Topic: Heart Failure

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

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

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

Preventing Complications in Pregnant Women With Cardiac Disease.

Pfaller B, Sathananthan G, Grewal J, Mason J, ... Siu SC, Silversides CK
Background
Pregnancy can lead to complications in women with heart disease, and these complications can be life threatening. Understanding serious complications and how they can be prevented is important.
Objectives
The primary objectives were to determine the incidence of serious cardiac events (SCEs) in pregnant women with heart disease, whether they were preventable, and their impact on fetal and neonatal outcomes. Serious obstetric events were also examined.
Methods
A prospectively assembled cohort of 1,315 pregnancies in women with heart disease was studied. SCEs included cardiac death or arrest, ventricular arrhythmias, congestive heart failure or arrhythmias requiring admission to an intensive care unit, myocardial infarction, stroke, aortic dissection, valve thrombosis, endocarditis, and urgent cardiac intervention. The Harvard Medical Study criteria were used to adjudicate preventability.
Results
Overall, 3.6% of pregnancies (47 of 1,315) were complicated by SCEs. The most frequent SCEs were cardiac death or arrest, heart failure, arrhythmias, and urgent interventions. Most SCEs (66%) occurred in the antepartum period. Almost one-half of SCEs (49%) were preventable; the majority of preventable SCEs (74%) were secondary to provider management factors. Adverse fetal and neonatal events were more common in pregnancies with SCEs compared with those without cardiac events (62% vs. 29%; p < 0.001). Serious obstetric events were less common (1.7%) and were primarily due to pre-eclampsia with severe features.
Conclusions
Pregnant women with heart disease are at risk for serious cardiac complications, and approximately one-half of all SCEs are preventable. Strategies to prevent serious cardiac complications in this high-risk cohort of women need to be developed.

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

J Am Coll Cardiol: 30 Mar 2020; 75:1443-1452
Pfaller B, Sathananthan G, Grewal J, Mason J, ... Siu SC, Silversides CK
J Am Coll Cardiol: 30 Mar 2020; 75:1443-1452 | PMID: 32216913
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Abstract

Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy.

Nijst P, Martens P, Dauw J, Tang WHW, ... Dupont M, Mullens W
Background
The necessity of neurohumoral blockers in patients with heart failure who demonstrate normalized ejection fractions after cardiac resynchronization therapy remains unclear.
Objectives
The aim of this study was to investigate the feasibility and safety of neurohumoral blocker withdrawal in patients with normalized ejection fractions after cardiac resynchronization therapy.
Methods
In this prospective, open-label, randomized controlled pilot trial with a 2 × 2 factorial design, subjects were randomized to withdrawal of renin-angiotensin-aldosterone system inhibitors and/or beta-blockers versus continuation of treatment. The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular end-systolic volume index of >15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure-related hospitalizations, and incidence of sustained ventricular arrhythmias at 24 months.
Results
Eighty subjects were consecutively enrolled and randomized among 4 groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). Of the 80 subjects, 6 (7.5%) met the primary and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 subjects because of hypertension or supraventricular arrhythmias.
Conclusions
The incidence of the primary and secondary endpoints over a follow-up period of 2 years was low in both the control group and in the groups in which neurohumoral blockers were discontinued. However, neurohumoral blocker withdrawal was hampered by cardiac comorbidities. (Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients [STOP-CRT]; NCT02200822).

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

J Am Coll Cardiol: 30 Mar 2020; 75:1426-1438
Nijst P, Martens P, Dauw J, Tang WHW, ... Dupont M, Mullens W
J Am Coll Cardiol: 30 Mar 2020; 75:1426-1438 | PMID: 32216911
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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

Evaluation for Heart Transplantation and LVAD Implantation: JACC Council Perspectives.

Guglin M, Zucker MJ, Borlaug BA, Breen E, ... Bozkurt B,

Timely referrals for transplantation and left ventricular assist device implantation play a key role in favorable outcomes in patients with advanced heart failure. Nonetheless, evaluation usually occurs at advanced heart failure centers and is obscured from referring physicians. The purposes of this review are to explain the decision-making process for candidacy for advanced therapies and to describe the potential impact of the new organ allocation algorithm on center decision making. The document first addresses the signs of advanced heart failure, specifically focusing on the importance of the syndrome of low cardiac output as a key feature of advanced heart failure, and then summarizes the evaluation as a 3-step process addressing the following questions: 1) Is transplantation or durable assist device placement indicated? 2) Are there contraindications to either intervention? 3) How can one choose between transplantation and left ventricular assist device implantation if advanced therapies are indicated and not contraindicated?

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

J Am Coll Cardiol: 30 Mar 2020; 75:1471-1487
Guglin M, Zucker MJ, Borlaug BA, Breen E, ... Bozkurt B,
J Am Coll Cardiol: 30 Mar 2020; 75:1471-1487 | PMID: 32216916
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Abstract

Effect of Smoking on Outcomes of Primary PCI in Patients With STEMI.

Redfors B, Furer A, Selker HP, Thiele H, ... Ben-Yehuda O, Stone GW
Background
Smoking is a well-established risk factor for ST-segment elevation myocardial infarction (STEMI); however, once STEMI occurs, smoking has been associated with favorable short-term outcomes, an observation termed the \"smoker\'s paradox.\" It has been postulated that smoking might exert protective effects that could reduce infarct size, a strong independent predictor of worse outcomes after STEMI.
Objectives
The purpose of this study was to determine the relationship among smoking, infarct size, microvascular obstruction (MVO), and adverse outcomes after STEMI.
Methods
Individual patient-data were pooled from 10 randomized trials of patients with STEMI undergoing primary percutaneous coronary intervention. Infarct size was assessed at median 4 days by either cardiac magnetic resonance imaging or technetium-99m sestamibi single-photon emission computed tomography. Multivariable analysis was used to assess the relationship between smoking, infarct size, and the 1-year rates of death or heart failure (HF) hospitalization and reinfarction.
Results
Among 2,564 patients with STEMI, 1,093 (42.6%) were recent smokers. Smokers were 10 years younger and had fewer comorbidities. Infarct size was similar in smokers and nonsmokers (adjusted difference: 0.0%; 95% confidence interval [CI]: -3.3% to 3.3%; p = 0.99). Nor was the extent of MVO different between smokers and nonsmokers. Smokers had lower crude 1-year rates of all-cause death (1.0% vs. 2.9%; p < 0.001) and death or HF hospitalization (3.3% vs. 5.1%; p = 0.009) with similar rates of reinfarction. After adjustment for age and other risk factors, smokers had a similar 1-year risk of death (adjusted hazard ratio [adjHR]: 0.92; 95% CI: 0.46 to 1.84) and higher risks of death or HF hospitalization (adjHR: 1.49; 95% CI: 1.09 to 2.02) as well as reinfarction (adjHR: 1.97; 95% CI: 1.17 to 3.33).
Conclusions
In the present large-scale individual patient-data pooled analysis, recent smoking was unrelated to infarct size or MVO, but was associated with a worse prognosis after primary PCI in STEMI. The smoker\'s paradox may be explained by the younger age and fewer cardiovascular risk factors in smokers compared with nonsmokers.

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

J Am Coll Cardiol: 20 Apr 2020; 75:1743-1754
Redfors B, Furer A, Selker HP, Thiele H, ... Ben-Yehuda O, Stone GW
J Am Coll Cardiol: 20 Apr 2020; 75:1743-1754 | PMID: 32299585
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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

AntimiR-21 Prevents Myocardial Dysfunction in a Pig Model of Ischemia/Reperfusion Injury.

Hinkel R, Ramanujam D, Kaczmarek V, Howe A, ... Kupatt C, Engelhardt S
Background
miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro-ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure.
Objectives
The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition.
Methods
Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis.
Results
AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment.
Conclusions
This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure.

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

J Am Coll Cardiol: 20 Apr 2020; 75:1788-1800
Hinkel R, Ramanujam D, Kaczmarek V, Howe A, ... Kupatt C, Engelhardt S
J Am Coll Cardiol: 20 Apr 2020; 75:1788-1800 | PMID: 32299591
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Abstract

Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.

Docherty KF, Jhund PS, Inzucchi SE, Køber L, ... Solomon SD, McMurray JJV
Aims
In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy.
Methods and results
In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin-angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 [95% confidence interval (CI) 0.65-0.85] for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61-0.86) compared with 0.77 (95% CI 0.63-0.94) in those not on all three of these treatments (P-interaction 0.64).
Conclusion
The benefit of dapagliflozin was consistent regardless of background therapy for HF.

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

Eur Heart J: 27 Mar 2020; epub ahead of print
Docherty KF, Jhund PS, Inzucchi SE, Køber L, ... Solomon SD, McMurray JJV
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221582
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Abstract

Initial Invasive or Conservative Strategy for Stable Coronary Disease.

Maron DJ, Hochman JS, Reynolds HR, Bangalore S, ... Rosenberg Y,
Background
Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.
Methods
We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.
Results
Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).
Conclusions
Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Maron DJ, Hochman JS, Reynolds HR, Bangalore S, ... Rosenberg Y,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227755
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Abstract

Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure.

Zhou W, Brown JM, Bajaj NS, Chandra A, ... O\'Gara P, Di Carli MF
Aims
Hypertension is a well-established heart failure (HF) risk factor, especially in the context of adverse left ventricular (LV) remodelling. We aimed to use myocardial flow reserve (MFR) and global longitudinal strain (GLS), markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive HF risk assessment.
Methods and results
Consecutive patients undergoing symptom-prompted stress cardiac positron emission tomography (PET)-computed tomography and transthoracic echocardiogram within 90 days without reduced left ventricular ejection fraction (<40%) or flow-limiting coronary artery disease (summed stress score ≥ 3) were included. Global MFR was quantified by PET, and echocardiograms were retrospectively analysed for cardiac structure and function. Patients were followed over a median 8.75 (Q1-3 4.56-10.04) years for HF hospitalization and a composite of death, HF hospitalization, MI, or stroke. Of 194 patients, 155 had adaptive LV remodelling while 39 had maladaptive remodelling, which was associated with lower MFR and impaired GLS. Across the remodelling spectrum, diastolic parameters, GLS, and N-terminal pro-B-type natriuretic peptide were independently associated with MFR. Maladaptive LV remodelling was associated with increased adjusted incidence of HF hospitalization and death. Importantly, the combination of abnormal MFR and GLS was associated with a higher rate of HF hospitalization compared to normal MFR and GLS [adjusted hazard ratio (HR) 3.21, 95% confidence interval (CI) 1.09-9.45, P = 0.034), including in the adaptive remodelling subset (adjusted HR 3.93, 95% CI 1.14-13.56, P = 0.030).
Conclusion
We have demonstrated important associations between coronary microvascular dysfunction and myocardial mechanics that refine disease characterization and HF risk assessment of patients with hypertension based on subclinical target organ injury.

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: 27 Mar 2020; epub ahead of print
Zhou W, Brown JM, Bajaj NS, Chandra A, ... O'Gara P, Di Carli MF
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221588
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Abstract

Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction.

Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, ... O\'Connor CM,
Background
The effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear.
Methods
In this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure.
Results
Over a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P = 0.02). A total of 691 patients (27.4%) in the vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P = 0.02). Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P = 0.12), and syncope occurred in 4.0% of the patients in the vericiguat group and in 3.5% of the patients in the placebo group (P = 0.30).
Conclusions
Among patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 Mar 2020; epub ahead of print
Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, ... O'Connor CM,
N Engl J Med: 27 Mar 2020; epub ahead of print | PMID: 32222134
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Abstract

A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction.

Vaduganathan M, Jhund PS, Claggett BL, Packer M, ... McMurray JJV, Solomon SD
Aims
The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin-angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF).
Methods and results
We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), first HF hospitalization (RR 0.67, 95% CI 0.58-0.78), cardiovascular death (RR 0.76, 95% CI 0.64-0.89), and all-cause death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02.
Conclusion
This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

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

Eur Heart J: 27 Mar 2020; epub ahead of print
Vaduganathan M, Jhund PS, Claggett BL, Packer M, ... McMurray JJV, Solomon SD
Eur Heart J: 27 Mar 2020; epub ahead of print | PMID: 32221596
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Abstract

Management of Coronary Disease in Patients with Advanced Kidney Disease.

Bangalore S, Maron DJ, O\'Brien SM, Fleg JL, ... Hochman JS,
Background
Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease.
Methods
We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.
Results
At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03).
Conclusions
Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Mar 2020; epub ahead of print
Bangalore S, Maron DJ, O'Brien SM, Fleg JL, ... Hochman JS,
N Engl J Med: 29 Mar 2020; epub ahead of print | PMID: 32227756
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Abstract

Genetic predisposition to smoking in relation to 14 cardiovascular diseases.

Larsson SC, Mason AM, Bäck M, Klarin D, ... Michaëlsson K, Burgess S
Aims
The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs).
Methods and results
Our primary genetic instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage.
Conclusion
This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.

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

Eur Heart J: 15 Apr 2020; epub ahead of print
Larsson SC, Mason AM, Bäck M, Klarin D, ... Michaëlsson K, Burgess S
Eur Heart J: 15 Apr 2020; epub ahead of print | PMID: 32300774
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Abstract

Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar.

Wilcox T, De Block C, Schwartzbard AZ, Newman JD

Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.

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

J Am Coll Cardiol: 27 Apr 2020; 75:1956-1974
Wilcox T, De Block C, Schwartzbard AZ, Newman JD
J Am Coll Cardiol: 27 Apr 2020; 75:1956-1974 | PMID: 32327107
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Abstract

Myocardial Interstitial Fibrosis in Nonischemic Heart Disease, Part 3/4: JACC Focus Seminar.

Díez J, González A, Kovacic JC

Myocardial interstitial fibrosis (MIF) is a histological hallmark of several cardiac diseases that alter myocardial architecture and function and are associated with progression to heart failure. MIF is a diffuse and patchy process, appearing as a combination of interstitial microscars, perivascular collagen fiber deposition, and increased thickness of mysial collagen strands. Although MIF arises mainly because of alterations in fibrillar collagen turnover leading to collagen fiber accumulation, there are also alterations in other nonfibrillar extracellular matrix components, such as fibronectin and matricellular proteins. Furthermore, in addition to an excess of collagen, qualitative changes in collagen fibers also contribute to the detrimental impact of MIF. In this part 3 of a 4-part JACC Focus Seminar, we review the evidence on the complex mechanisms leading to MIF, as well as its contribution to systolic and diastolic cardiac dysfunction and impaired clinical outcomes in patients with nonischemic heart disease.

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

J Am Coll Cardiol: 04 May 2020; 75:2204-2218
Díez J, González A, Kovacic JC
J Am Coll Cardiol: 04 May 2020; 75:2204-2218 | PMID: 32354386
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Abstract

Omics phenotyping in heart failure: the next frontier.

Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, ... Emdin M, Januzzi JL

This state-of-the-art review aims to provide an up-to-date look at breakthrough omic technologies that are helping to unravel heart failure (HF) disease mechanisms and heterogeneity. Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and physiology involved in HF than achieved by either one alone and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible and can be validated across multiple independent populations to ensure confidence in clinical decision-making.

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: 25 Apr 2020; epub ahead of print
Bayes-Genis A, Liu PP, Lanfear DE, de Boer RA, ... Emdin M, Januzzi JL
Eur Heart J: 25 Apr 2020; epub ahead of print | PMID: 32337540
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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

Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.

Karam S, Margaria JP, Bourcier A, Mika D, ... Leroy J, Vandecasteele G

The cAMP-hydrolyzing phosphodiesterase 4B (PDE4B) is a key negative regulator of cardiac β-adrenergic receptor (β-AR) stimulation. PDE4B deficiency leads to abnormal Ca handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure (HF).We measured PDE4B expression in human cardiac tissues, developed two transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B (PDE4B-TG), and an adeno-associated virus serotype 9 encoding PDE4B (AAV9-PDE4B). Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Cyclic AMP and PKA activity were monitored by Förster resonance energy transfer, I by whole cell patch-clamp, and cardiomyocyte shortening and Ca transients with an Ionoptix system. HF was induced by 2 weeks infusion of isoproterenol (Iso) or transverse aortic constriction (TAC). Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis and histology.PDE4B protein was decreased in human failing hearts. The first PDE4B-TG mouse line (TG15) had a ~15-fold increase in cardiac cAMP-PDE activity and a ~30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basalmyocardial function was unchanged, but β-AR stimulation of cardiac inotropy, cAMP, PKA, I, Ca transients and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion and fibrosis induced by chronic Iso treatment. In the second PDE4B-TG mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ~50-fold increase in cardiac cAMP-PDE activity caused a ~50% decrease in fractional shortening, hypertrophy, dilatation and premature death. In contrast, mice injected with AAV9-PDE4B (10 viral particles/mouse) had a ~50% increase in cardiac cAMP-PDE activity which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis and fibrosis, while attenuating hypertrophy induced by chronic Iso infusion. Similarly, AAV9-PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion and prevented apoptosis and fibrotic remodeling in TAC.Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat HF.



Circulation: 07 Apr 2020; epub ahead of print
Karam S, Margaria JP, Bourcier A, Mika D, ... Leroy J, Vandecasteele G
Circulation: 07 Apr 2020; epub ahead of print | PMID: 32264695
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Abstract

From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases.

Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Lüscher TF

Nucleic acid-based therapeutics are currently developed at large scale for prevention and management of cardiovascular diseases (CVDs), since: (i) genetic studies have highlighted novel therapeutic targets suggested to be causal for CVD; (ii) there is a substantial recent progress in delivery, efficacy, and safety of nucleic acid-based therapies; (iii) they enable effective modulation of therapeutic targets that cannot be sufficiently or optimally addressed using traditional small molecule drugs or antibodies. Nucleic acid-based therapeutics include (i) RNA-targeted therapeutics for gene silencing; (ii) microRNA-modulating and epigenetic therapies; (iii) gene therapies; and (iv) genome-editing approaches (e.g. CRISPR-Cas-based): (i) RNA-targeted therapeutics: several large-scale clinical development programmes, using antisense oligonucleotides (ASO) or short interfering RNA (siRNA) therapeutics for prevention and management of CVD have been initiated. These include ASO and/or siRNA molecules to lower apolipoprotein (a) [apo(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoCIII, ANGPTL3, or transthyretin (TTR) for prevention and treatment of patients with atherosclerotic CVD or TTR amyloidosis. (ii) MicroRNA-modulating and epigenetic therapies: novel potential therapeutic targets are continually arising from human non-coding genome and epigenetic research. First microRNA-based therapeutics or therapies targeting epigenetic regulatory pathways are in clinical studies. (iii) Gene therapies: EMA/FDA have approved gene therapies for non-cardiac monogenic diseases and LDL receptor gene therapy is currently being examined in patients with homozygous hypercholesterolaemia. In experimental studies, gene therapy has significantly improved cardiac function in heart failure animal models. (iv) Genome editing approaches: these technologies, such as using CRISPR-Cas, have proven powerful in stem cells, however, important challenges are remaining, e.g. low rates of homology-directed repair in somatic cells such as cardiomyocytes. In summary, RNA-targeted therapies (e.g. apo(a)-ASO and PCSK9-siRNA) are now in large-scale clinical outcome trials and will most likely become a novel effective and safe therapeutic option for CVD in the near future. MicroRNA-modulating, epigenetic, and gene therapies are tested in early clinical studies for CVD. CRISPR-Cas-mediated genome editing is highly effective in stem cells, but major challenges are remaining in somatic cells, however, this field is rapidly advancing.

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: 28 Apr 2020; epub ahead of print
Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Lüscher TF
Eur Heart J: 28 Apr 2020; epub ahead of print | PMID: 32350510
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Abstract

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19.

Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN
Background
Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context.
Methods
Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020.
Results
Of the 8910 patients with Covid-19 for whom discharge status was available at the time of the analysis, a total of 515 died in the hospital (5.8%) and 8395 survived to discharge. The factors we found to be independently associated with an increased risk of in-hospital death were an age greater than 65 years (mortality of 10.0%, vs. 4.9% among those ≤65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41), coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51), heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40), and current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 2.47). No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74).
Conclusions
Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women\'s Hospital.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 30 Apr 2020; epub ahead of print
Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN
N Engl J Med: 30 Apr 2020; epub ahead of print | PMID: 32356626
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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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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

Secondary valve regurgitation in patients with heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction, and heart failure with reduced ejection fraction.

Bartko PE, Hülsmann M, Hung J, Pavo N, ... Stone GW, Goliasch G

Secondary mitral regurgitation and secondary tricuspid regurgitation due to heart failure (HF) remain challenging in almost every aspect: increasing prevalence, poor prognosis, notoriously elusive in diagnosis, and complexity of therapeutic management. Recently, defined HF subgroups according to three ejection fraction (EF) ranges (reduced, mid-range, and preserved) have stimulated a structured understanding of the HF syndrome but the role of secondary valve regurgitation (SVR) across the spectrum of EF remains undefined. This review expands this structured understanding by consolidating the underlying phenotype of myocardial impairment with each type of SVR. Specifically, the current understanding, epidemiological considerations, impact, public health burden, mechanisms, and treatment options of SVR are discussed separately for each lesion across the HF spectrum. Furthermore, this review identifies important gaps in knowledge, future directions for research, and provides potential solutions for diagnosis and treatment. Mastering the challenge of SVR requires a multidisciplinary collaborative effort, both, in clinical practice and scientific approach to optimize patient outcomes.

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: 28 Apr 2020; epub ahead of print
Bartko PE, Hülsmann M, Hung J, Pavo N, ... Stone GW, Goliasch G
Eur Heart J: 28 Apr 2020; epub ahead of print | PMID: 32350503
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Impact:
Abstract

The Science Underlying COVID-19: Implications for the Cardiovascular System.

Liu PP, Blet A, Smyth D, Li H

Corona Virus Disease 2019 (COVID-19) pandemic has impacted health and economy worldwide on an unprecedented scale. Patients have diverse clinical outcomes, but those with pre-existing cardiovascular (CV) disease, hypertension, and related conditions incur disproportionately worse outcome. The high infectivity of the SARS-CoV-2 virus is in part related to new mutations in the receptor binding domain, and acquisition of a furin cleavage site in the S spike protein. The continued viral shedding in the asymptomatic and pre-symptomatic individuals enhances its community transmission. The virus uses the ACE2 receptor for internalization, aided by TMPRSS2 protease. The tissue localization of the receptors correlates with COVDI-19 presenting symptoms and organ dysfunction. Virus-induced ACE2 down regulation may attenuate its function, diminish its anti-inflammatory role, and heightened angiotensin II effects in the predisposed patients. Lymphopenia occurs early and is prognostic, potentially associated with reduction of the CD4+ and some CD8+ T cells. This leads to imbalance of the innate/acquired immune response, delayed viral clearance, and hyper stimulated macrophages and neutrophils. Appropriate type I interferon pathway activation is critical for virus attenuation, and balanced immune response. Persistent immune activation in predisposed patients, such as the elderly and those with CV risk, can lead to hemophagocytosis like syndrome, with uncontrolled amplification of cytokine production, leading to multi-organ failure and death. In addition to the airways and lungs, the cardiovascular system is often involved in COVID-19 early, reflected in the release of highly sensitive troponin and natriuretic peptides, which are all extremely prognostic, particularly in those showing continued rise, along with cytokines such as IL-6. Inflammation in the vascular system can result in diffuse microangiopathy with thrombosis. Inflammation in the myocardium can result in myocarditis, heart failure, cardiac arrhythmias, acute coronary syndrome, rapid deterioration and sudden death. Aggressive support based on early prognostic indicators with expectant management can potentially improve recovery. Appropriate treatment for heart failure, arrhythmias, acute coronary syndrome and thrombosis remain important. Specific evidence based treatment strategies for COVID-19 will emerge with ongoing global collaboration on multiple approaches being evaluated. To protect the wider population, antibody testing and effective vaccine will be needed to make COVID-19 history.



Circulation: 14 Apr 2020; epub ahead of print
Liu PP, Blet A, Smyth D, Li H
Circulation: 14 Apr 2020; epub ahead of print | PMID: 32293910
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Impact:
Abstract

Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.

Inciardi RM, Adamo M, Lupi L, Cani DS, ... Bezzi M, Metra M
Aims
To compare demographic characteristics, clinical presentation, and outcomes of patients with and without concomitant cardiac disease, hospitalized for COVID-19 in Brescia, Lombardy, Italy.
Methods and results
The study population includes 99 consecutive patients with COVID-19 pneumonia admitted to our hospital between 4 March and 25 March 2020. Fifty-three patients with a history of cardiac disease were compared with 46 without cardiac disease. Among cardiac patients, 40% had a history of heart failure, 36% had atrial fibrillation, and 30% had coronary artery disease. Mean age was 67 ± 12 years, and 80 (81%) patients were males. No differences were found between cardiac and non-cardiac patients except for higher values of serum creatinine, N-terminal probrain natriuretic peptide, and high sensitivity troponin T in cardiac patients. During hospitalization, 26% patients died, 15% developed thrombo-embolic events, 19% had acute respiratory distress syndrome, and 6% had septic shock. Mortality was higher in patients with cardiac disease compared with the others (36% vs. 15%, log-rank P = 0.019; relative risk 2.35; 95% confidence interval 1.08-5.09). The rate of thrombo-embolic events and septic shock during the hospitalization was also higher in cardiac patients (23% vs. 6% and 11% vs. 0%, respectively).
Conclusions
Hospitalized patients with concomitant cardiac disease and COVID-19 have an extremely poor prognosis compared with subjects without a history of cardiac disease, with higher mortality, thrombo-embolic events, and septic shock rates.

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: 07 May 2020; epub ahead of print
Inciardi RM, Adamo M, Lupi L, Cani DS, ... Bezzi M, Metra M
Eur Heart J: 07 May 2020; epub ahead of print | PMID: 32383763
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Impact:
Abstract

Evaluation and Management of Premature Ventricular Complexes.

Marcus GM

Premature ventricular complexes (PVCs) are extremely common, found in the majority of individuals undergoing long-term ambulatory monitoring. Increasing age, a taller height, a higher blood pressure, a history of heart disease, performance of less physical activity, and smoking each predict a greater PVC frequency. Although the fundamental causes of PVCs remain largely unknown, potential mechanisms for any given PVC include triggered activity, automaticity, and reentry. PVCs are commonly asymptomatic but can also result in palpitations, dyspnea, presyncope, and fatigue. The history, physical examination, and 12-lead ECG are each critical to the diagnosis and evaluation of a PVC. An echocardiogram is indicated in the presence of symptoms or particularly frequent PVCs, and cardiac magnetic resonance imaging is helpful when the evaluation suggests the presence of associated structural heart disease. Ambulatory monitoring is required to assess PVC frequency. The prognosis of those with PVCs is variable, with ongoing uncertainty regarding the most informative predictors of adverse outcomes. An increased PVC frequency may be a risk factor for heart failure and death, and the resolution of systolic dysfunction after successful catheter ablation of PVCs demonstrates that a causal relationship can be present. Patients with no or mild symptoms, a low PVC burden, and normal ventricular function may be best served with simple reassurance. Either medical treatment or catheter ablation are considered first-line therapies in most patients with PVCs associated with symptoms or a reduced left ventricular ejection fraction, and patient preference plays a role in determining which to try first. If medical treatment is selected, either β-blockers or nondihydropyridine calcium channel blockers are reasonable drugs in patients with normal ventricular systolic function. Other antiarrhythmic drugs should be considered if those initial drugs fail and ablation has been declined, has been unsuccessful, or has been deemed inappropriate. Catheter ablation is the most efficacious approach to eradicate PVCs but may confer increased upfront risks. Original research remains necessary to identify individuals at risk for PVC-induced cardiomyopathy and to identify preventative and therapeutic approaches targeting the root causes of PVCs to maximize effectiveness while minimizing risk.



Circulation: 27 Apr 2020; 141:1404-1418
Marcus GM
Circulation: 27 Apr 2020; 141:1404-1418 | PMID: 32339046
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Abstract

The NCDR Left Atrial Appendage Occlusion Registry.

Freeman JV, Varosy P, Price MJ, Slotwiner D, ... Curtis JP, Masoudi FA
Background
Left atrial appendage occlusion (LAAO) to prevent stroke in patients with atrial fibrillation has been evaluated in 2 randomized trials; post-approval clinical data are limited.
Objectives
The purpose of this study was to describe the National Cardiovascular Data Registry (NCDR) LAAO Registry and present patient, hospital, and physician characteristics and in-hospital adverse event rates for Watchman procedures in the United States during its first 3 years.
Methods
The authors describe the LAAO Registry structure and governance, the outcome adjudication processes, and the data quality and collection processes. They characterize the patient population, performing hospitals, and in-hospital adverse event rates.
Results
A total of 38,158 procedures from 495 hospitals performed by 1,318 physicians in the United States were included between January 2016 and December 2018. The mean patient age was 76.1 ± 8.1 years, the mean CHADS-VASc (congestive heart failure, hypertension, 65 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, female) score was 4.6 ± 1.5, and the mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score was 3.0 ± 1.1. The median annual number of LAAO procedures performed for hospitals was 30 (interquartile range: 4 to 56) and for physicians was 12 (interquartile range: 0 to 14). Procedures were canceled or aborted in 7% of cases; among cases in which a device was deployed, 98.1% were implanted with <5-mm leak. Major in-hospital adverse events occurred in 2.16% of patients; the most common complications were pericardial effusion requiring intervention (1.39%) and major bleeding (1.25%), whereas stroke (0.17%) and death (0.19%) were rare.
Conclusions
The LAAO Registry has enrolled >38,000 patients implanted with the device. Patients were generally older with more comorbidities than those enrolled in the pivotal trials; however, major in-hospital adverse event rates were lower than reported in those trials.

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

J Am Coll Cardiol: 12 Mar 2020; epub ahead of print
Freeman JV, Varosy P, Price MJ, Slotwiner D, ... Curtis JP, Masoudi FA
J Am Coll Cardiol: 12 Mar 2020; epub ahead of print | PMID: 32238316
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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

Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors.

Sama IE, Ravera A, Santema BT, van Goor H, ... van Veldhuisen DJ, Voors AA
Aims
The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.
Methods
We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).
Results
The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.
Conclusion
In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

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: 09 May 2020; epub ahead of print
Sama IE, Ravera A, Santema BT, van Goor H, ... van Veldhuisen DJ, Voors AA
Eur Heart J: 09 May 2020; epub ahead of print | PMID: 32388565
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Impact:
Abstract

Obesity and weight loss are inversely related to mortality and cardiovascular outcome in prediabetes and type 2 diabetes: data from the ORIGIN trial.

Doehner W, Gerstein HC, Ried J, Jung H, ... Hess S, Anker SD
Aims
The association of body weight and weight change with mortality and cardiovascular (CV) outcome in patients with diabetes mellitus (DM) is not clearly established. We assessed the relationship between weight, weight change, and outcomes in patients with established CV risk factors and type 2 DM or pre-diabetes.
Methods and results
A total of 12 521 participants from the ORIGIN trial were grouped in BMI categories of low body weight [body mass index (BMI) < 22 kg/m2] normal (22-24.9), overweight (25-29.9), obesity Grades 1-3 (30-34.9, 35-39.9, ≥40 kg/m2, respectively). Outcome variables included total and CV mortality and composite outcomes of CV death, non-fatal stroke, or myocardial infarction plus revascularization or heart failure hospitalization. Follow-up was 6.2 years (interquartile range 5.8-6.7 years). After multivariable adjustment, lowest risks were seen in patients with overweight and mild obesity for total mortality [overweight: hazard ratio (HR) 0.80 (95% confidence interval (CI) 0.69-0.91); obesity Grade 1: HR 0.82 (0.71-0.95), both P < 0.01)] and CV mortality [overweight: HR 0.79 (0.66-0.94); obesity Grade 1: 0.79 (0.65-0.95), all compared to patients with normal BMI, P < 0.05]. Obesity of any severity was not associated with higher mortality. Low body weight was related to higher mortality [HR 1.28 (1.02-1.61); CV mortality: HR 1.34 (1.01-1.79), P < 0.05]. A continued 2-year weight loss was associated with higher risk of mortality [HR 1.32 (1.18-1.46), P < 0.0001] and CV mortality [HR 1.18 (1.02-1.35), compared to patients without weight loss, P < 0.05]. In turn, weight gain was not related to any adverse outcome.
Conclusion
Obesity in patients with DM or pre-diabetes and CV risk profile was not associated with higher mortality or adverse CV outcome. The lowest mortality risk was seen in patients with overweight and moderate obesity (BMI 25-35 kg/m2). Weight loss was an independent risk factor for higher mortality compared to no weight loss.

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

Eur Heart J: 12 May 2020; epub ahead of print
Doehner W, Gerstein HC, Ried J, Jung H, ... Hess S, Anker SD
Eur Heart J: 12 May 2020; epub ahead of print | PMID: 32402060
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Impact:
Abstract

The Role of Non-Glycolytic Glucose Metabolism in Myocardial Recovery upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure.

Badolia R, Ramadurai DKA, Abel ED, Ferrin P, ... Rutter J, Drakos SG

Significant improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients (termed Responders-R) following left ventricular assist device (LVAD)-induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our prior work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation via the TCA cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and one-carbon metabolism, which may mediate myocardial recovery in Responders.We prospectively obtained paired LV apical myocardial tissue from non-failing donor hearts as well as responders and non-responders at LVAD implant (Pre-LVAD) and transplantation (Post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy.Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and one-carbon metabolism in Post-LVAD responders (Post-R) as compared to post-LVAD non-responders (Post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (one-carbon metabolism) were also decreased in Post-R. Furthermore, Post-R had significantly higher NADPH levels, reduced ROS levels, improved mitochondrial density and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and one-carbon metabolism that correlated with the observed myocardial recovery.The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and one-carbon metabolism which could contribute to cardioprotection by generating NADPH to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial impact of glycolysis induction during the recovery of failing human hearts following mechanical unloading.



Circulation: 29 Apr 2020; epub ahead of print
Badolia R, Ramadurai DKA, Abel ED, Ferrin P, ... Rutter J, Drakos SG
Circulation: 29 Apr 2020; epub ahead of print | PMID: 32351122
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Impact:
Abstract

Addressing Social Determinants of Health in the Care of Patients With Heart Failure: A Scientific Statement From the American Heart Association.

White-Williams C, Rossi LP, Bittner VA, Driscoll A, ... Shirey M,

Heart failure is a clinical syndrome that affects >6.5 million Americans, with an estimated 550 000 new cases diagnosed each year. The complexity of heart failure management is compounded by the number of patients who experience adverse downstream effects of the social determinants of health (SDOH). These patients are less able to access care and more likely to experience poor heart failure outcomes over time. Many patients face additional challenges associated with the cost of complex, chronic illness management and must make difficult decisions about their own health, particularly when the costs of medications and healthcare appointments are at odds with basic food and housing needs. This scientific statement summarizes the SDOH and the current state of knowledge important to understanding their impact on patients with heart failure. Specifically, this document includes a definition of SDOH, provider competencies, and SDOH assessment tools and addresses the following questions: (1) What models or frameworks guide healthcare providers to address SDOH? (2) What are the SDOH affecting the delivery of care and the interventions addressing them that affect the care and outcomes of patients with heart failure? (3) What are the opportunities for healthcare providers to address the SDOH affecting the care of patients with heart failure? We also include a case study (Data Supplement) that highlights an interprofessional team effort to address and mitigate the effects of SDOH in an underserved patient with heart failure.



Circulation: 29 Apr 2020:CIR0000000000000767; epub ahead of print
White-Williams C, Rossi LP, Bittner VA, Driscoll A, ... Shirey M,
Circulation: 29 Apr 2020:CIR0000000000000767; epub ahead of print | PMID: 32349541
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Impact:
Abstract

Family Caregiving for Individuals With Heart Failure: A Scientific Statement From the American Heart Association.

Kitko L, McIlvennan CK, Bidwell JT, Dionne-Odom JN, ... Strömberg A,

Many individuals living with heart failure (HF) rely on unpaid support from their partners, family members, friends, or neighbors as caregivers to help manage their chronic disease. Given the advancements in treatments and devices for patients with HF, caregiving responsibilities have expanded in recent decades to include more intensive care for increasingly precarious patients with HF-tasks that would previously have been undertaken by healthcare professionals in clinical settings. The specific tasks of caregivers of patients with HF vary widely based on the patient\'s symptoms and comorbidities, the relationship between patient and caregiver, and the complexity of the treatment regimen. Effects of caregiving on the caregiver and patient range from physical and psychological to financial. Therefore, it is critically important to understand the needs of caregivers to support the increasingly complex medical care they provide to patients living with HF. This scientific statement synthesizes the evidence pertaining to caregiving of adult individuals with HF in order to (1) characterize the HF caregiving role and how it changes with illness trajectory; (2) describe the financial, health, and well-being implications of caregiving in HF; (3) evaluate HF caregiving interventions to support caregiver and patient outcomes; (4) summarize existing policies and resources that support HF caregivers; and (5) identify knowledge gaps and future directions for providers, investigators, health systems, and policymakers.



Circulation: 29 Apr 2020:CIR0000000000000768; epub ahead of print
Kitko L, McIlvennan CK, Bidwell JT, Dionne-Odom JN, ... Strömberg A,
Circulation: 29 Apr 2020:CIR0000000000000768; epub ahead of print | PMID: 32349542
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Impact:
Abstract

Cardiovascular Biology of Prostanoids and Drug Discovery.

Zhu L, Zhang Y, Guo Z, Wang M

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs, which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.



Arterioscler Thromb Vasc Biol: 15 Apr 2020:ATVBAHA119313234; epub ahead of print
Zhu L, Zhang Y, Guo Z, Wang M
Arterioscler Thromb Vasc Biol: 15 Apr 2020:ATVBAHA119313234; epub ahead of print | PMID: 32295420
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Impact:
Abstract

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.

Chen T, Wu D, Chen H, Yan W, ... Zhao J, Ning Q
Objective
To delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died.
Design
Retrospective case series.
Setting
Tongji Hospital in Wuhan, China.
Participants
Among a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed. Data were collected until 28 February 2020.
Main outcome measures
Clinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms.
Results
The median age of deceased patients (68 years) was significantly older than recovered patients (51 years). Male sex was more predominant in deceased patients (83; 73%) than in recovered patients (88; 55%). Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)). Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)). The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days. Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively. Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients. Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113; 100%), type I respiratory failure (18/35; 51%), sepsis (113; 100%), acute cardiac injury (72/94; 77%), heart failure (41/83; 49%), alkalosis (14/35; 40%), hyperkalaemia (42; 37%), acute kidney injury (28; 25%), and hypoxic encephalopathy (23; 20%). Patients with cardiovascular comorbidity were more likely to develop cardiac complications. Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients.
Conclusion
Severe acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk. Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19.

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

BMJ: 25 Mar 2020; 368:m1091
Chen T, Wu D, Chen H, Yan W, ... Zhao J, Ning Q
BMJ: 25 Mar 2020; 368:m1091 | PMID: 32217556
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Impact:
Abstract

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.

Packer M

The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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

Eur Heart J: 26 May 2020; epub ahead of print
Packer M
Eur Heart J: 26 May 2020; epub ahead of print | PMID: 32460327
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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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Impact:
Abstract

Video-based AI for beat-to-beat assessment of cardiac function.

Ouyang D, He B, Ghorbani A, Yuan N, ... Ashley EA, Zou JY

Accurate assessment of cardiac function is crucial for the diagnosis of cardiovascular disease, screening for cardiotoxicity and decisions regarding the clinical management of patients with a critical illness. However, human assessment of cardiac function focuses on a limited sampling of cardiac cycles and has considerable inter-observer variability despite years of training. Here, to overcome this challenge, we present a video-based deep learning algorithm-EchoNet-Dynamic-that surpasses the performance of human experts in the critical tasks of segmenting the left ventricle, estimating ejection fraction and assessing cardiomyopathy. Trained on echocardiogram videos, our model accurately segments the left ventricle with a Dice similarity coefficient of 0.92, predicts ejection fraction with a mean absolute error of 4.1% and reliably classifies heart failure with reduced ejection fraction (area under the curve of 0.97). In an external dataset from another healthcare system, EchoNet-Dynamic predicts the ejection fraction with a mean absolute error of 6.0% and classifies heart failure with reduced ejection fraction with an area under the curve of 0.96. Prospective evaluation with repeated human measurements confirms that the model has variance that is comparable to or less than that of human experts. By leveraging information across multiple cardiac cycles, our model can rapidly identify subtle changes in ejection fraction, is more reproducible than human evaluation and lays the foundation for precise diagnosis of cardiovascular disease in real time. As a resource to promote further innovation, we also make publicly available a large dataset of 10,030 annotated echocardiogram videos.



Nature: 30 Mar 2020; 580:252-256
Ouyang D, He B, Ghorbani A, Yuan N, ... Ashley EA, Zou JY
Nature: 30 Mar 2020; 580:252-256 | PMID: 32269341
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Abstract

Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

Wang L, Halliday G, Huot JR, Satoh T, ... Gladwin MT, Lai YC
Objective
Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.
Conclusions
Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.



Arterioscler Thromb Vasc Biol: 08 Apr 2020:ATVBAHA119313883; epub ahead of print
Wang L, Halliday G, Huot JR, Satoh T, ... Gladwin MT, Lai YC
Arterioscler Thromb Vasc Biol: 08 Apr 2020:ATVBAHA119313883; epub ahead of print | PMID: 32268788
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Abstract

Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects.

Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i\'s) improve heart failure (HF) related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics, such as furosemide, induce substantial neurohormonal activation contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the SGLT-2i\'s may help circumvent these limitations.20 patients with type-2 diabetes and chronic, stable HF completed a randomized placebo-controlled crossover study of empagliflozin 10mg daily vs. placebo. Patients underwent an intensive 6-hour biospecimen collection and cardio-renal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with repeat of the above protocol.Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (p<0.0001). Fractional excretion of sodium (FENa) increased significantly with empagliflozin monotherapy vs. placebo (FENa 1.2 ± 0.7% vs. 0.7 ± 0.4% p=0.001) and there was a synergistic effect in combination with bumetanide (FENa 5.8 ± 2.5% vs. 3.9 ± 1.9%, p=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208mL, IQR -536 to 153 mL vs -14mL, IQR -282 to 335 mL, p=0.035), and plasma volume (-138mL, IQR -379 to 154mL ± 453 mL, p=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation as change in norepinephrine was superior (p = 0.02) and all other neurohormones similar (p<0.34) during the empagliflozin vs. placebo period. Furthermore, there was no evidence of potassium wasting (p=0.20), or renal dysfunction (p>0.11 for all biomarkers), whereas both serum magnesium (p<0.001) and uric acid levels (p=0.008) improved. Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in HF patients and may represent a mechanism contributing to the superior long-term HF outcomes observed with these agents.URL: https://clinicaltrials.gov Unique Identifier: NCT03029760.



Circulation: 14 May 2020; epub ahead of print
Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM
Circulation: 14 May 2020; epub ahead of print | PMID: 32410463
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Abstract

Pulmonary Hypertension Due to Left Heart Disease: Diagnosis, Pathophysiology, and Therapy.

Al-Omary MS, Sugito S, Boyle AJ, Sverdlov AL, Collins NJ

Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common type of PH and is defined as mean pulmonary artery systolic pressure of >20 mm Hg and pulmonary capillary wedge pressure >15 mm Hg during right heart catheterization. LHD may lead to elevated left atrial pressure alone, which in the absence of intrinsic pulmonary vascular disease will result in PH without changes in pulmonary vascular resistance. Persistent elevation in left atrial pressure may, however, also be associated with subsequent pulmonary vascular remodeling, vasoconstriction, and an increase in pulmonary vascular resistance. Hence, there are 2 subgroups of PH due to LHD, isolated postcapillary PH and combined post- and precapillary PH, with these groups have differing clinical implications. Differentiation of pulmonary arterial hypertension and PH due to LHD is critical to guide management planning; however, this may be challenging. Older patients, patients with metabolic syndrome, and patients with imaging and clinical features consistent with left ventricular dysfunction are suggestive of LHD etiology rather than pulmonary arterial hypertension. Hemodynamic measures such as diastolic pressure gradient, transpulmonary gradient, and pulmonary vascular resistance may assist to differentiate pre- from postcapillary PH and offer prognostic insights. However, these are influenced by fluid status and heart failure treatment. Pulmonary arterial hypertension therapies have been trialed in the treatment with concerning results reflecting disease heterogeneity, variation in inclusion criteria, and mixed end point criteria. The aim of this review is to provide an updated definition, discuss possible pathophysiology, clinical aspects, and the available treatment options for PH due to LHD.



Hypertension: 26 Apr 2020:HYPERTENSIONAHA11914330; epub ahead of print
Al-Omary MS, Sugito S, Boyle AJ, Sverdlov AL, Collins NJ
Hypertension: 26 Apr 2020:HYPERTENSIONAHA11914330; epub ahead of print | PMID: 32336230
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Abstract

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.

Belhadjer Z, Méot M, Bajolle F, Khraiche D, ... Renolleau S, Bonnet D

Cardiac injury and myocarditis have been described in adults with COVID-19. SARS-CoV-2 infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children (MIS-C) as defined by the US Centers for Disease Control.Over a two-month period contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction and severe inflammatory state.Thirty-five children were identified and included in the study. Median age at admission was 10 years (range 2-16 years). Co-morbidities were present in 28% including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one third; 80% required inotropic support with 28% treated with ECMO. Inflammation markers were suggestive of cytokine storm (interleukin 6 median 135 pg/mL) and macrophage activation (D-dimer median 5284 ng/mL). Mean brain natriuretic peptide was elevated (5743 pg/mL). Thirty-one/35 (88%) patients tested positive for SARS-CoV-2 infection by PCR of nasopharyngeal swab or serology. All patients received intravenous immune globulin, with adjunctive steroid therapy used in one third. Left ventricular function was restored in the 25/35 of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned.Children may experience an acute cardiac decompensation due to severe inflammatory state following SARS-CoV-2 infection (multisystem inflammatory syndrome in children - MIS-C). Treatment with immune globulin appears to be associated with recovery of left ventricular systolic function.



Circulation: 16 May 2020; epub ahead of print
Belhadjer Z, Méot M, Bajolle F, Khraiche D, ... Renolleau S, Bonnet D
Circulation: 16 May 2020; epub ahead of print | PMID: 32418446
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Abstract

The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared to Aspirin in Patients Chronic Vascular Disease.

Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA

Rivaroxaban 2.5mg twice daily plus aspirin 100mg reduced the risk of cardiovascular events as compared to aspirin monotherapy in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial but increased the risk of major bleedings. Analysis of net clinical benefit (NCB) is of key clinical relevance and represents an integrated measure of overall patient outcome.The current pre-specified analysis was performed to assess the NCB of adding rivaroxaban 2.5mg twice daily to aspirin monotherapy in patients with chronic vascular disease in the COMPASS study cohort (intention-to treat study population), with a specific focus on high-risk subgroups. The pre-defined NCB outcome was the composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ.A lower number of NCB adverse outcomes was observed with rivaroxaban 2.5mg twice daily + ASA vs. ASA alone (Hazard Ratio (HR) 0.80, 95% Confidence Interval (CI) 0.70-0.91), p=0.0005), which became increasingly favorable with longer treatment duration. The main drivers of NCB outcomes were \'efficacy\' events, in particular stroke (0.5%/yr vs. 0.8%/yr, HR 0.58, 95% CI 0.44-0.76, p<0.0001) and cardiovascular death (0.9%/vr vs. 1.2%/yr, HR 0.78, 95% CI 0.64-0.96, p=0.02), while the bleeding components of the NCB, in particular fatal bleeding (0.09%/yr vs. 0.06%/yr, HR 1.49, 95% CI 0.67-3.33, p=0.32), only represented a minority of NCB events. In selected high-risk subgroups, including patients with polyvascular disease (≥2 vascular beds affected with atherosclerosis), impaired renal function, heart failure, and / or diabetes, a larger absolute risk reduction for experiencing a NCB event was observed.Compared to ASA monotherapy the combination of rivaroxaban 2.5mg twice daily+ ASA resulted in fewer NCB events primarily by preventing adverse efficacy events, particularly stroke and cardiovascular mortality, whereas severe bleedings were less frequent and with less clinical impact. The NCB was particularly favorable in high-risk subgroups and those with multiple risk characteristics.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.



Circulation: 20 May 2020; epub ahead of print
Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA
Circulation: 20 May 2020; epub ahead of print | PMID: 32436455
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Abstract

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Aims
Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.
Methods and results
Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.
Conclusions
Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.
Trial registration
ClinicalTrials.gov number: NCT01947621.

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 Jun 2020; epub ahead of print
Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Eur Heart J: 01 Jun 2020; epub ahead of print | PMID: 32484517
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Abstract

Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.

Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, ... McMurray JJV, Solomon SD
Background
Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.
Methods
In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).
Findings
The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.
Interpretation
Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.
Funding
None.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 20 May 2020; epub ahead of print
Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, ... McMurray JJV, Solomon SD
Lancet: 20 May 2020; epub ahead of print | PMID: 32446323
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Abstract

Prognosis of unrecognised myocardial infarction determined by electrocardiography or cardiac magnetic resonance imaging: systematic review and meta-analysis.

Yang Y, Li W, Zhu H, Pan XF, ... Cai X, Huang Y
Objective
To evaluate the prognosis of unrecognised myocardial infarction determined by electrocardiography (UMI-ECG) or cardiac magnetic resonance imaging (UMI-CMR).
Design
Systematic review and meta-analysis of prospective studies.
Data sources
Electronic databases, including PubMed, Embase, and Google Scholar.
Study selection
Prospective cohort studies were included if they reported adjusted relative risks, odds ratios, or hazard ratios and 95% confidence intervals for all cause mortality or cardiovascular outcomes in participants with unrecognised myocardial infarction compared with those without myocardial infarction.
Data extraction and synthesis
The primary outcomes were composite major adverse cardiac events, all cause mortality, and cardiovascular mortality associated with UMI-ECG and UMI-CMR. The secondary outcomes were the risks of recurrent coronary heart disease or myocardial infarction, stroke, heart failure, and atrial fibrillation. Pooled hazard ratios and 95% confidence intervals were reported. The heterogeneity of outcomes was compared in clinically recognised and unrecognised myocardial infarction.
Results
The meta-analysis included 30 studies with 253 425 participants and 1 621 920 person years of follow-up. UMI-ECG was associated with increased risks of all cause mortality (hazard ratio 1.50, 95% confidence interval 1.30 to 1.73), cardiovascular mortality (2.33, 1.66 to 3.27), and major adverse cardiac events (1.61, 1.38 to 1.89) compared with the absence of myocardial infarction. UMI-CMR was also associated with increased risks of all cause mortality (3.21, 1.43 to 7.23), cardiovascular mortality (10.79, 4.09 to 28.42), and major adverse cardiac events (3.23, 2.10 to 4.95). No major heterogeneity was observed for any primary outcomes between recognised myocardial infarction and UMI-ECG or UMI-CMR. The absolute risk differences were 7.50 (95% confidence interval 4.50 to 10.95) per 1000 person years for all cause mortality, 11.04 (5.48 to 18.84) for cardiovascular mortality, and 27.45 (17.1 to 40.05) for major adverse cardiac events in participants with UMI-ECG compared with those without myocardial infarction. The corresponding data for UMI-CMR were 32.49 (6.32 to 91.58), 37.2 (11.7 to 104.20), and 51.96 (25.63 to 92.04), respectively.
Conclusions
UMI-ECG or UMI-CMR is associated with an adverse long term prognosis similar to that of recognised myocardial infarction. Screening for unrecognised myocardial infarction could be useful for risk stratification among patients with a high risk of cardiovascular disease.

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

BMJ: 06 May 2020; 369:m1184
Yang Y, Li W, Zhu H, Pan XF, ... Cai X, Huang Y
BMJ: 06 May 2020; 369:m1184 | PMID: 32381490
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Impact:
Abstract

Blood Pressure-Lowering Profiles and Clinical Effects of Angiotensin Receptor Blockers Versus Calcium Channel Blockers.

Mehlum MH, Liestøl K, Kjeldsen SE, Wyller TB, ... Weber MA, Berge E

Blood pressure-lowering drugs have different blood pressure-lowering profiles. We studied if differences in blood pressure mean and variability can explain the differences in risks of cardiovascular events and death among 15 245 high-risk hypertensive patients randomized to valsartan or amlodipine and followed for 4.2 years in the VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation). We selected patients with ≥3 visits and performed Cox regression analyses, defining mean blood pressure as a time-dependent covariate and visit-to-visit and within-visit blood pressure variability as the SD. Of 14 996 eligible patients, participants in the valsartan group had higher systolic mean blood pressure by 2.2 mm Hg, higher visit-to-visit systolic variability by 1.4 mm Hg, and higher within-visit systolic variability by 0.2 mm Hg (values <0.0001). The higher risks of myocardial infarction and stroke in the valsartan group was attenuated after adjustment for mean and variability of systolic blood pressure, from HR, 1.19 (95% CI, 1.02-1.39) to 1.11 (0.96-1.30) and from HR, 1.13 (0.96-1.33) to 1.00 (0.85-1.18), respectively. The lower risk of congestive heart failure in the valsartan group was accentuated after adjustment, from HR, 0.86 (0.74-1.00) to 0.76 (0.65-0.89). A smaller effect was seen on risk of death, from 1.01 (0.92-1.12) to 0.94 (0.85-1.04). In conclusion, the higher risks of myocardial infarction and stroke in patients randomized to valsartan versus amlodipine were related to the drugs\' different blood pressure modulating profiles. The risk of congestive heart failure with valsartan was lower, independent of the less favorable blood pressure modulating profile.



Hypertension: 26 Apr 2020:HYPERTENSIONAHA11914443; epub ahead of print
Mehlum MH, Liestøl K, Kjeldsen SE, Wyller TB, ... Weber MA, Berge E
Hypertension: 26 Apr 2020:HYPERTENSIONAHA11914443; epub ahead of print | PMID: 32336236
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Impact:
Abstract

Increased Arterial Stiffness Amplifies the Association Between Home Blood Pressure Variability and Cardiac Overload: The J-HOP Study.

Ishiyama Y, Hoshide S, Kanegae H, Kario K

Increased blood pressure (BP) variability, an index of hemodynamic stress, leads to cardiac overload and worse cardiovascular prognosis. The association between day-by-day home BP variability and NT-proBNP (N-terminal pro-B-type natriuretic peptide) as an index of cardiac overload may be amplified by increased arterial stiffness as assessed by brachial-ankle pulse wave velocity (baPWV). J-HOP (Japan Morning Surge-Home Blood Pressure) Study participants who were selected from a practitioner-based population with at least one cardiovascular risk factor underwent home BP monitoring, and their BP levels and SD, coefficient of variation, and average real variability as indexes of systolic BP variability were assessed. We analyzed 2115 individuals without prevalent heart failure and divided them into lower (<1800 cm/s, n=1464) and higher (≥1800 cm/s, n=651) baPWV groups. The higher baPWV group had significantly higher SD, CV, ARV values, and NT-proBNP levels than the lower baPWV group (all <0.001). In the higher baPWV group, a multiple linear regression analysis revealed that the SD was associated with the NT-proBNP level after adjustment for traditional cardiovascular risk factors including the average home systolic BP (coefficient per 1 SD increase, 0.049 [95% CI, 0.018-0.081]; =0.002). Similar trends were found for CV (=0.003) and ARV (=0.004). However, these associations were not found in the lower baPWV group. There was an interaction between all indexes of systolic BP variability and the NT-proBNP level according to lower or higher baPWV group (all <0.05). Arterial stiffness amplified the association between home BP variability and cardiac overload.



Hypertension: 26 Apr 2020:HYPERTENSIONAHA11914246; epub ahead of print
Ishiyama Y, Hoshide S, Kanegae H, Kario K
Hypertension: 26 Apr 2020:HYPERTENSIONAHA11914246; epub ahead of print | PMID: 32336235
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Abstract

Incidence and Implications of Atrial Fibrillation/Flutter in Hypertension: Insights From the SPRINT Trial.

Parcha V, Patel N, Kalra R, Kim J, ... Arora G, Arora P

We evaluated the impact of intensive blood pressure control on the incidence of new-onset atrial fibrillation/flutter (AF) and the prognostic implications of preexisting and new-onset AF in SPRINT (Systolic Blood Pressure Intervention Trial) participants. New-onset AF was defined as occurrence of AF in 12-lead electrocardiograms after randomization in participants free of AF at baseline. Poisson regression modeling was used to calculate incident rates of new-onset AF. Multivariable-adjusted Cox proportional hazard models were used to evaluate the risk of adverse cardiovascular events (composite of myocardial infarction, non-myocardial infarction acute coronary syndrome, stroke, heart failure, or cardiovascular death). In 9327 participants, 8.45% had preexisting AF, and 1.65% had new-onset AF. The incidence of new-onset AF was 4.53 per 1000-person years, with similar rates in the standard and intensive treatment arms (4.95 versus 4.11 per 1000-person years; adjusted =0.14). Participants with preexisting AF (adjusted hazard ratio, 1.83 [95% CI, 1.46-2.31]; <0.001) and new-onset AF (adjusted hazard ratio, 2.45 [95% CI, 1.58-3.80]; <0.001) had a greater risk for development of adverse cardiovascular events compared with those with no AF. Participants with preexisting AF who achieved blood pressure <120/80 mm Hg at 3 months continued have a poor prognosis (adjusted hazard ratio, 1.88 [95% CI, 1.32-2.70]; =0.001) compared with those with no AF. Intensive blood pressure control does not diminish the incidence of new-onset AF in an older, high-risk, nondiabetic population. Both preexisting and new-onset AF have adverse prognostic implications. In participants with preexisting AF, residual cardiovascular risk is evident even with on-treatment blood pressure <120/80 mm Hg. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.



Hypertension: 03 May 2020:HYPERTENSIONAHA12014690; epub ahead of print
Parcha V, Patel N, Kalra R, Kim J, ... Arora G, Arora P
Hypertension: 03 May 2020:HYPERTENSIONAHA12014690; epub ahead of print | PMID: 32362231
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Abstract

Angiotensin Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System.

Gheblawi M, Wang K, Viveiros A, Nguyen Q, ... Grant MB, Oudit GY

Angiotensin-converting enzyme (ACE2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system (RAS), facilitator of amino acid transport, and the SARS-CoV and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for COVID-19, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1-7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated RAS. Recombinant human ACE2 has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the RAS, together with implications for the COVID-19 pandemic and associated cardiovascular diseases.



Circ Res: 07 Apr 2020; epub ahead of print
Gheblawi M, Wang K, Viveiros A, Nguyen Q, ... Grant MB, Oudit GY
Circ Res: 07 Apr 2020; epub ahead of print | PMID: 32264791
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Abstract

Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults.

Lee H, Yano Y, Cho SMJ, Park JH, ... Lloyd-Jones DM, Kim HC
Background
Little is known regarding health outcomes associated with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults with stage 1 hypertension, defined using the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline.
Methods
From a nationwide health screening database, we included 6 424 090 participants, aged 20 to 39 years, who were not taking antihypertensive medication at the baseline examination in 2003 to 2007. Participants were categorized as having normal BP (untreated systolic BP [SBP] <120/diastolic BP [DBP] <80 mm Hg; n=2 665 310); elevated BP (SBP 120-129/DBP <80 mm Hg; n=705 344); stage 1 IDH (SBP <130/DBP 80-89 mm Hg; n=1 271 505); stage 1 ISH (SBP 130-139/DBP <80 mm Hg; n=255 588); stage 1 SDH (SBP 130-139/DBP 80-89 mm Hg; n=711 503); and stage 2 hypertension (SBP ≥140, DBP ≥90 mm Hg; n=814 840). The primary outcome was composite cardiovascular disease (CVD) events, including myocardial infarction, stroke, heart failure, and CVD-related death.
Results
The median age of the participants was 30 years and 60.9% were male. Over a median follow-up of 13.2 years, 44 070 new CVD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (95% CIs) for CVD events were 1.14 (1.09-1.18) for elevated BP, 1.32 (1.28-1.36) for stage 1 IDH, 1.36 (1.29-1.43) for stage 1 ISH, 1.67 (1.61-1.72) for stage 1 SDH, and 2.40 (2.33-2.47) for stage 2 hypertension.
Conclusions
Among young adults, stage 1 ISH, IDH, and SDH were all associated with higher CVD risks than normal BP. The CVD risks of stage 1 ISH and IDH were similar to each other but lower than the risk of stage 1 SDH. Categorizing young adults with stage 1 hypertension further into stage 1 ISH, IDH, and SDH may improve risk stratification for identifying high-risk individuals.



Circulation: 01 Jun 2020; 141:1778-1786
Lee H, Yano Y, Cho SMJ, Park JH, ... Lloyd-Jones DM, Kim HC
Circulation: 01 Jun 2020; 141:1778-1786 | PMID: 32479205
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Abstract

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure.

Selvaraj S, Kelly DP, Margulies KB

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.



Circulation: 01 Jun 2020; 141:1800-1812
Selvaraj S, Kelly DP, Margulies KB
Circulation: 01 Jun 2020; 141:1800-1812 | PMID: 32479196
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Abstract

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association.

Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, ... Ruberg FL,

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.



Circulation: 31 May 2020:CIR0000000000000792; epub ahead of print
Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, ... Ruberg FL,
Circulation: 31 May 2020:CIR0000000000000792; epub ahead of print | PMID: 32476490
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Abstract

Early Cardiac Remodeling Promotes Tumor Growth and Metastasis.

Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A

Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure (HF) and stress correlate with poor cancer prognosis. Yet, whether cardiac remodeling in the absence of HF is sufficient to promote cancer is unknown.To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload-induced cardiac hypertrophy, and followed it by cancer cell implantation.TAC-operated mice developed larger primary tumors with higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation , suggesting the existence of secreted tumor-promoting factors. Using RNA-seq data, we identified elevated mRNA levels ofin the hearts of TAC-operated mice. Periostin levels were also found high in the serum following TAC. Interestingly, depletion of Periostin from the serum abrogated the proliferation of cancer cells, conversely, the addition of Periostin enhanced cancer cell proliferation . Collectively, this is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis, and therefore promotes cancer progression.Our study highlights the importance of early diagnosis and treatment of cardiac remodeling as it may attenuate cancer progression and improve cancer outcome.



Circulation: 31 May 2020; epub ahead of print
Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A
Circulation: 31 May 2020; epub ahead of print | PMID: 32475164
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Abstract

Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes.

Petrie MC, Verma S, Docherty KF, Inzucchi SE, ... Jhund PS, McMurray JJV
Importance
Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes.
Objective
To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes.
Design, setting, and participants
Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019.
Interventions
Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy.
Main outcomes and measures
The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%.
Results
Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes.
Conclusions and relevance
In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status.
Trial registration
ClinicalTrials.gov Identifier: NCT03036124.



JAMA: 26 Mar 2020; epub ahead of print
Petrie MC, Verma S, Docherty KF, Inzucchi SE, ... Jhund PS, McMurray JJV
JAMA: 26 Mar 2020; epub ahead of print | PMID: 32219386
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Abstract

Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction.

Houssari M, Dumesnil A, Tardif V, Kivelä R, ... Mulder P, Brakenhielm E
Objective
Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4 and CD8 T cells potently suppress, in part, through interferon-γ, cardiac lymphangiogenesis post-MI.
Conclusions
We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C. Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.



Arterioscler Thromb Vasc Biol: 13 May 2020:ATVBAHA120314370; epub ahead of print
Houssari M, Dumesnil A, Tardif V, Kivelä R, ... Mulder P, Brakenhielm E
Arterioscler Thromb Vasc Biol: 13 May 2020:ATVBAHA120314370; epub ahead of print | PMID: 32404007
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Abstract

Implantable cardiac electronic device therapy for patients with a systemic right ventricle.

Barracano R, Brida M, Guarguagli S, Palmieri R, ... Gatzoulis MA, Wong T

The systemic right ventricle (SRV), defined as the morphological right ventricle supporting the systemic circulation, is relatively common in congenital heart disease (CHD). Our review aimed at examining the current evidence, knowledge gaps and technical considerations regarding implantable cardiac electronic device therapy in patients with SRV. The risk of sinus node dysfunction (SND) after atrial switch repair and/or complete heart block in congenitally corrected transposition of great arteries requiring permanent pacing increases with age. Similar to acquired heart disease, indication for pacing includes symptomatic bradycardia, SND and high degree atrioventricular nodal block. Right ventricular dysfunction and heart failure also represent important complications in SRV patients. Cardiac resynchronisation therapy (CRT) has been proposed to improve systolic function in SRV patients, although indications for CRT are not well defined and its potential benefit remains uncertain. Amongst adult CHD, patients with SRV are at the highest risk for sudden cardiac death (SCD). Nevertheless, risk stratification for SCD is scarce in this cohort and implantable cardioverter-defibrillator indication is currently limited to secondary prevention. Vascular access and the incidence of device-related complications, such as infections, inappropriate shocks and device system failure, represent additional challenges to implantable cardiac electronic device therapy in patients with SRV. A multidisciplinary approach with tertiary expertise and future collaborative research are all paramount to further the care for this challenging nonetheless ever increasing cohort of patients.

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

Heart: 07 Apr 2020; epub ahead of print
Barracano R, Brida M, Guarguagli S, Palmieri R, ... Gatzoulis MA, Wong T
Heart: 07 Apr 2020; epub ahead of print | PMID: 32269130
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Abstract

Average pixel intensity method for prediction of outcome in secondary mitral regurgitation.

Kamoen V, De Buyzere M, El Haddad M, de Backer TLM, Timmermans F
Background
Echocardiographic grading of secondary mitral regurgitation (SMR) severity is challenging and involves multiple guideline-recommended parameters. We previously introduced the average pixel intensity (API) method for grading SMR. In this study, the clinical outcome in SMR based on the API method for grading MR was compared with conventional grading methods.
Methods
231 patients with systolic heart failure and reduced ejection fraction (ischaemic/non-ischaemic) and SMR were prospectively enrolled. MR was graded using all guideline-recommended parameters and the API method, which is based on the pixel intensity of the continuous wave Doppler signal. The primary outcome was MACE (major adverse cardiac event).
Results
The API method was applicable in 98% of patients with SMR (n=227). During a median follow-up of 24 months, 98 patients (43%) had a MACE (cardiovascular mortality (n=50, 22%), heart failure hospitalisation (n=44, 19%), mitral valve surgery (n=11, 5%), percutaneous mitral intervention (n=12, 5%), heart transplantation (n=5, 2%)). On log-rank test, the API method was highly significant in predicting clinical outcome. On multivariable Cox proportional hazard analysis, SMR grading with the API method was an independent predictor of clinical outcome (along with NYHA class and right ventricular systolic pressure; p<0.001), increasing the event risk by 9% per 10 au API rise (p=0.001). In the same multivariable analysis, proximal isovelocity surface area (PISA)-effective regurgitant orifice area or PISA-regurgitant volume were not independent predictors of events (p=0.18 and 0.26, respectively).
Conclusion
SMR grading with the API method is an independent predictor of clinical outcome and provides prognostic information in addition to clinical and other echocardiographic variables.

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

Heart: 21 Mar 2020; epub ahead of print
Kamoen V, De Buyzere M, El Haddad M, de Backer TLM, Timmermans F
Heart: 21 Mar 2020; epub ahead of print | PMID: 32201372
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Abstract

Temporal Trends in Prevalence & Prognostic Implications of Comorbidities Among Patients with Acute Decompensated Heart Failure: The ARIC Study Community Surveillance.

Pandey A, Vaduganathan M, Arora S, Qamar A, ... Rosamond WD, Caughey MC

Patients with heart failure (HF) have multiple co-existing comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well-established.HF related hospitalizations were sampled by stratified design from four US areas in 2005 to 2014 by the community surveillance component of the ARIC (Atherosclerosis Risk in Communities) study. Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction <50% was considered HFrEF. A total of 15 co-morbidities were abstracted from the medical record. Mortality outcomes were ascertained for up to 1-year post-admission, by linking hospital records with death files.A total of 5,460 hospitalizations (24,937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF vs. HFrEF, both for women (5.53 vs. 4.94, <0.0001) and men (5.20 vs. 4.82, <0.0001). There was a significant temporal increase in the overall burden of co-morbidities, both for patients with HFpEF (Women: 5.17 in 2005-2009 to 5.87 in 2010-2013; Men: 4.94 in 2005-2009 and 5.45 in 2010-2013) and HFrEF (Women: 4.78 in 2005-2009 to 5.14 in 2010-2013; Men: 4.62 in 2005-2009 and 5.06 in 2010-2013, -trend<0.0001 for all). Higher comorbidity burden was significantly associated with higher adjusted risk of 1-year mortality, with a stronger association noted for HFpEF [HR (95% CI) per 1-higher co-morbidity:1.19(1.14-1.25) vs. HFrEF [HR (95%CI): 1.10(1.05-1.14); -interaction by HF type = 0.02]. The associated mortality risk per 1-higher co-morbidity also increased significantly over time for patients with HFpEF as well HFrEF (P-for interaction with time =0.002 and 0.02 respectively).The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF vs. HFrEF.



Circulation: 02 Jun 2020; epub ahead of print
Pandey A, Vaduganathan M, Arora S, Qamar A, ... Rosamond WD, Caughey MC
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32486833
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Abstract

Obesity, Hypertension, and Cardiac Dysfunction: Novel Roles of Immunometabolism in Macrophage Activation and Inflammation.

Mouton AJ, Li X, Hall ME, Hall JE

Obesity and hypertension, which often coexist, are major risk factors for heart failure and are characterized by chronic, low-grade inflammation, which promotes adverse cardiac remodeling. While macrophages play a key role in cardiac remodeling, dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypes promotes excessive inflammation and cardiac injury. Metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation has been implicated in macrophage polarization. M1 macrophages primarily rely on glycolysis, whereas M2 macrophages rely on the tricarboxylic acid cycle and oxidative phosphorylation; thus, factors that affect macrophage metabolism may disrupt M1/M2 homeostasis and exacerbate inflammation. The mechanisms by which obesity and hypertension may synergistically induce macrophage metabolic dysfunction, particularly during cardiac remodeling, are not fully understood. We propose that obesity and hypertension induce M1 macrophage polarization via mechanisms that directly target macrophage metabolism, including changes in circulating glucose and fatty acid substrates, lipotoxicity, and tissue hypoxia. We discuss canonical and novel proinflammatory roles of macrophages during obesity-hypertension-induced cardiac injury, including diastolic dysfunction and impaired calcium handling. Finally, we discuss the current status of potential therapies to target macrophage metabolism during heart failure, including antidiabetic therapies, anti-inflammatory therapies, and novel immunometabolic agents.



Circ Res: 12 Mar 2020; 126:789-806
Mouton AJ, Li X, Hall ME, Hall JE
Circ Res: 12 Mar 2020; 126:789-806 | PMID: 32163341
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Abstract

Prognostic value of von Willebrand factor in adult patients with congenital heart disease.

Ohuchi H, Hayama Y, Miike H, Suzuki D, ... Kurosaki KI, Nakai M
Objectives
von Willebrand factor (vWF) has prognostic value in patients with heart failure (HF) and in those with liver disease. Liver congestion, due to right-sided HF (RHF), is one of the major clinical pathophysiologic manifestations in adults with congenital heart disease (ACHD). The present study\'s purpose was to clarify the prognostic value of plasma levels of vWF antigen (vWF:Ag) in ACHD.
Methods
We measured vWF:Ag (%) in 382 consecutive patients (20 unrepaired cyanotic ACHD, 172 Fontan patients and 190 ACHD after biventricular repair) and compared the results with the clinical profiles and prognosis.
Results
The plasma vWF:Ag level was 130±53 (normal range: 55%-190%), and 48 patients (13%) showed high levels of vWF:Ag (≥190%). Older age, Fontan circulation, higher central venous pressure, lower arterial oxygen saturation and lower plasma levels of albumin were independently associated with high log (vWF:Ag) (p<0.05-0.0001). During the follow-up of 2.4±1.4 years, 15 patients died. High log (vWF:Ag) predicted the all-cause mortality (HR 1.63 per 0.1, 95% CI 1.40 to 1.96, p<0.0001). Specifically, patients with high vWF:Ag (≥165%) had a substantially higher risk of all-cause mortality (HR 56.4, 95% CI 11.4 to 1020, p<0.0001), and this prognostic value was independent of plasma levels of brain-type natriuretic peptide.
Conclusions
High vWF:Ag may reflect RHF severity and related liver dysfunction with a strong prognostic value of all-cause mortality in ACHD. Thus, vWF:Ag might be an excellent biomarker for monitoring ACHD with RHF.

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

Heart: 17 Mar 2020; epub ahead of print
Ohuchi H, Hayama Y, Miike H, Suzuki D, ... Kurosaki KI, Nakai M
Heart: 17 Mar 2020; epub ahead of print | PMID: 32188625
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Abstract

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.

Petrilli CM, Jones SA, Yang J, Rajagopalan H, ... Francois F, Horwitz LI
Objective
To describe outcomes of people admitted to hospital with coronavirus disease 2019 (covid-19) in the United States, and the clinical and laboratory characteristics associated with severity of illness.
Design
Prospective cohort study.
Setting
Single academic medical center in New York City and Long Island.
Participants
5279 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection between 1 March 2020 and 8 April 2020. The final date of follow up was 5 May 2020.
Main outcome measures
Outcomes were admission to hospital, critical illness (intensive care, mechanical ventilation, discharge to hospice care, or death), and discharge to hospice care or death. Predictors included patient characteristics, medical history, vital signs, and laboratory results. Multivariable logistic regression was conducted to identify risk factors for adverse outcomes, and competing risk survival analysis for mortality.
Results
Of 11 544 people tested for SARS-Cov-2, 5566 (48.2%) were positive. After exclusions, 5279 were included. 2741 of these 5279 (51.9%) were admitted to hospital, of whom 1904 (69.5%) were discharged alive without hospice care and 665 (24.3%) were discharged to hospice care or died. Of 647 (23.6%) patients requiring mechanical ventilation, 391 (60.4%) died and 170 (26.2%) were extubated or discharged. The strongest risk for hospital admission was associated with age, with an odds ratio of >2 for all age groups older than 44 years and 37.9 (95% confidence interval 26.1 to 56.0) for ages 75 years and older. Other risks were heart failure (4.4, 2.6 to 8.0), male sex (2.8, 2.4 to 3.2), chronic kidney disease (2.6, 1.9 to 3.6), and any increase in body mass index (BMI) (eg, for BMI >40: 2.5, 1.8 to 3.4). The strongest risks for critical illness besides age were associated with heart failure (1.9, 1.4 to 2.5), BMI >40 (1.5, 1.0 to 2.2), and male sex (1.5, 1.3 to 1.8). Admission oxygen saturation of <88% (3.7, 2.8 to 4.8), troponin level >1 (4.8, 2.1 to 10.9), C reactive protein level >200 (5.1, 2.8 to 9.2), and D-dimer level >2500 (3.9, 2.6 to 6.0) were, however, more strongly associated with critical illness than age or comorbidities. Risk of critical illness decreased significantly over the study period. Similar associations were found for mortality alone.
Conclusions
Age and comorbidities were found to be strong predictors of hospital admission and to a lesser extent of critical illness and mortality in people with covid-19; however, impairment of oxygen on admission and markers of inflammation were most strongly associated with critical illness and mortality. Outcomes seem to be improving over time, potentially suggesting improvements in care.

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

BMJ: 21 May 2020; 369:m1966
Petrilli CM, Jones SA, Yang J, Rajagopalan H, ... Francois F, Horwitz LI
BMJ: 21 May 2020; 369:m1966 | PMID: 32444366
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Abstract

Multimorbidity, mortality, and HbA1c in type 2 diabetes: A cohort study with UK and Taiwanese cohorts.

Chiang JI, Hanlon P, Li TC, Jani BD, ... Thuraisingam S, Mair FS
Background
There is emerging interest in multimorbidity in type 2 diabetes (T2D), which can be either concordant (T2D related) or discordant (unrelated), as a way of understanding the burden of disease in T2D. Current diabetes guidelines acknowledge the complex nature of multimorbidity, the management of which should be based on the patient\'s individual clinical needs and comorbidities. However, although associations between multimorbidity, glycated haemoglobin (HbA1c), and mortality in people with T2D have been studied to some extent, significant gaps remain, particularly regarding different patterns of multimorbidity, including concordant and discordant conditions. This study explores associations between multimorbidity (total condition counts/concordant/discordant/different combinations of conditions), baseline HbA1c, and all-cause mortality in T2D.
Methods and findings
We studied two longitudinal cohorts of people with T2D using the UK Biobank (n = 20,569) and the Taiwan National Diabetes Care Management Program (NDCMP) (n = 59,657). The number of conditions in addition to T2D was used to quantify total multimorbidity, concordant, and discordant counts, and the effects of different combinations of conditions were also studied. Outcomes of interest were baseline HbA1c and all-cause mortality. For the UK Biobank and Taiwan NDCMP, mean (SD) ages were 60.2 (6.8) years and 60.8 (11.3) years; 7,579 (36.8%) and 31,339 (52.5%) were female; body mass index (BMI) medians (IQR) were 30.8 (27.7, 34.8) kg/m2 and 25.6 (23.5, 28.7) kg/m2; and 2,197 (10.8%) and 9,423 (15.8) were current smokers, respectively. Increasing total and discordant multimorbidity counts were associated with lower HbA1c and increased mortality in both datasets. In Taiwan NDCMP, for those with four or more additional conditions compared with T2D only, the mean difference (95% CI) in HbA1c was -0.82% (-0.88, -0.76) p < 0.001. In UK Biobank, hazard ratios (HRs) (95% CI) for all-cause mortality in people with T2D and one, two, three, and four or more additional conditions compared with those without comorbidity were 1.20 (0.91-1.56) p < 0.001, 1.75 (1.35-2.27) p < 0.001, 2.17 (1.67-2.81) p < 0.001, and 3.14 (2.43-4.03) p < 0.001, respectively. Both concordant/discordant conditions were significantly associated with mortality; however, HRs were largest for concordant conditions. Those with four or more concordant conditions had >5 times the mortality (5.83 [4.28-7.93] p <0.001). HRs for NDCMP were similar to those from UK Biobank for all multimorbidity counts. For those with two conditions in addition to T2D, cardiovascular diseases featured in 18 of the top 20 combinations most highly associated with mortality in UK Biobank and 12 of the top combinations in the Taiwan NDCMP. In UK Biobank, a combination of coronary heart disease and heart failure in addition to T2D had the largest effect size on mortality, with a HR (95% CI) of 4.37 (3.59-5.32) p < 0.001, whereas in the Taiwan NDCMP, a combination of painful conditions and alcohol problems had the largest effect size on mortality, with an HR (95% CI) of 4.02 (3.08-5.23) p < 0.001. One limitation to note is that we were unable to model for changes in multimorbidity during our study period.
Conclusions
Multimorbidity patterns associated with the highest mortality differed between UK Biobank (a population predominantly comprising people of European descent) and the Taiwan NDCMP, a predominantly ethnic Chinese population. Future research should explore the mechanisms underpinning the observed relationship between increasing multimorbidity count and reduced HbA1c alongside increased mortality in people with T2D and further examine the implications of different patterns of multimorbidity across different ethnic groups. Better understanding of these issues, especially effects of condition type, will enable more effective personalisation of care.



PLoS Med: 29 Apr 2020; 17:e1003094
Chiang JI, Hanlon P, Li TC, Jani BD, ... Thuraisingam S, Mair FS
PLoS Med: 29 Apr 2020; 17:e1003094 | PMID: 32379755
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Abstract

Associations of symptoms and quality of life with outcomes in patients with atrial fibrillation.

Krisai P, Blum S, Aeschbacher S, Beer JH, ... Conen D,
Objective
We aimed to investigate changes in atrial fibrillation (AF)-related symptoms and quality of life (QoL) over time, and their impact on prognosis.
Methods
We prospectively followed 3836 patients with known AF for a mean of 3.7 years. Information on AF-related symptoms and QoL was obtained yearly. The primary end point was a composite of stroke or systemic embolism. Main secondary end points included stroke subtypes, all-cause mortality, cardiovascular death, hospitalisation for congestive heart failure (CHF), myocardial infarction and major bleeding. We assessed associations using multivariable, time-updated Cox proportional hazards models.
Results
Mean age was 72 years, 72% were male. Patients with AF-related symptoms (66%) were younger (70 vs 74 years, p<0.0001), more often had paroxysmal AF (56% vs 37%, p<0.0001) and had lower QoL (71 vs 72 points, p=0.009). The incidence of the primary end point was 1.05 and 1.02 per 100 person-years in patients with and without symptoms, respectively. The multivariable adjusted HR (aHR) (95% CIs) for the primary end point was 1.11 (0.77 to 1.59; p=0.56) for AF-related symptoms. AF-related symptoms were not associated with any of the secondary end points. QoL was not significantly related to the primary end point (aHR per 5-point increase 0.98 (0.94 to 1.03; p=0.37)), but was significantly related to CHF hospitalisations (0.92 (0.90 to 0.94; p<0.0001)), cardiovascular death (0.90 (0.86 to 0.95; p<0.0001)) and all-cause mortality (0.88 (0.86 to 0.90; p<0.0001)).
Conclusions
AF-related symptoms were not associated with adverse outcomes and should therefore not be the basis for prognostic treatment decisions. QoL was strongly associated with CHF, cardiovascular death and all-cause mortality.

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

Heart: 30 Mar 2020; epub ahead of print
Krisai P, Blum S, Aeschbacher S, Beer JH, ... Conen D,
Heart: 30 Mar 2020; epub ahead of print | PMID: 32234819
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Abstract

Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease.

Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment-elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.



Circ Res: 23 Apr 2020; 126:1260-1280
Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA
Circ Res: 23 Apr 2020; 126:1260-1280 | PMID: 32324502
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Abstract

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes.

Chen CY, Salomon AK, Caporizzo MA, Curry S, ... Margulies KB, Prosser BL

Impaired myocardial relaxation is an intractable feature of several heart failure (HF) etiologies. In human HF, detyrosinated microtubules stiffen cardiomyocytes and impair relaxation. Yet the identity of detyrosinating enzymes have remained ambiguous, hindering mechanistic study and therapeutic development. We aimed to determine if the recently identified complex of VASH1/2 and SVBP is an active detyrosinase in cardiomyocytes and if genetic inhibition of VASH-SVBP is sufficient to lower stiffness and improve contractility in HF.Transcriptional profiling revealed that VASH1 transcript is >10-fold more abundant than VASH2 in human hearts. Using short hairpin RNAs (shRNAs) against VASH1, VASH2, and SVBP, we showed that both VASH1- and VASH2-SVBP complexes function as tubulin carboxypeptidases in cardiomyocytes, with a predominant role for VASH1. We also generated a catalytically dead version of the tyrosinating enzyme TTL (TTL-E331Q) to separate the microtubule depolymerizing effects of TTL from its enzymatic activity. Assays of microtubule stability revealed that both TTL and TTL-E331Q depolymerize microtubules, while VASH1 and SVBP depletion reduce detyrosination independent of depolymerization. We next probed effects on human cardiomyocyte contractility. Contractile kinetics were slowed in HF, with dramatically slowed relaxation in cardiomyocytes from patients with HF with preserved ejection fraction (HFpEF). Knockdown of VASH1 conferred subtle kinetic improvements in non-failing cardiomyocytes, while markedly improving kinetics in failing cardiomyocytes. Further, TTL, but not TTL-E331Q, robustly sped relaxation. Simultaneous measurements of calcium transients and contractility demonstrated that VASH1 depletion speeds kinetics independent from alterations to calcium cycling. Finally, atomic force microscopy confirmed that VASH1 depletion reduces the stiffness of failing human cardiomyocytes.VASH-SVBP complexes are active tubulin carboxypeptidases in cardiomyocytes. Inhibition of VASH1 or activation of TTL is sufficient to lower stiffness and speed relaxation in cardiomyocytes from HF patients, supporting further pursuit of detyrosination as a therapeutic target for diastolic dysfunction.



Circ Res: 09 Apr 2020; epub ahead of print
Chen CY, Salomon AK, Caporizzo MA, Curry S, ... Margulies KB, Prosser BL
Circ Res: 09 Apr 2020; epub ahead of print | PMID: 32272864
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Abstract

Cardiovascular risk factors and outcomes in early rheumatoid arthritis: a population-based study.

Nikiphorou E, de Lusignan S, Mallen CD, Khavandi K, ... Galloway J, Raza K
Objective
To assess the burden of cardiovascular disease (CVD) at and prior to diagnosis in people with early rheumatoid arthritis (RA) and subsequent CVD in these patients.
Methods
A retrospective case-control study using a large English primary care database. People with RA (n=6591) diagnosed between 2004 and 2016 (inclusive) were identified using a validated algorithm, matched 1:1 by age and gender to those without RA (n=6591) and followed for a median of 5.4 years. We assessed differences in CVD at, before and after diagnosis, and the impact of traditional and RA-related risk factors (C reactive protein, RA-related autoantibodies and medication use) on incident CVD (a composite of myocardial infarction (MI), stroke or heart failure).
Results
RA cases and their matched controls were both of mean age 58.7 (SD 15.5) at cohort entry, and 67.5% were female. Some CVD risk factors were more common at RA diagnosis including smoking and diabetes; however, total and low-density lipoprotein cholesterol were lower in patients with RA. CVD was more common in RA at cohort entry; stroke (3.9% vs 2.7%, p<0.001), heart failure (1.6% vs 1.0%, p=0.001), and non-significantly MI (3.1% vs 2.8%, p=0.092). Excess CVD developed in the 5 years preceding diagnosis. After adjustment for traditional and RA-related risk factors, RA was associated with greater risk of post-diagnosis CVD (HR 1.33, 95% CI 1.07 to 1.65, p=0.010).
Conclusions
An excess of stroke and heart failure occurs before diagnosis of RA. There is excess risk for further cardiovascular events after diagnosis, which is not explained by differences in traditional CVD or RA-related risk factors at diagnosis.

© 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: 23 Mar 2020; epub ahead of print
Nikiphorou E, de Lusignan S, Mallen CD, Khavandi K, ... Galloway J, Raza K
Heart: 23 Mar 2020; epub ahead of print | PMID: 32209618
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Abstract

Sectm1a Deficiency Aggravates Inflammation-Triggered Cardiac Dysfunction through Disruption of LXRα Signaling in Macrophages.

Li Y, Deng S, Wang X, Huang W, ... Peng J, Fan GC
Aim
Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown.
Methods and results
Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after LPS injection, when compared to wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly downregulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls.
Conclusion
This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signaling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction.
Translational perspective
Better understanding on the interaction between inflammatory responses and cardiac health is prominent for the development of safer and more efficacious therapies for heart failure patients. The present study, using both acute (LPS) and chronic (high-fat diet) inflammation models, reiterated the adverse effects of abnormal macrophages activation on cardiac function. Our Sectm1a knockout mouse model showed exacerbated cardiac and systemic inflammatory responses, resulting in further aggravation of contractile dysfunction on the heart after endotoxin challenge. We also demonstrated Sectm1a as a new regulator of macrophage function through LXRα pathway. These data suggest a novel approach to regulate macrophage-elicited inflammation.

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

Cardiovasc Res: 13 Mar 2020; epub ahead of print
Li Y, Deng S, Wang X, Huang W, ... Peng J, Fan GC
Cardiovasc Res: 13 Mar 2020; epub ahead of print | PMID: 32170929
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Abstract

Gamma-glutamyl transferase variability and the risk of hospitalisation for heart failure.

Hong SH, Lee JS, Kim JA, Lee YB, ... Baik SH, Choi KM
Objective
Gamma-glutamyl transferase (GGT) is associated with oxidative stress, inflammation, cardiovascular disease and mortality. Variability in metabolic parameters has recently emerged as an indicator of adverse health outcomes, including heart failure (HF).
Methods
We investigated whether GGT variability was associated with the incidence of hospitalisation for heart failure (HHF) in a Korean population without previous HF, ischaemic heart disease or liver disease. This longitudinal cohort study analysed 119 201 individuals from the Korean National Health Insurance Service-National Health Screening Cohort. GGT variability was calculated as the coefficient of variation (CV), SD and variability independent of the mean (VIM).
Results
During the 8.4 years of follow-up, 1387 cases of HHF (1.16%) developed. In the multivariable-adjusted model, the HR of HHF was 1.22 (95% CI 1.05 to 1.42) in the highest quartile of GGT variability compared with the lowest quartile, as assessed by CV after adjusting for confounding factors, including alcohol consumption and mean GGT levels. Consistent results were obtained using other indices of GGT variability such as SD (HR 1.37, 95% CI 1.16 to 1.62) and VIM (HR 1.29, 95% CI 1.11 to 1.50). In a subgroup analysis stratified by risk factor variables, although a similar relationship was observed, it was more prominent in individuals with dyslipidaemia.
Conclusions
The results of the present study demonstrated that variability in GGT was independently associated with the incidence of HHF. These findings suggest that higher GGT variability may be useful as an indicator of future risk of HF.

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

Heart: 16 Apr 2020; epub ahead of print
Hong SH, Lee JS, Kim JA, Lee YB, ... Baik SH, Choi KM
Heart: 16 Apr 2020; epub ahead of print | PMID: 32303630
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Abstract

Pim1 Maintains Telomere Length in Mouse Cardiomyocytes by Inhibiting TGFβ Signaling.

Ebeid DE, Khalafalla FG, Broughton KM, Monsanto MM, ... Goumans MJ, Sussman MA
Aims
Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and upregulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signaling pathway where inhibiting TGFβ signaling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signaling pathways in proliferating A549 cells and post-mitotic cardiomyocytes.
Methods and results
Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFβ signaling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signaling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes.
Conclusions
Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of TERT. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.
Translational perspective
Telomere maintenance is associated with preservation of cardiomyocyte functional competency and survival, with telomeric shortening linked to cardiomyopathic disease. Aging also contributes to telomere erosion that contributes to deterioration of myocardial performance. Pim1 kinase mediates beneficial effects to preserve cardiomyocyte survival and function and this report demonstrates a novel molecular mechanism of Pim1 action to mitigate telomeric shortening. Findings linking Pim1 to telomere biology introduce another facet of cardioprotection that can be developed as a molecular interventional approach to treat myocardial injury and heart failure.

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

Cardiovasc Res: 15 Mar 2020; epub ahead of print
Ebeid DE, Khalafalla FG, Broughton KM, Monsanto MM, ... Goumans MJ, Sussman MA
Cardiovasc Res: 15 Mar 2020; epub ahead of print | PMID: 32176281
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Abstract

Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis.

Giugliano RP, Pedersen TR, Saver JL, Sever PS, ... Sabatine MS,

Background and Purpose- The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5-1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods- FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results- Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66-0.95]; =0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62-0.92]; =0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68-1.98]; =0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72-1.00) for the cardiovascular composite, 0.90 (0.68-1.19) for all stroke, and 0.92 (0.68-1.25) for ischemic stroke ( interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions- Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633.



Stroke: 20 Apr 2020:STROKEAHA119027759; epub ahead of print
Giugliano RP, Pedersen TR, Saver JL, Sever PS, ... Sabatine MS,
Stroke: 20 Apr 2020:STROKEAHA119027759; epub ahead of print | PMID: 32312223
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Abstract

RUNX1: an emerging therapeutic target for cardiovascular disease.

Riddell A, McBride M, Braun T, Nicklin SA, ... Loughrey CM, Martin TP

Runt-related transcription factor-1 (RUNX1), also known as acute myeloid leukaemia 1 protein (AML1), is a member of the core-binding factor family of transcription factors which modulate cell proliferation, differentiation, and survival in multiple systems. It is a master-regulator transcription factor, which has been implicated in diverse signalling pathways and cellular mechanisms during normal development and disease. RUNX1 is best characterized for its indispensable role for definitive haematopoiesis and its involvement in haematological malignancies. However, more recently RUNX1 has been identified as a key regulator of adverse cardiac remodelling following myocardial infarction. This review discusses the role RUNX1 plays in the heart and highlights its therapeutic potential as a target to limit the progression of adverse cardiac remodelling and heart failure.

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

Cardiovasc Res: 09 Mar 2020; epub ahead of print
Riddell A, McBride M, Braun T, Nicklin SA, ... Loughrey CM, Martin TP
Cardiovasc Res: 09 Mar 2020; epub ahead of print | PMID: 32154891
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Abstract

Impact of atrial fibrillation in patients with heart failure and reduced, mid-range or preserved ejection fraction.

Son MK, Park JJ, Lim NK, Kim WH, Choi DJ
Objective
To determine the prognostic value of atrial fibrillation (AF) in patients with heart failure (HF) and preserved, mid-range or reduced ejection fraction (EF).
Methods
Patients hospitalised for acute HF were enrolled in the Korean Acute Heart Failure registry, a prospective, observational, multicentre cohort study, between March 2011 and February 2014. HF types were defined as reduced EF (HFrEF, LVEF <40%), mid-range EF (HFmrEF, LVEF 40%-49%) or preserved EF (HFpEF, LVEF ≥50%).
Results
Of 5414 patients enrolled, HFrEF, HFmrEF and HFpEF were seen in 3182 (58.8%), 875 (16.2%) and 1357 (25.1%) patients, respectively. The prevalence of AF significantly increased with increasing EF (HFrEF 28.9%, HFmrEF 39.8%, HFpEF 45.2%; p for trend <0.001). During follow-up (median, 4.03 years; IQR, 1.39-5.58 years), 2806 (51.8%) patients died. The adjusted HR of AF for all-cause death was 1.06 (0.93-1.21) in the HFrEF, 1.10 (0.87-1.39) in the HFmrEF and 1.22 (1.02-1.46) in the HFpEF groups. The HR for the composite of all-cause death or readmission was 0.97 (0.87-1.07), 1.14 (0.93-1.38) and 1.03 (0.88-1.19) in the HFrEF, HFmrEF and HFpEF groups, respectively, and the HR for stroke was 1.53 (1.03-2.29), 1.04 (0.57-1.91) and 1.90 (1.13-3.20), respectively. Similar results were observed after propensity score matching analysis.
Conclusions
AF was more common with increasing EF. AF was seen to be associated with increased mortality only in patients with HFpEF and was associated with an increased risk of stroke in patients with HFrEF or HFpEF.
Trial registration number
NCT01389843.

© 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: 26 Apr 2020; epub ahead of print
Son MK, Park JJ, Lim NK, Kim WH, Choi DJ
Heart: 26 Apr 2020; epub ahead of print | PMID: 32341140
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Abstract

Single cell RNA sequencing reveals profound changes in circulating immune cells in patients with heart failure.

Abplanalp WT, John D, Cremer S, Assmus B, ... Vasa-Nicotera M, Dimmeler S
Aims
Identification of signatures of immune cells at single cell level may provide novel insights into changes of immune related disorders. Therefore, we used single cell RNA sequencing to determine the impact of heart failure on circulating immune cells.
Methods and results
We demonstrate a significant change in monocyte to T cell ratio in patients with heart failure, compared to healthy subjects, which were validated by flow cytometry analysis. Subclustering of monocytes and stratification of the clusters according to relative CD14 and FCGR3A (CD16) expression allowed annotation of classical, intermediate and non-classical monocytes. Heart failure had a specific impact on the gene expression patterns in these subpopulations. Metabolically active genes such as FABP5 were highly enriched in classical monocytes of heart failure patients, whereas β-catenin expression was significantly higher in intermediate monocytes. The selective regulation of signatures in the monocyte subpopulations was validated by classical and multifactor dimensionality reduction flow cytometry analyses.
Conclusion
Together this study shows that circulating cells derived from patients with heart failure have altered phenotypes. These data provide a rich source for identification of signatures of immune cells in heart failure compared to healthy subjects. The observed increase in FABP5 and signatures of Wnt signaling may contribute to enhanced monocyte activation.
Translational perspective
This study is the first to identify the impact of chronic ischemic heart disease on monocyte signatures at a single cell level. The study demonstrates profound changes in the transcriptome of monocytes which can be recapitulated in multidimensional flow cytometry analysis. The bioinformatic assessment of monocyte signatures provides the basis for future studies assessing the impact of single cell analysis as prognostic tool or for guiding anti-inflammatory therapies associated with cardiovascular disease.

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

Cardiovasc Res: 19 Apr 2020; epub ahead of print
Abplanalp WT, John D, Cremer S, Assmus B, ... Vasa-Nicotera M, Dimmeler S
Cardiovasc Res: 19 Apr 2020; epub ahead of print | PMID: 32311026
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Abstract

Natriuretic peptide analogues with distinct vasodilatory or renal activity: Integrated effects in health and experimental heart failure.

Rademaker MT, Scott NJA, Koh CY, Kini RM, Richards AM
Aims
Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation.We investigate for the first time the integrated hemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF.
Methods and results
We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep.ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in Normal and HF sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to Control only during the high dose in Normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF.
Conclusions
These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.
Translational perspective
In acute decompensated heart failure (ADHF) there is an unmet need for a menu of therapeutic agents allowing controlled vasodilation without excess diuresis at one end of the spectrum and effective diuresis without excess blood pressure lowering at the other. The present study investigates the effects of atrial natriuretic peptide (ANP) analogues engineered for exclusive vasodilatory or diuretic activities in experimental HF, and demonstrated the variants differentially exerted blood pressure and volume-eliminating actions.These peptides offer a unique treatment strategy which could fill the gap in current ADHF therapy by providing personalized care for ADHF patients with ends-of-the-spectrum clinical characteristics.

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 Mar 2020; epub ahead of print
Rademaker MT, Scott NJA, Koh CY, Kini RM, Richards AM
Cardiovasc Res: 12 Mar 2020; epub ahead of print | PMID: 32167565
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Abstract

Abnormalities in Sodium Current and Calcium Homeostasis as Drivers of Arrhythmogenesis in Hypertrophic Cardiomyopathy.

Coppini R, Santini L, Olivotto I, Ackerman MJ, Cerbai E

Hypertrophic cardiomyopathy (HCM) is a common inherited monogenic disease with a prevalence of 1/500 in the general population, representing an important cause of arrhythmic sudden cardiac death (SCD), heart failure, and atrial fibrillation in the young. HCM is a global condition, diagnosed in more than 50 countries and in all continents, HCM affects people of both sexes and various ethnic and racial origins, with similar clinical course and phenotypic expression. The most unpredictable and devastating consequence of HCM is represented by arrhythmic SCD, most commonly caused by sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Indeed, HCM represents one of the main causes of arrhythmic SCD in the young, with a marked preference for children and adults <30 years. SCD is most prevalent in patients with pediatric onset of HCM but may occur at any age. However, risk is substantially lower after 60 years, suggesting that the potential for ventricular tachyarrhythmias is mitigated by ageing. SCD had been linked originally to sports and vigorous activity in HCM patients. However, it is increasingly clear that the majority of events occur at rest or during routine daily occupations, suggesting that triggers are far from consistent. In general, the pathophysiology of SCD in HCM remains unresolved. While the pathologic and physiologic substrates abound and have been described in detail, specific factors precipitating ventricular tachyarrhythmias are still unknown. SCD is a rare phenomenon in HCM cohorts (<1%/year) and attempts to identify patients at risk, while generating clinically useful algorithms for primary prevention, remain very inaccurate on an individual basis. One of the reasons for our limited understanding of these phenomena is that limited translational research exists in the field, while most efforts have focused on clinical markers of risk derived from pathology, instrumental patient evaluation and imaging. Specifically, few studies conducted in animal models and human samples have focused on targeting the cellular mechanisms of arrhythmogenesis in HCM, despite potential implications for therapeutic innovation and SCD prevention. These studies found that altered intracellular Ca2+ homeostasis and increased late Na+ current, leading to an increased likelihood of early and delayed after-depolarizations, contribute to generate arrhythmic events in diseased cardiomyocytes. As an array of novel experimental opportunities have emerged to investigate these mechanisms, including novel \"disease-in-the-dish\" cellular models with patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), important gaps in knowledge remain. Accordingly, the aim of the present review is to provide a contemporary reappraisal of the cellular basis of SCD-predisposing arrhythmias in patients with HCM and discuss the implications for risk stratification and management.

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

Cardiovasc Res: 03 May 2020; epub ahead of print
Coppini R, Santini L, Olivotto I, Ackerman MJ, Cerbai E
Cardiovasc Res: 03 May 2020; epub ahead of print | PMID: 32365196
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Abstract

Arrhythmogenic cardiomyopathy: pathogenesis, pro-arrhythmic remodeling, and novel approaches for risk stratification and therapy.

van der Voorn SM, Te Riele ASJM, Basso C, Calkins H, Remme CA, van Veen TAB

Arrhythmogenic cardiomyopathy (ACM) is a life-threatening cardiac disease caused by mutations in predominantly desmosomal genes that lead to instability and dysfunction of the intercalated disc. ACM is characterized by progressive replacement of cardiomyocytes by fibrofatty tissue, ultimately resulting in ventricular dilatation, cardiac dysfunction and heart failure but mostly dominated by the occurrence of life-threatening arrhythmias and sudden cardiac death (SCD). As SCD appears mostly in apparently healthy young individuals, there is a demand for better risk stratification of suspected ACM mutation carriers. Moreover, disease severity, progression and outcome are highly variable in patients with ACM. In this review we discuss the etiology of ACM with a focus on pro-arrhythmic disease mechanisms in the early concealed phase of the disease. We summarize potential new biomarkers which might be useful for risk stratification and prediction of disease course. Lastly, we explore novel therapeutic strategies to prevent arrhythmias and SCD in the early stages of ACM.

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

Cardiovasc Res: 03 Apr 2020; epub ahead of print
van der Voorn SM, Te Riele ASJM, Basso C, Calkins H, Remme CA, van Veen TAB
Cardiovasc Res: 03 Apr 2020; epub ahead of print | PMID: 32246823
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Abstract

Critical Examination of Mechanisms Underlying the Reduction in Heart Failure Events With SGLT2 Inhibitors: Identification of a Molecular Link Between Their Actions to Stimulate Erythrocytosis and to Alleviate Cellular Stress.

Packer M

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase hematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 (SIRT1) and hypoxia inducible factors (HIF-1α/HIF-2α). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of SIRT1 and HIF-1α/HIF-2α also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and and stimulate autophagy in the heart, and thereby, favorably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation.

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

Cardiovasc Res: 02 Apr 2020; epub ahead of print
Packer M
Cardiovasc Res: 02 Apr 2020; epub ahead of print | PMID: 32243505
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Abstract

Gene Therapy for the Heart Lessons Learned and Future Perspectives.

Cannatà A, Ali H, Sinagra G, Giacca M

While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, the transition from gene addition studies using protein-coding cDNAs to the modulation of gene expression using small RNA therapeutics and the improvement of precise gene editing now pave the way to applications such as cardiac regeneration after myocardial infarction and gene correction for inherited cardiomyopathies that were unapproachable until a decade ago.



Circ Res: 07 May 2020; 126:1394-1414
Cannatà A, Ali H, Sinagra G, Giacca M
Circ Res: 07 May 2020; 126:1394-1414 | PMID: 32379579
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Abstract

Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis.

Fang X, Cai Z, Wang H, Han D, ... Min J, Wang F

Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown.To characterize the functional role of ferritin H (Fth) in mediating cardiac iron homeostasis and heart disease.Mice expressing a conditional Fth knockout allele were crossed with two distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis.Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.



Circ Res: 29 Apr 2020; epub ahead of print
Fang X, Cai Z, Wang H, Han D, ... Min J, Wang F
Circ Res: 29 Apr 2020; epub ahead of print | PMID: 32349646
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Abstract

The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2.

Chen L, Li X, Chen M, Feng Y, Xiong C

A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries. This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition. Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients. Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly. This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2. The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction. And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition. The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.

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 Mar 2020; epub ahead of print
Chen L, Li X, Chen M, Feng Y, Xiong C
Cardiovasc Res: 29 Mar 2020; epub ahead of print | PMID: 32227090
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Abstract

Human induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies.

Ramachandra CJA, Chua J, Cong S, Kp MMJ, ... Wu JC, Hausenloy DJ

Normal cardiac contractile and relaxation function are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human induced pluripotent stem cells (hiPSCs) has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalised therapeutics for improving health outcomes in patients with cardiomyopathy.

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

Cardiovasc Res: 03 May 2020; epub ahead of print
Ramachandra CJA, Chua J, Cong S, Kp MMJ, ... Wu JC, Hausenloy DJ
Cardiovasc Res: 03 May 2020; epub ahead of print | PMID: 32365198
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Abstract

COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.

Guzik TJ, Mohiddin SA, Dimarco A, Patel V, ... Thomson EC, McInnes IB

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.

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 Apr 2020; epub ahead of print
Guzik TJ, Mohiddin SA, Dimarco A, Patel V, ... Thomson EC, McInnes IB
Cardiovasc Res: 29 Apr 2020; epub ahead of print | PMID: 32352535
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