeder GS, Guerrero M, Alkhouli M, ... Rihal CS, Eleid MF
Heart: 23 Jan 2020; epub ahead of print | PMID: 31980440
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Abstract

Brain Damage with Heart Failure: Cardiac Biomarker Alterations and Gray Matter Decline.

Mueller K, Thiel F, Beutner F, Teren A, ... Villringer A, Schroeter ML

Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF, however, the underlying mechanisms leading to the observed brain changes remain unclear. To study the relationship between impaired heart function, hampered blood circulation and structural brain change in a case-control study.Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain\'s gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain\'s gray matter. Moreover, we also obtained a relationship between GMD and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) - a biomarker that is used for screening, diagnosis and prognosis of HF. Here we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia.We obtained significant correlations between brain structure and markers of heart failure including EF and NT-proBNP. A diminished GMD was found with decreased EF and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition, however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.



Circ Res: 22 Jan 2020; epub ahead of print
Mueller K, Thiel F, Beutner F, Teren A, ... Villringer A, Schroeter ML
Circ Res: 22 Jan 2020; epub ahead of print | PMID: 31969053
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Abstract

Role of atrial arrhythmia and ventricular response in atrial fibrillation induced atrial remodeling.

Guichard JB, Xiong F, Qi XY, L\'Heureux N, ... Costa AD, Nattel S
Aims
No studies have assessed the specific contributions of atrial fibrillation (AF)-related atrial versus associated ventricular arrhythmia to remodeling. This study assessed the roles of atrial arrhythmia versus high ventricular rate in AF-associated remodeling.
Methods and results
Four primary dog-groups (12/group) were subjected to 3-week pacing: 600-bpm atrial-tachypacing maintaining AF (AF w/o-AVB); atrial-tachypacing with atrioventricular-node ablation (AF+AVB) and ventricular-demand pacing (80-bpm); 160-bpm ventricular-tachypacing (V160) reproducing the response-rate during AF; and sinus rhythm with AVB/ventricular-pacing at 80-bpm (CTL). At terminal study, left-atrial (LA) effective refractory period (ERP) was reduced equally in both AF-groups (w/o-AVB and AF+AVB). AF-inducibility was increased strongly in AF-groups (w/o-AVB and AF+AVB) and modestly in V160. AF-duration was significantly increased in AF w/o-AVB but not in AF+AVB or V160. Conduction velocity was decreased in AF w/o-AVB, to a greater extent than in AF+AVB and V160. Atrial fibrous-tissue content was increased in AF w/o-AVB, AF+AVB and V160, with collagen-gene upregulation only in AF w/o-AVB. Connexin43 gene-expression was reduced only in AF w/o-AVB. An additional group of 240-bpm ventricular tachypacing dogs (VTP240; to induce heart failure) was studied: versus other tachypaced groups, VTP240 caused greater fibrosis, but no change in LA-ERP or AF-inducibility. VTP240 also increased AF-duration, strongly decreased left-ventricular ejection fraction, and was the only group with LA natriuretic-peptide activation.
Conclusions
The atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodeling; both contribute to the arrhythmogenic substrate, providing new insights into AF-related remodeling and novel considerations for ventricular rate-control.
Translational perspective
AF often produces a rapid and irregular arrhythmia in both the atria and ventricles. This study evaluates the contributions of AF-induced atrial versus ventricular arrhythmia to atrial remodeling. Each component produced discrete features: AF-induced atrial arrhythmia caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF-induction by premature ectopic beats, conduction slowing and moderate atrial fibrosis; whereas ventricular arrhythmia slightly increased vulnerability, slowed conduction and induced moderate fibrosis without affecting repolarization/refractoriness,. Combined atrial and ventricular arrhythmia abbreviated refractoriness, strongly increased vulnerability and fibrosis and greatly increased AF stability/duration. This work suggests that in the absence of ventricular rate control, the rapid ventricular response can cause AF-promoting atrial remodeling without overt heart failure; further research is needed to clarify the clinical relevance of these findings.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 23 Jan 2020; epub ahead of print
Guichard JB, Xiong F, Qi XY, L'Heureux N, ... Costa AD, Nattel S
Cardiovasc Res: 23 Jan 2020; epub ahead of print | PMID: 31977017
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Abstract

Secondary mitral regurgitation: pathophysiology, proportionality and prognosis.

Chehab O, Roberts-Thomson R, Ng Yin Ling C, Marber M, ... Rajani R, Redwood SR

Secondary mitral regurgitation (SMR) occurs as a result of multifactorial left atrioventricular dysfunction and maleficent remodelling. It is the most common and undertreated form of mitral regurgitation (MR) and is associated with a very poor prognosis. Whether SMR is a bystander reflecting the severity of the cardiomyopathy disease process has long been the subject of debate. Studies suggest that SMR is an independent driver of prognosis in patients with an intermediate heart failure (HF) phenotype and not those with advanced HF. There is also no universal agreement regarding the quantitative thresholds defining severe SMR and indeed there are challenges with echocardiographic quantification. Until recently, no surgical or transcatheter intervention for SMR had demonstrated prognostic benefit, in contrast with HF medical therapy and cardiac resynchronisation therapy. In 2018, the first two randomised controlled trials (RCTs) of edge-to-edge transcatheter mitral valve repair versus guideline-directed medical therapy in HF (Percutaneous Repair with the MitraClip Device for Severe (MITRA-FR), Transcather mitral valve repair in patients with heart failure (COAPT)) reported contrasting yet complimentary results. Unlike in MITRA-FR, COAPT demonstrated significant prognostic benefit, largely attributed to the selection of patients with disproportionately severe MR relative to their HF phenotype. Consequently, quantifying the degree of SMR in relation to left ventricular volume may be a useful discriminator in predicting the success of transcatheter intervention. The challenge going forward is the identification and validation of such parameters while in parallel maintaining a heart-team guided holistic approach.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 12 Feb 2020; epub ahead of print
Chehab O, Roberts-Thomson R, Ng Yin Ling C, Marber M, ... Rajani R, Redwood SR
Heart: 12 Feb 2020; epub ahead of print | PMID: 32054671
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Abstract

Extracellular Vesicles from Human Cardiovascular Progenitors Trigger a Reparative Immune Response in Infarcted Hearts.

Harane NE, Correa BL, Gomez I, Hocine HR, ... Menasché P, Silvestre JS
Aims
The cardio-protective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behavior of EV-CPC, which is a prerequisite for their clinical translation.
Methods and results
Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA class I, CD80, CD274 (PD-L1), CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the IFN-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNFα and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2 and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages.
Conclusions
EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.
Translational perspective
Mounting evidence suggests that the release of extracellular vesicles (EV) conveys the therapeutic efficacy of various progenitor cells in the failing heart. In the present study, we showed that intra-myocardial delivery of EV isolated from human iPSC-derived cardiovascular progenitor cells does not trigger an allogenic immune response and seems rather to induce a systemic anti-inflammatory effect. Our results therefore suggest that human EV administration might not require immunosuppression. It remains to establish whether the systemic delivery of EV would trigger similar anti-inflammatory effects, positively impacting heart function.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 11 Feb 2020; epub ahead of print
Harane NE, Correa BL, Gomez I, Hocine HR, ... Menasché P, Silvestre JS
Cardiovasc Res: 11 Feb 2020; epub ahead of print | PMID: 32049348
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Abstract

Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.

Zhang D, Tu H, Wang C, Cao L, ... Wadman MC, Li YL
Aims
Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic postganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF.
Methods and results
Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time PCR and Western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry ECG recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/fibrillation (VT/VF), but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats.
Conclusions
Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.
Translational perspectives
Our present study demonstrates that inhibition of N-type Ca2+ channels in CSP neurons attenuates CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias. The clinical significance of this study is to open a new avenue in therapeutics working against lethal ventricular arrhythmias in patients with CHF. N-type Ca2+ channels in CSP neurons could be a new therapeutic target for cardiac sympathetic overactivation and ventricular arrhythmias in CHF. Exploring specific, small-molecule N-type Ca2+ channel blockers with local targeting drug delivery system could translate to clinical trials and applications that improve outcomes for patients with CHF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 28 Jan 2020; epub ahead of print
Zhang D, Tu H, Wang C, Cao L, ... Wadman MC, Li YL
Cardiovasc Res: 28 Jan 2020; epub ahead of print | PMID: 31995173
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Abstract

The Impact of Patient Sex on the Response to Intramyocardial Mesenchymal Stem Cell Administration in Patients with Non-Ischemic Dilated Cardiomyopathy.

Florea V, Rieger AC, Natsumeda M, Tompkins BA, ... Mitrani RD, Hare JM
Aims
Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy.
Methods and results
Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-TESI. At baseline, EF was lower (p = 0.004) and end diastolic volume (EDV; p = 0.0002) and end systolic volume (ESV; p = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-minute walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (p = 0.04) and in females by 8.6 units (p = 0.04; males vs. females, p = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units (EPC-CFUs), and serum TNF-α improved similarly in both groups.
Conclusions
Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.
Translational perspective
Important patient sex differences exist in NIDCM clinical phenotype and gene expression profiles. The effectiveness of pharmacological treatment relative to patient sex requires evaluation due to the paucity of sex-specific data in clinical trials. Herein, we report that despite baseline phenotypic differences in left ventricular remodeling, MSC treatment improves the NIDCM phenotype irrespective of patient sex. Importantly, MSC administration to female patients may lead to an increased rate of heart failure with recovered EF, which carries an improved mortality, transplant rate, and hospitalization rate. This hypothesis-generating study encourages the design of future trials that evaluate patient sex differences in response to cell-based therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 12 Feb 2020; epub ahead of print
Florea V, Rieger AC, Natsumeda M, Tompkins BA, ... Mitrani RD, Hare JM
Cardiovasc Res: 12 Feb 2020; epub ahead of print | PMID: 32053144
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Abstract

Coagulation factor VIII: Relationship to Cardiovascular Disease Risk and Whole Genome Sequence and Epigenome-Wide Analysis in African Americans.

Raffield LM, Lu AT, Szeto MD, Little A, ... Zakai NA, Reiner AP
Background
Prospective studies have suggested higher factor VIII (FVIII) levels is an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans.
Objectives
We measured FVIII levels in ~3,400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations.
Methods
We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array.
Results
Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant.
Conclusions
Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.

© 2020 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 26 Jan 2020; epub ahead of print
Raffield LM, Lu AT, Szeto MD, Little A, ... Zakai NA, Reiner AP
J Thromb Haemost: 26 Jan 2020; epub ahead of print | PMID: 31985870
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Abstract

Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes.

Poulet C, Sanchez-Alonso J, Swiatlowska P, Mouy F, ... Houser S, Gorelik J
Aim
In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodeling in cardiac diseases is associated with down-regulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signaling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes.
Methods and results
Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodeling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with Methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2.
Conclusions
JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signaling complexes to regulate LTCC activity.
Translational perspective
By tethering T-tubules to the sarcoplasmic reticulum, junctophilin-2 (JPH2) supports the assembly of junctional membrane complexes (JMCs), major sites of excitation-contraction coupling in cardiomyocytes. JPH2 downregulation underlies the disruption of JMCs and T-tubules in cardiomyopathies and enhancing JPH2 expression is a promising therapeutic approach for the treatment of heart failure. Our study demonstrates a new role for JPH2 in the recruitment of calcium channels to the membrane and provides innovative insights into the formation and organization of JMCs as well as into the regulation of excitation-contraction coupling. Our results are of significant importance when considering JPH2 as a therapeutic target.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 12 Feb 2020; epub ahead of print
Poulet C, Sanchez-Alonso J, Swiatlowska P, Mouy F, ... Houser S, Gorelik J
Cardiovasc Res: 12 Feb 2020; epub ahead of print | PMID: 32053184
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Abstract

Promise of Autologous CD34+ Stem/Progenitor Cell Therapy for Treatment of Cardiovascular Disease.

Prasad M, Corban MT, Henry TD, Dietz AB, Lerman LO, Lerman A

CD34+ cells are hematopoietic stem cells used therapeutically in patients undergoing radiation or chemotherapy due to their regenerative potential and ability to restore the hematopoietic system. In animal models, CD34+ cells have been associated with therapeutic angiogenesis in response to ischemia. Several trials have shown the potential safety and efficacy of CD34+ cell delivery in various cardiovascular diseases. Moreover, Phase III trials have now begun to explore the potential role of CD34+ cells in treatment of both myocardial and peripheral ischemia. CD34+ cells have been shown to be safe and well-tolerated in the acute myocardial infarction, heart failure, and angina models. Several studies have suggested potential benefit of CD34+ cell therapy in patients with coronary microvascular disease as well. In this review we will discuss the therapeutic potential of CD34+ cells, and describe the pertinent trials that have used autologous CD34+ cells in no-options refractory angina, acute myocardial infarction, and heart failure. Lastly, we will review the potential utility of autologous CD34+ cells in coronary endothelial and microvascular dysfunction.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 04 Feb 2020; epub ahead of print
Prasad M, Corban MT, Henry TD, Dietz AB, Lerman LO, Lerman A
Cardiovasc Res: 04 Feb 2020; epub ahead of print | PMID: 32022845
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Abstract

ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on \'coronary microvascular dysfunction in cardiovascular disease\'.

Padro T, Manfrini O, Bugiardini R, Canty J, ... de Wit C, Badimon L

Although myocardial ischaemia usually manifests as a consequence of atherosclerosis-dependent obstructive epicardial coronary artery disease, a significant percentage of patients suffer ischaemic events in the absence of epicardial coronary artery obstruction. Experimental and clinical evidence highlight the abnormalities of the coronary microcirculation as a main cause of myocardial ischaemia in patients with \'normal or near normal\' coronary arteries on angiography. Coronary microvascular disturbances have been associated with early stages of atherosclerosis even prior to any angiographic evidence of epicardial coronary stenosis, as well as to other cardiac pathologies such as myocardial hypertrophy and heart failure. The main objectives of the manuscript are (i) to provide updated evidence in our current understanding of the pathophysiological consequences of microvascular dysfunction in the heart; (ii) to report on the current knowledge on the relevance of cardiovascular risk factors and comorbid conditions for microcirculatory dysfunction; and (iii) to evidence the relevance of the clinical consequences of microvascular dysfunction. Highlighting the clinical importance of coronary microvascular dysfunction will open the field for research and the development of novel strategies for intervention will encourage early detection of subclinical disease and will help in the stratification of cardiovascular risk in agreement with the new concept of precision medicine.

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

Cardiovasc Res: 07 Feb 2020; epub ahead of print
Padro T, Manfrini O, Bugiardini R, Canty J, ... de Wit C, Badimon L
Cardiovasc Res: 07 Feb 2020; epub ahead of print | PMID: 32034397
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Abstract

Inborn errors of apolipoprotein A-I metabolism: implications for disease, research and development.

Zanoni P, von Eckardstein A
Purpose of review
We review current knowledge regarding naturally occurring mutations in the human apolipoprotein A-I (APOA1) gene with a focus on their clinical complications as well as their exploitation for the elucidation of structure-function-(disease) relationships and therapy.
Recent findings
Bi-allelic loss-of-function mutations in APOA1 cause HDL deficiency and, in the majority of patients, premature atherosclerotic cardiovascular disease (ASCVD) and corneal opacities. Heterozygous HDL-cholesterol decreasing mutations in APOA1 were associated with increased risk of ASCVD in several but not all studies. Some missense mutations in APOA1 cause familial amyloidosis. Structure-function-reationships underlying the formation of amyloid as well as the manifestion of amyloidosis in specific tissues are better understood. Lessons may also be learnt from the progress in the treatment of amyloidoses induced by transthyretin variants. Infusion of reconstituted HDL (rHDL) containing apoA-I (Milano) did not cause regression of atherosclerosis in coronary arteries of patients with acute coronary syndrome. However, animal experiments indicate that rHDL with apoA-I (Milano) or apoA-I mimetic peptides may be useful for the treatment of heart failure of inflammatory bowel disease.
Summary
Specific mutations in APOA1 are the cause of premature ASCVD or familial amyloidosis. Synthetic mimetics of apoA-I (mutants) may be useful for the treatment of several diseases beyond ASCVD.



Curr Opin Lipidol: 03 Feb 2020; epub ahead of print
Zanoni P, von Eckardstein A
Curr Opin Lipidol: 03 Feb 2020; epub ahead of print | PMID: 32022753
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Abstract

The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications.

Eisner DA, Caldwell JL, Trafford AW, Hutchings DC

Normal cardiac function requires that intracellular Ca concentration be reduced to low levels in diastole so that the ventricle can relax and refill with blood. Heart failure is often associated with impaired cardiac relaxation. Little, however, is known about how diastolic intracellular Ca concentration is regulated. This article first discusses the reasons for this ignorance before reviewing the basic mechanisms that control diastolic intracellular Ca concentration. It then considers how the control of systolic and diastolic intracellular Ca concentration is intimately connected. Finally, it discusses the changes that occur in heart failure and how these may result in heart failure with preserved versus reduced ejection fraction.



Circ Res: 30 Jan 2020; 126:395-412
Eisner DA, Caldwell JL, Trafford AW, Hutchings DC
Circ Res: 30 Jan 2020; 126:395-412 | PMID: 31999537
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Abstract

Coronary microvascular dysfunction in hypertrophy and heart failure.

Camici PG, Tschöpe C, Carli MFD, Rimoldi O, Van Linthout S

Left ventricular (LV) hypertrophy (LVH) is a growth in left myocardial mass mainly caused by increased cardiomyocyte size. LVH can be a physiological adaptation to physical exercise or a pathologic condition either primary, i.e. genetic, or secondary to LV overload. Patients with both primary and secondary LVH have evidence of coronary microvascular dysfunction (CMD). The latter is mainly due to capillary rarefaction and adverse remodeling of intramural coronary arterioles due to medial wall thickening with an increased wall/lumen ratio. An important feature of this phenomenon is the diffuse nature of this remodeling, which generally affects the coronary microvessels in the whole of the LV. Patients with LVH secondary to arterial hypertension can develop both heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). These patients can develop HFrEF via a \"direct pathway\" with an interval myocardial infarction, but also in its absence. On the other hand, patients can develop HFpEF that can then progress to HFrEF with or without interval myocardial infarction. A similar evolution towards LV dysfunction and both HFpEF and HFrEF can occur in patients with hypertrophic cardiomyopathy (HCM), the most common genetic cardiomyopathy with a phenotype characterized by massive LVH. In this review article, we will discuss both the experimental and clinical studies explaining the mechanisms responsible for CMD in LVH as well as the evidence linking CMD with HFpEF and HFrEF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions please email: [email protected]

Cardiovasc Res: 29 Jan 2020; epub ahead of print
Camici PG, Tschöpe C, Carli MFD, Rimoldi O, Van Linthout S
Cardiovasc Res: 29 Jan 2020; epub ahead of print | PMID: 31999329
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Abstract

Celastrol Attenuates Angiotensin II-Induced Cardiac Remodeling by Targeting STAT3.

Ye S, Luo W, Khan ZA, Wu G, ... Huang W, Liang G

Excessive angiotensin II (Ang II) levels lead to a pro-fibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II-induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure.We have examined the potential effect of Celastrol, a bioactive compound derived from the Celastraceae family, on Ang II-induced cardiac dysfunction.In rat primary cardiomyocytes and H9C2 cells, Celastrol attenuates Ang II-induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of Celastrol. Our data showed that Celastrol directly binds to and inhibits signal transducer and activator of transcription-3 (STAT3) phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of Celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of Celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of Celastrol treatment in mice challenged with Ang II and in the Transverse aortic constriction (TAC) model. We show that Celastrol administration protected heart function in Ang II- and TAC-challenged mice by inhibiting cardiac fibrosis and hypertrophy.Our studies show that Celastrol inhibits Ang II-induced cardiac dysfunction by inhibiting STAT3 activity.



Circ Res: 25 Feb 2020; epub ahead of print
Ye S, Luo W, Khan ZA, Wu G, ... Huang W, Liang G
Circ Res: 25 Feb 2020; epub ahead of print | PMID: 32098592
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Abstract

N-Cadherin Overexpression Mobilizes the Protective Effects of Mesenchymal Stromal Cells Against Ischemic Heart Injury Through A Β-Catenin Dependent Manner.

Yan W, Lin C, Guo Y, Chen Y, ... Ma XL, Tao L

Mesenchymal stromal cells (MSC)-based therapy is promising against ischemic heart failure (IHF). However, its efficacy is limited due to low cell retention and poor paracrine function. A transmembrane protein capable of enhancing cell-cell adhesion, N-cadherin garnered attention in the field of stem cell biology only recently.The current study investigates whether and how N-cadherin may regulate MSC retention and cardioprotective capability against IHF.Adult mice-derived adipose tissue-derived MSC (ADSC) were transfected with adenovirus harboring N-cadherin (ADSC-Ncad), T-cadherin (ADSC-Tcad), or control adenovirus (ADSC-con). CM-DiI-labeled ADSC were intramyocardially injected into the infarct border zone at 3 sites immediately after myocardial infarction (MI) or myocardial ischemia/reperfusion (MI/R). ADSC retention/survival, cardiomyocyte apoptosis/proliferation, capillary density, cardiac fibrosis, and cardiac function were determined. Discovery-driven/cause-effect analysis was employed to determine the molecular mechanisms. Compared to ADSC-con, N-cadherin overexpression (but not T-cadherin) markedly increased engrafted ADSC survival/retention up to 7 days post-MI. Histological analysis revealed that ADSC-Ncad significantly preserved capillary density and increased cardiomyocyte proliferation, and moderately reduced cardiomyocyte apoptosis 3 days post-MI. More importantly, ADSC-Ncad (but not ADSC-Tcad) significantly increased LVEF and reduced fibrosis in both MI and MI/R mice. In vitro experiments demonstrated that N-cadherin overexpression promoted ADSC-cardiomyocyte adhesion and ADSC migration, enhancing their capability to increase angiogenesis and cardiomyocyte proliferation. MMP-10/13 and/or HGF upregulation is responsible for N-cadherin\'s effect upon ADSC migration and paracrine angiogenesis. N-cadherin overexpression promotes cardiomyocyte proliferation by HGF release. Mechanistically, N-cadherin overexpression significantly increased N-cadherin/β-catenin complex formation and active β-catenin levels in the nucleus. β-catenin knockdown abolished N-cadherin overexpression induced MMP-10, MMP-13, and HGF expression, and blocked the cellular actions and cardioprotective effects of ADSC overexpressing N-cadherin.We demonstrate for the first time that N-cadherin overexpression enhances MSC protective effects against IHF via β-catenin mediated MMP-10/MMP-13/HGF expression and production, promoting ADSC/cardiomyocyte adhesion and ADSC retention.



Circ Res: 20 Feb 2020; epub ahead of print
Yan W, Lin C, Guo Y, Chen Y, ... Ma XL, Tao L
Circ Res: 20 Feb 2020; epub ahead of print | PMID: 32079489
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Abstract

Impact of comorbidities on peak troponin levels and mortality in acute myocardial infarction.

Sundaram V, Rothnie K, Bloom C, Zakeri R, ... Rajagopalan S, Quint JK
Objectives
To characterise peak cardiac troponin levels, in patients presenting with acute myocardial infarction (AMI), according to their comorbid condition and determine the influence of peak cardiac troponin (cTn) levels on mortality.
Methods
We included patients with the first admission for AMI in the UK. We used linear regression to estimate the association between eight common comorbidities (diabetes mellitus, previous angina, peripheral arterial disease, previous myocardial infarction (MI), chronic kidney disease (CKD), cerebrovascular disease, chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD)) and peak cTn. Peak cTn levels were adjusted for age, sex, smoking status and comorbidities. Logistic regression and restricted cubic spline models were employed to investigate the association between peak cTn and 180-day mortality for each comorbidity.
Results
330 367 patients with ST elevation myocardial infarction and non-ST elevation myocardial infarction were identified. Adjusted peak cTn levels were significantly higher in patients with CKD (adjusted % difference in peak cTnT for CKD=42%, 95% CI 13.1 to 78.4) and significantly lower for patients with COPD, previous angina, previous MI and CHF when compared with patients without the respective comorbidities (reference group) (cTnI; COPD=-21.7%, 95% CI -29.1 to -13.4; previous angina=-24.2%, 95% CI -29.6 to -8.3; previous MI=-13.5%, 95% CI -20.6 to -5.9; CHF=-28%, 95% CI -37.2 to -17.6). Risk of 180-day mortality in most of the comorbidities did not change substantially after adjusting for peak cTn. In general, cTnI had a stronger association with mortality than cTnT.
Conclusions
In this nationwide analysis of patients presenting with AMI, comorbidities substantially influenced systemic concentrations of peak cTn. Comorbid illness is a significant predictor of mortality regardless of peak cTn levels and should be taken into consideration while interpreting cTn both as a diagnostic and prognostic biomarker.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 25 Feb 2020; epub ahead of print
Sundaram V, Rothnie K, Bloom C, Zakeri R, ... Rajagopalan S, Quint JK
Heart: 25 Feb 2020; epub ahead of print | PMID: 32102896
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