Journal: Eur Heart J

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Abstract

Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome.

Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Aims 
Necrotizing coronary vasculitis (NCV) is a rare entity usually associated to myocarditis which incidence, cause, and response to therapy is unreported.
Methods and results 
Among 1916 patients with biopsy-proven myocarditis, 30 had NCV. Endomyocardial samples were retrospectively investigated with immunohistochemistry for toll-like receptor 4 (TLR4) and real-time polymerase chain reaction (PCR) for viral genomes. Serum samples were processed for anti-heart autoantibodies (Abs), IL-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α. Identification of an immunologic pathway (including virus-negativity, TLR4-, and Ab-positivity) was followed by immunosuppression. Myocarditis-NCV cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance and compared with 60 Myocarditis patients and 30 controls. Increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Control endomyocardial biopsy followed the end of treatment. Twenty-six Myocarditis-NCV patients presented with heart failure; four with electrical instability. Cause of Myocarditis-NCV included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). Abs were positive in immune-mediated Myocarditis-NCV and virus-negative Myocarditis; Myocarditis-NCV patients with Ab+ presented autoreactivity in vessel walls. Toll-like receptor 4 was overexpressed in immune-mediated forms and poorly detectable in viral. Interleukin-1β was significantly higher in Myocarditis-NCV than Myocarditis, the former presenting 24% in-hospital mortality compared with 1.5% of Myocarditis cohort. Immunosuppression induced improvement of cardiac function in 88% of Myocarditis-NCV and 86% of virus-negative Myocarditis patients.
Conclusion 
Necrotizing coronary vasculitis is histologically detectable in 1.5% of Myocarditis. Necrotizing coronary vasculitis includes viral and immune-mediated causes. Intra-hospital mortality is 24%. The immunologic pathway is associated with beneficial response to immunosuppression.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 20 Apr 2021; 42:1609-1617
Frustaci A, Alfarano M, Verardo R, Agrati C, ... Letizia C, Chimenti C
Eur Heart J: 20 Apr 2021; 42:1609-1617 | PMID: 33355356
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Abstract

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

Frey A, Homola GA, Henneges C, Mühlbauer L, ... Störk S, Stoll G
Aims
We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years.
Methods and results
A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I-II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: -62 mm3 [95% confidence interval (CI) -81 to -42, P < 0.0001). This corresponded to a relative change of -1.8% (95% CI -2.3 to -1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with \'intensity of attention\' as the only domain declining (LSmean -1.82 points, 95% CI -3.05 to -0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29).
Conclusion
In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 20 Apr 2021; 42:1569-1578
Frey A, Homola GA, Henneges C, Mühlbauer L, ... Störk S, Stoll G
Eur Heart J: 20 Apr 2021; 42:1569-1578 | PMID: 33496311
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Abstract

A phenomapping-derived tool to personalize the selection of anatomical vs. functional testing in evaluating chest pain (ASSIST).

Oikonomou EK, Van Dijk D, Parise H, Suchard MA, ... Miller EJ, Khera R
Aims
Coronary artery disease is frequently diagnosed following evaluation of stable chest pain with anatomical or functional testing. A more granular understanding of patient phenotypes that benefit from either strategy may enable personalized testing.
Methods and results
Using participant-level data from 9572 patients undergoing anatomical (n = 4734) vs. functional (n = 4838) testing in the PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial, we created a topological representation of the study population based on 57 pre-randomization variables. Within each patient\'s 5% topological neighbourhood, Cox regression models provided individual patient-centred hazard ratios for major adverse cardiovascular events and revealed marked heterogeneity across the phenomap [median 1.11 (10th to 90th percentile: 0.52-2.61]), suggestive of distinct phenotypic neighbourhoods favouring anatomical or functional testing. Based on this risk phenomap, we employed an extreme gradient boosting algorithm in 80% of the PROMISE population to predict the personalized benefit of anatomical vs. functional testing using 12 model-derived, routinely collected variables and created a decision support tool named ASSIST (Anatomical vs. Stress teSting decIsion Support Tool). In both the remaining 20% of PROMISE and an external validation set consisting of patients from SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) undergoing anatomical-first vs. functional-first assessment, the testing strategy recommended by ASSIST was associated with a significantly lower incidence of each study\'s primary endpoint (P = 0.0024 and P = 0.0321 for interaction, respectively), as well as a harmonized endpoint of all-cause mortality or non-fatal myocardial infarction (P = 0.0309 and P < 0.0001 for interaction, respectively).
Conclusion
We propose a novel phenomapping-derived decision support tool to standardize the selection of anatomical vs. functional testing in the evaluation of stable chest pain, validated in two large and geographically diverse clinical trial populations.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 20 Apr 2021; epub ahead of print
Oikonomou EK, Van Dijk D, Parise H, Suchard MA, ... Miller EJ, Khera R
Eur Heart J: 20 Apr 2021; epub ahead of print | PMID: 33881513
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Abstract

Sleep arousal burden is associated with long-term all-cause and cardiovascular mortality in 8001 community-dwelling older men and women.

Shahrbabaki SS, Linz D, Hartmann S, Redline S, Baumert M
Aims 
To quantify the arousal burden (AB) across large cohort studies and determine its association with long-term cardiovascular (CV) and overall mortality in men and women.
Methods and results 
We measured the AB on overnight polysomnograms of 2782 men in the Osteoporotic Fractures in Men Study (MrOS) Sleep study, 424 women in the Study of Osteoporotic Fractures (SOF) and 2221 men and 2574 women in the Sleep Heart Health Study (SHHS). During 11.2 ± 2.1 years of follow-up in MrOS, 665 men died, including 236 CV deaths. During 6.4 ± 1.6 years of follow-up in SOF, 105 women died, including 47 CV deaths. During 10.7 ± 3.1 years of follow-up in SHHS, 987 participants died, including 344 CV deaths. In women, multivariable Cox proportional hazard analysis adjusted for common confounders demonstrated that AB is associated with all-cause mortality [SOF: hazard ratio (HR) 1.58 (1.01-2.42), P = 0.038; SHHS-women: HR 1.21 (1.06-1.42), P = 0.012] and CV mortality [SOF: HR 2.17 (1.04-4.50), P = 0.037; SHHS-women: HR 1.60 (1.12-2.28), P = 0.009]. In men, the association between AB and all-cause mortality [MrOS: HR 1.11 (0.94-1.32), P = 0.261; SHHS-men: HR 1.31 (1.06-1.62), P = 0.011] and CV mortality [MrOS: HR 1.35 (1.02-1.79), P = 0.034; SHHS-men: HR 1.24 (0.86-1.79), P = 0.271] was less clear.
Conclusions
Nocturnal AB is associated with long-term CV and all-cause mortality in women and to a lesser extent in men.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 19 Apr 2021; epub ahead of print
Shahrbabaki SS, Linz D, Hartmann S, Redline S, Baumert M
Eur Heart J: 19 Apr 2021; epub ahead of print | PMID: 33876221
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Abstract

Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research.

VARC-3 WRITING COMMITTEE, Généreux P, Piazza N, Alu MC, ... Cohen DJ, Leon MB
Aims
The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.
Methods and results
Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.
Conclusions
Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 18 Apr 2021; epub ahead of print
VARC-3 WRITING COMMITTEE, Généreux P, Piazza N, Alu MC, ... Cohen DJ, Leon MB
Eur Heart J: 18 Apr 2021; epub ahead of print | PMID: 33871579
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Abstract

A call to action for new global approaches to cardiovascular disease drug solutions.

Figtree GA, Broadfoot K, Casadei B, Califf R, ... Xiao J, Zannad F
Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic \'buckets\'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased \'omic\' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

This article has been co-published with permission in the European Heart Journal and Circulation. All rights reserved. © the Author(s) 2021. The articles are identical except for minor stylistic and spelling differences in keeping with each journal\'s style. Either citation can be used when citing this article.

Eur Heart J: 12 Apr 2021; epub ahead of print
Figtree GA, Broadfoot K, Casadei B, Califf R, ... Xiao J, Zannad F
Eur Heart J: 12 Apr 2021; epub ahead of print | PMID: 33847746
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Abstract

The physical activity paradox in cardiovascular disease and all-cause mortality: the contemporary Copenhagen General Population Study with 104 046 adults.

Holtermann A, Schnohr P, Nordestgaard BG, Marott JL
Aims 
Leisure time physical activity associates with reduced risk of cardiovascular disease and all-cause mortality, while these relationships for occupational physical activity are unclear. We tested the hypothesis that leisure time physical activity associates with reduced major adverse cardiovascular events (MACE) and all-cause mortality risk, while occupational physical activity associates with increased risks.
Methods and results 
We studied 104 046 women and men aged 20-100 years in the Copenhagen General Population Study with baseline measurements in 2003-2014 and median 10-year follow-up. Both leisure and occupational physical activity were based on self-report with four response categories. We observed 7913 (7.6%) MACE and 9846 (9.5%) deaths from all causes. Compared to low leisure time physical activity, multivariable adjusted (for lifestyle, health, living conditions, and socioeconomic factors) hazard ratios for MACE were 0.86 (0.78-0.96) for moderate, 0.77 (0.69-0.86) for high, and 0.85 (0.73-0.98) for very high activity; corresponding values for higher occupational physical activity were 1.04 (0.95-1.14), 1.15 (1.04-1.28), and 1.35 (1.14-1.59), respectively. For all-cause mortality, corresponding hazard ratios for higher leisure time physical activity were 0.74 (0.68-0.81), 0.59 (0.54-0.64), and 0.60 (0.52-0.69), and for higher occupational physical activity 1.06 (0.96-1.16), 1.13 (1.01-1.27), and 1.27 (1.05-1.54), respectively. Similar results were found within strata on lifestyle, health, living conditions, and socioeconomic factors, and when excluding individuals dying within the first 5 years of follow-up. Levels of the two domains of physical activity did not interact on risk of MACE (P = 0.40) or all-cause mortality (P = 0.31).
Conclusion 
Higher leisure time physical activity associates with reduced MACE and all-cause mortality risk, while higher occupational physical activity associates with increased risks, independent of each other.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 07 Apr 2021; epub ahead of print
Holtermann A, Schnohr P, Nordestgaard BG, Marott JL
Eur Heart J: 07 Apr 2021; epub ahead of print | PMID: 33831954
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Abstract

A proteomic atlas of the neointima identifies novel druggable targets for preventive therapy.

Wierer M, Werner J, Wobst J, Kastrati A, ... Schunkert H, Kessler T
Aims 
In-stent restenosis is a complication after coronary stenting associated with morbidity and mortality. Here, we sought to investigate the molecular processes underlying neointima formation and to identify new treatment and prevention targets.
Methods and results 
Neointima formation was induced by wire injury in mouse femoral arteries. High-accuracy proteomic measurement of single femoral arteries to a depth of about 5000 proteins revealed massive proteome remodelling, with more than half of all proteins exhibiting expression differences between injured and non-injured vessels. We observed major changes in the composition of the extracellular matrix and cell migration processes. Among the latter, we identified the classical transient receptor potential channel 6 (TRPC6) to drive neointima formation. While Trpc6-/- mice presented reduced neointima formation compared to wild-type mice (1.44 ± 0.39 vs. 2.16 ± 0.48, P = 0.01), activating or repressing TRPC6 in human vascular smooth muscle cells resulted in increased [vehicle 156.9 ± 15.8 vs. 1-oleoyl-2-acetyl-sn-glycerol 179.1 ± 8.07 (103 pixels), P = 0.01] or decreased migratory capacity [vehicle 130.0 ± 26.1 vs. SAR7334 111.4 ± 38.0 (103 pixels), P = 0.04], respectively. In a cohort of individuals with angiographic follow-up (n = 3068, males: 69.9%, age: 59 ± 11 years, follow-up 217.1 ± 156.4 days), homozygous carriers of a common genetic variant associated with elevated TRPC6 expression were at increased risk of restenosis after coronary stenting (adjusted odds ratio 1.49, 95% confidence interval 1.08-2.05; P = 0.01).
Conclusions 
Our study provides a proteomic atlas of the healthy and injured arterial wall that can be used to define novel factors for therapeutic targeting. We present TRPC6 as an actionable target to prevent neointima formation secondary to vascular injury and stent implantation.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 07 Apr 2021; epub ahead of print
Wierer M, Werner J, Wobst J, Kastrati A, ... Schunkert H, Kessler T
Eur Heart J: 07 Apr 2021; epub ahead of print | PMID: 33829256
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Abstract

The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction.

Li L, Fu W, Gong X, Chen Z, ... Wang WE, Zeng C
Aims
G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI.
Methods and results
We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers.
Conclusion
GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

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: 06 Apr 2021; 42:1415-1430
Li L, Fu W, Gong X, Chen Z, ... Wang WE, Zeng C
Eur Heart J: 06 Apr 2021; 42:1415-1430 | PMID: 33280021
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Abstract

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

© European Society of Cardiology 2021 This article has been co-published with permission in European Heart Journal (published by Oxford University Press on behalf of European Society of Cardiology) and European Journal of Heart Failure (published by John Wiley & Sons Ltd on behalf of European Society of Cardiology) These articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

Eur Heart J: 06 Apr 2021; epub ahead of print
Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Eur Heart J: 06 Apr 2021; epub ahead of print | PMID: 33825853
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Abstract

Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease.

Ten Berg J, Sibbing D, Rocca B, Van Belle E, ... Witkowski A, Mehilli J
Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 04 Apr 2021; epub ahead of print
Ten Berg J, Sibbing D, Rocca B, Van Belle E, ... Witkowski A, Mehilli J
Eur Heart J: 04 Apr 2021; epub ahead of print | PMID: 33822924
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Abstract

Immediate post-procedural functional assessment of percutaneous coronary intervention: current evidence and future directions.

Ding D, Huang J, Westra J, Cohen DJ, ... Tu S, Wijns W
Percutaneous coronary intervention (PCI) guided by coronary physiology provides symptomatic benefit and improves patient outcomes. Nevertheless, over one-fourth of patients still experience recurrent angina or major adverse cardiac events following the index procedure. Coronary angiography, the current workhorse for evaluating PCI efficacy, has limited ability to identify suboptimal PCI results. Accumulating evidence supports the usefulness of immediate post-procedural functional assessment. This review discusses the incidence and possible mechanisms behind a suboptimal physiology immediately after PCI. Furthermore, we summarize the current evidence base supporting the usefulness of immediate post-PCI functional assessment for evaluating PCI effectiveness, guiding PCI optimization, and predicting clinical outcomes. Multiple observational studies and post hoc analyses of datasets from randomized trials demonstrated that higher post-PCI functional results are associated with better clinical outcomes as well as a reduced rate of residual angina and repeat revascularization. As such, post-PCI functional assessment is anticipated to impact patient management, secondary prevention, and resource utilization. Pre-PCI physiological guidance has been shown to improve clinical outcomes and reduce health care costs. Whether similar benefits can be achieved using post-PCI physiological assessment requires evaluation in randomized clinical outcome trials.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 04 Apr 2021; epub ahead of print
Ding D, Huang J, Westra J, Cohen DJ, ... Tu S, Wijns W
Eur Heart J: 04 Apr 2021; epub ahead of print | PMID: 33822922
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Abstract

Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank.

Ai S, Zhang J, Zhao G, Wang N, ... Lu L, Wing YK
Aims
Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs.
Methods and results
Genetic variants associated with continuous, short (≤6 h) and long (≥9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P < 0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P < 0.001), and suggestive evidence for atrial fibrillation (P < 0.05). However, genetically predicted long sleep duration was not associated with any CVD.
Conclusion
This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long sleep duration is unlikely to be a causal risk factor for most CVDs.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 04 Apr 2021; epub ahead of print
Ai S, Zhang J, Zhao G, Wang N, ... Lu L, Wing YK
Eur Heart J: 04 Apr 2021; epub ahead of print | PMID: 33822910
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Abstract

Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.

Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Aims
In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction.
Methods and results
Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains.
Conclusion
Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 30 Mar 2021; 42:1203-1212
Butler J, Anker SD, Filippatos G, Khan MS, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Eur Heart J: 30 Mar 2021; 42:1203-1212 | PMID: 33420498
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Abstract

The cardiovascular-dialysis nexus: the transition to dialysis is a treacherous time for the heart.

Chan K, Moe SM, Saran R, Libby P
Chronic kidney disease (CKD) patients require dialysis to manage the progressive complications of uraemia. Yet, many physicians and patients do not recognize that dialysis initiation, although often necessary, subjects patients to substantial risk for cardiovascular (CV) death. While most recognize CV mortality risk approximately doubles with CKD the new data presented here show that this risk spikes to >20 times higher than the US population average at the initiation of chronic renal replacement therapy, and this elevated CV risk continues through the first 4 months of dialysis. Moreover, this peak reflects how dialysis itself changes the pathophysiology of CV disease and transforms its presentation, progression, and prognosis. This article reviews how dialysis initiation modifies the interpretation of circulating biomarkers, alters the accuracy of CV imaging, and worsens prognosis. We advocate a multidisciplinary approach and outline the issues practitioners should consider to optimize CV care for this unique and vulnerable population during a perilous passage.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 30 Mar 2021; 42:1244-1253
Chan K, Moe SM, Saran R, Libby P
Eur Heart J: 30 Mar 2021; 42:1244-1253 | PMID: 33458768
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Impact:
Abstract

Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial.

Heerspink HJL, Sjöström CD, Jongs N, Chertow GM, ... Wheeler DC, DAPA-CKD Trial Committees and Investigators
Aims 
Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death.
Methods and results 
DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.
Conclusion 
In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 30 Mar 2021; 42:1216-1227
Heerspink HJL, Sjöström CD, Jongs N, Chertow GM, ... Wheeler DC, DAPA-CKD Trial Committees and Investigators
Eur Heart J: 30 Mar 2021; 42:1216-1227 | PMID: 33792669
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Impact:
Abstract

Association of the combined effects of air pollution and changes in physical activity with cardiovascular disease in young adults.

Kim SR, Choi S, Kim K, Chang J, ... Kim KH, Park SM
Aims
Little is known about the trade-off between the health benefits of physical activity (PA) and the potential harmful effects of increased exposure to air pollution during outdoor PA. We examined the association of the combined effects of air pollution and changes in PA with cardiovascular disease (CVD) in young adults.
Methods and results
This nationwide cohort study included 1 469 972 young adults aged 20-39 years. Air pollution exposure was estimated by the annual average cumulative level of particulate matter (PM). PA was calculated as minutes of metabolic equivalent tasks per week (MET-min/week) based on two consecutive health examinations from 2009 to 2012. Compared with the participants exposed to low-to-moderate levels of PM2.5 or PM10 who continuously engaged in ≥1000 MET-min/week of PA, those who decreased their PA from ≥1000 MET-min/week to 1-499 MET-min/week [PM10 adjusted hazard ratio (aHR) 1.22; 95% confidence interval (CI) 1.00-1.48] and to 0 MET-min/week (physically inactive; PM10 aHR 1.38; 95% CI 1.07-1.78) had an increased risk of CVD (P for trend <0.01). Among participants exposed to high levels of PM2.5 or PM10, the risk of CVD was elevated with an increase in PA above 1000 MET-min/week.
Conclusion
Reducing PA may lead to subsequent elevation of CVD risk in young adults exposed to low-to-moderate levels of PM2.5 or PM10, whereas a large increase in PA in a high-pollution environment may adversely affect cardiovascular health.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 28 Mar 2021; epub ahead of print
Kim SR, Choi S, Kim K, Chang J, ... Kim KH, Park SM
Eur Heart J: 28 Mar 2021; epub ahead of print | PMID: 33780974
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Impact:
Abstract

Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials.

Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Aims
Recent randomized trials demonstrated a benefit of low-dose colchicine added to guideline-based treatment in patients with recent myocardial infarction or chronic coronary disease. We performed a systematic review and meta-analysis to obtain best estimates of the effects of colchicine on major adverse cardiovascular events (MACE).
Methods and results
We searched the literature for randomized clinical trials of long-term colchicine in patients with atherosclerosis published up to 1 September 2020. The primary efficacy endpoint was MACE, the composite of myocardial infarction, stroke, or cardiovascular death. We combined the results of five trials that included 11 816 patients. The primary endpoint occurred in 578 patients. Colchicine reduced the risk for the primary endpoint by 25% [relative risk (RR) 0.75, 95% confidence interval (CI) 0.61-0.92; P = 0.005], myocardial infarction by 22% (RR 0.78, 95% CI 0.64-0.94; P = 0.010), stroke by 46% (RR 0.54, 95% CI 0.34-0.86; P = 0.009), and coronary revascularization by 23% (RR 0.77, 95% CI 0.66-0.90; P < 0.001). We observed no difference in all-cause death (RR 1.08, 95% CI 0.71-1.62; P = 0.73), with a lower incidence of cardiovascular death (RR 0.82, 95% CI 0.55-1.23; P = 0.34) counterbalanced by a higher incidence of non-cardiovascular death (RR 1.38, 95% CI 0.99-1.92; P = 0.060).
Conclusion
Our meta-analysis indicates that low-dose colchicine reduced the risk of MACE as well as that of myocardial infarction, stroke, and the need for coronary revascularization in a broad spectrum of patients with coronary disease. There was no difference in all-cause mortality and fewer cardiovascular deaths were counterbalanced by more non-cardiovascular deaths.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, ... Tijssen JGP, Cornel JH
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769515
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Impact:
Abstract

Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

Grilz E, Posch F, Nopp S, Königsbrügge O, ... Pabinger I, Ay C
Aims
An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed.
Methods and results
International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 \'C\' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]).
Conclusion
The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Grilz E, Posch F, Nopp S, Königsbrügge O, ... Pabinger I, Ay C
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769475
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Impact:
Abstract

Validation of risk scores for ischaemic stroke in atrial fibrillation across the spectrum of kidney function.

de Jong Y, Fu EL, van Diepen M, Trevisan M, ... Carrero JJ, Ocak G
Aims 
The increasing prevalence of ischaemic stroke (IS) can partly be explained by the likewise growing number of patients with chronic kidney disease (CKD). Risk scores have been developed to identify high-risk patients, allowing for personalized anticoagulation therapy. However, predictive performance in CKD is unclear. The aim of this study is to validate six commonly used risk scores for IS in atrial fibrillation (AF) patients across the spectrum of kidney function.
Methods and results 
Overall, 36 004 subjects with newly diagnosed AF from SCREAM (Stockholm CREAtinine Measurements), a healthcare utilization cohort of Stockholm residents, were included. Predictive performance of the AFI, CHADS2, Modified CHADS2, CHA2DS2-VASc, ATRIA, and GARFIELD-AF risk scores was evaluated across three strata of kidney function: normal kidney function [estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2], mild CKD (eGFR 30-60 mL/min/1.73 m2), and advanced CKD (eGFR <30 mL/min/1.73 m2). Predictive performance was assessed by discrimination and calibration. During 1.9 years, 3069 (8.5%) patients suffered an IS. Discrimination was dependent on eGFR: the median c-statistic in normal eGFR was 0.75 (range 0.68-0.78), but decreased to 0.68 (0.58-0.73) and 0.68 (0.55-0.74) for mild and advanced CKD, respectively. Calibration was reasonable and largely independent of eGFR. The Modified CHADS2 score showed good performance across kidney function strata, both for discrimination [c-statistic: 0.78 (95% confidence interval 0.77-0.79), 0.73 (0.71-0.74) and 0.74 (0.69-0.79), respectively] and calibration.
Conclusion 
In the most clinically relevant stages of CKD, predictive performance of the majority of risk scores was poor, increasing the risk of misclassification and thus of over- or undertreatment. The Modified CHADS2 score performed good and consistently across all kidney function strata, and should therefore be preferred for risk estimation in AF patients.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 25 Mar 2021; epub ahead of print
de Jong Y, Fu EL, van Diepen M, Trevisan M, ... Carrero JJ, Ocak G
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769473
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Impact:
Abstract

Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy.

Marston NA, Han L, Olivotto I, Day SM, ... Helms AS, Ho CY
Aims
Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM.
Methods and results
We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [<1 year (infancy), 1-18 years (childhood), >18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36-4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16-2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03-1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23-3.23)].
Conclusion
Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Marston NA, Han L, Olivotto I, Day SM, ... Helms AS, Ho CY
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33769460
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Impact:
Abstract

Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome.

Radfar A, Abohashem S, Osborne MT, Wang Y, ... Wood MJ, Tawakol A
Aims
Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest.
Methods and results
Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028).
Conclusion
Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 25 Mar 2021; epub ahead of print
Radfar A, Abohashem S, Osborne MT, Wang Y, ... Wood MJ, Tawakol A
Eur Heart J: 25 Mar 2021; epub ahead of print | PMID: 33768230
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Impact:
Abstract

Antithrombotic therapy in diabetes: which, when, and for how long?

Ajjan RA, Kietsiriroje N, Badimon L, Vilahur G, ... Rocca B, Storey RF
Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 24 Mar 2021; epub ahead of print
Ajjan RA, Kietsiriroje N, Badimon L, Vilahur G, ... Rocca B, Storey RF
Eur Heart J: 24 Mar 2021; epub ahead of print | PMID: 33764414
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Impact:
Abstract

Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.

Oyama K, Giugliano RP, Berg DD, Ruff CT, ... Braunwald E, Morrow DA
Aims
We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding.
Methods and results
ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36-2.23 and adj-HR 1.27; 95% CI 1.07-1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02-1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36-0.65; NRI 0.42; 95% CI 0.33-0.51, respectively].
Conclusion
Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 23 Mar 2021; epub ahead of print
Oyama K, Giugliano RP, Berg DD, Ruff CT, ... Braunwald E, Morrow DA
Eur Heart J: 23 Mar 2021; epub ahead of print | PMID: 33760027
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Impact:
Abstract

The heart of the ageing endurance athlete: the role of chronic coronary stress.

Parry-Williams G, Gati S, Sharma S
Moderate physical exercise is associated with an irrefutable reduction in cardiac morbidity and mortality. The current guidelines recommend at least 150 min of moderate exercise or 75 min of vigorous exercise per week. Endurance athletes perform exercise at a level that is 10- to 20-fold greater than these recommendations. These athletes reveal several structural and functional cardiac adaptations including increased cardiac size, enhanced ventricular filling, and augmentation of stroke volume even at the highest heart rates. The long-term effects of endurance exercise on the heart are unknown. Endurance exercise is associated with a transient increase in serum concentrations of biomarkers of cardiac damage and ventricular dysfunction which improves within 72 h. Over the past decade, there have been emerging studies reporting attenuated mortality benefit amongst individuals who perform the highest volume of exercise. Studies in lifelong male athletes aged above 40 years old show a higher prevalence of high coronary artery calcium scores (>300 Agatston units), a higher coronary plaque burden, and myocardial fibrosis compatible with subclinical myocardial infarction compared with relatively sedentary healthy controls, raising speculation that lifelong intense exercise imposes chronic coronary stress on the heart. This review article will provide a critical analysis of the existing data.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 21 Mar 2021; epub ahead of print
Parry-Williams G, Gati S, Sharma S
Eur Heart J: 21 Mar 2021; epub ahead of print | PMID: 33748860
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Impact:
Abstract

Electrocardiogram screening for aortic valve stenosis using artificial intelligence.

Cohen-Shelly M, Attia ZI, Friedman PA, Ito S, ... Lopez-Jimenez F, Oh JK
Aims
Early detection of aortic stenosis (AS) is becoming increasingly important with a better outcome after aortic valve replacement in asymptomatic severe AS patients and a poor outcome in moderate AS. We aimed to develop artificial intelligence-enabled electrocardiogram (AI-ECG) using a convolutional neural network to identify patients with moderate to severe AS.
Methods and results
Between 1989 and 2019, 258 607 adults [mean age 63 ± 16.3 years; women 122 790 (48%)] with an echocardiography and an ECG performed within 180 days were identified from the Mayo Clinic database. Moderate to severe AS by echocardiography was present in 9723 (3.7%) patients. Artificial intelligence training was performed in 129 788 (50%), validation in 25 893 (10%), and testing in 102 926 (40%) randomly selected subjects. In the test group, the AI-ECG labelled 3833 (3.7%) patients as positive with the area under the curve (AUC) of 0.85. The sensitivity, specificity, and accuracy were 78%, 74%, and 74%, respectively. The sensitivity increased and the specificity decreased as age increased. Women had lower sensitivity but higher specificity compared with men at any age groups. The model performance increased when age and sex were added to the model (AUC 0.87), which further increased to 0.90 in patients without hypertension. Patients with false-positive AI-ECGs had twice the risk for developing moderate or severe AS in 15 years compared with true negative AI-ECGs (hazard ratio 2.18, 95% confidence interval 1.90-2.50).
Conclusion
An AI-ECG can identify patients with moderate or severe AS and may serve as a powerful screening tool for AS in the community.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 21 Mar 2021; epub ahead of print
Cohen-Shelly M, Attia ZI, Friedman PA, Ito S, ... Lopez-Jimenez F, Oh JK
Eur Heart J: 21 Mar 2021; epub ahead of print | PMID: 33748852
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Impact:
Abstract

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data.

Porcher R, Desguerre I, Amthor H, Chabrol B, ... Duboc D, Wahbi K
Aims
To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD).
Methods and results
We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results.
Conclusion
Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 21 Mar 2021; epub ahead of print
Porcher R, Desguerre I, Amthor H, Chabrol B, ... Duboc D, Wahbi K
Eur Heart J: 21 Mar 2021; epub ahead of print | PMID: 33748842
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Impact:
Abstract

Influenza vaccination: a \'shot\' at INVESTing in cardiovascular health.

Bhatt AS, Vardeny O, Udell JA, Joseph J, Kim K, Solomon SD
The link between viral respiratory infection and non-pulmonary organ-specific injury, including cardiac injury, has become increasingly appreciated during the current coronavirus disease 2019 (COVID-19) pandemic. Even prior to the pandemic, however, the association between acute infection with influenza and elevated cardiovascular risk was evident. The recently published results of the NHLBI-funded INfluenza Vaccine to Effectively Stop CardioThoracic Events and Decompensated (INVESTED) trial, a 5200 patient comparative effectiveness study of high-dose vs. standard-dose influenza vaccine to reduce cardiopulmonary events and mortality in a high-risk cardiovascular population, found no difference between strategies. However, the broader implications of influenza vaccine as a strategy to reduce morbidity in high-risk patients remain extremely important, with randomized controlled trial and observational data supporting vaccination in high-risk patients with cardiovascular disease. Given a favourable risk-benefit profile and widespread availability at generally low cost, we contend that influenza vaccination should remain a centrepiece of cardiovascular risk mitigation and describe the broader context of underutilization of this strategy. Few therapeutics in medicine offer seasonal efficacy from a single administration with generally mild, transient side effects, and exceedingly low rates of serious adverse effects. Infection control measures such as physical distancing, hand washing, and the use of masks during the COVID-19 pandemic have already been associated with substantially curtailed incidence of influenza outbreaks across the globe. Appending annual influenza vaccination to these measures represents an important public health and moral imperative.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 21 Mar 2021; epub ahead of print
Bhatt AS, Vardeny O, Udell JA, Joseph J, Kim K, Solomon SD
Eur Heart J: 21 Mar 2021; epub ahead of print | PMID: 33748833
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Impact:
Abstract

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Schunk SJ, Kleber ME, März W, Pang S, ... Speer T, eQTLGen consortium‡; BIOS consortium‡
Aims
Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.
Methods and results
We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.
Conclusion
The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 21 Mar 2021; epub ahead of print
Schunk SJ, Kleber ME, März W, Pang S, ... Speer T, eQTLGen consortium‡; BIOS consortium‡
Eur Heart J: 21 Mar 2021; epub ahead of print | PMID: 33748830
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Abstract

Vegetarians, fish, poultry, and meat-eaters: who has higher risk of cardiovascular disease incidence and mortality? A prospective study from UK Biobank.

Petermann-Rocha F, Parra-Soto S, Gray S, Anderson J, ... Celis-Morales C, Pell JP
Aims 
To compare the incidence and mortality risk for cardiovascular diseases (CVD) [CVD and also ischaemic heart disease (IHD), myocardial infarction (MI), stroke, and heart failure (HF)] among people with different types of diets-including vegetarians, fish eaters, fish and poultry eaters, and meat-eaters-using data from UK Biobank.
Methods and results 
A total of 422 791 participants (55.4% women) were included in this prospective analysis. Using data from a food frequency questionnaire, four types of diets were derived. Associations between types of diets and health outcomes were investigated using Cox proportional hazard models. Meat-eaters comprised 94.7% of the cohort and were more likely to be obese than other diet groups. After a median follow-up of 8.5 years, fish eaters, compared with meat-eaters, had lower risks of incident CVD {hazard ratios (HR): 0.93 [95% confidence intervals (CI): 0.88-0.97]}, IHD [HR: 0.79 (95% CI: 0.70-0.88)], MI [HR: 0.70 (95% CI: 0.56-0.88)], stroke [HR: 0.79 (95% CI: 0.63-0.98)] and HF [HR: 0.78 (95% CI: 0.63-0.97)], after adjusting for confounders. Vegetarians had lower risk of CVD incidence [HR: 0.91 (95% CI: 0.86-0.96)] relative to meat-eaters. In contrast, the risk of adverse outcomes was not different in fish and poultry eaters compared with meat-eaters. No associations were identified between types of diets and CVD mortality.
Conclusion 
Eating fish rather than meat or poultry was associated with a lower risk of a range of adverse cardiovascular outcomes. Vegetarianism was only associated with a lower risk of CVD incidence.

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: 20 Mar 2021; 42:1136-1143
Petermann-Rocha F, Parra-Soto S, Gray S, Anderson J, ... Celis-Morales C, Pell JP
Eur Heart J: 20 Mar 2021; 42:1136-1143 | PMID: 33313747
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Abstract

High-sugar feeding and increasing cholesterol levels in infants.

Zubin Maslov P, Hill JA, Lüscher TF, Narula J
Hypercholesterolaemia is an important risk factor for cardiovascular disease. Both total and LDL cholesterol levels are three-fold higher at the end of the first year of life and about four-fold higher in adulthood compared with the neonatal period. In the USA, only 25% of infants are exclusively breastfed and simple carbohydrate-rich formulas are preferentially consumed. Spikes in fasting glucose and insulin have been reported in formula-fed infants and are associated with higher levels of proprotein convertase subtilisin/kexin type 9, suggesting a potential link between high simple sugar intake and consequent increase in LDL cholesterol in early childhood.

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: 20 Mar 2021; 42:1132-1135
Zubin Maslov P, Hill JA, Lüscher TF, Narula J
Eur Heart J: 20 Mar 2021; 42:1132-1135 | PMID: 33326580
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Abstract

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.

Wang Q, Oliver-Williams C, Raitakari OT, Viikari J, ... Holmes MV, Ala-Korpela M
Aims 
Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.
Methods and results 
Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.
Conclusions 
Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.

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

Eur Heart J: 20 Mar 2021; 42:1160-1169
Wang Q, Oliver-Williams C, Raitakari OT, Viikari J, ... Holmes MV, Ala-Korpela M
Eur Heart J: 20 Mar 2021; 42:1160-1169 | PMID: 33351885
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Abstract

Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes.

Csengeri D, Sprünker NA, Di Castelnuovo A, Niiranen T, ... Iacoviello L, Schnabel RB
Aims 
There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.
Methods and results 
In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.
Conclusions 
In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 20 Mar 2021; 42:1170-1177
Csengeri D, Sprünker NA, Di Castelnuovo A, Niiranen T, ... Iacoviello L, Schnabel RB
Eur Heart J: 20 Mar 2021; 42:1170-1177 | PMID: 33438022
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Abstract

Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study.

Langsted A, Nordestgaard BG, Kamstrup PR
Aims
With the current focus on lipoprotein(a) as a likely causal risk factor for cardiovascular disease and new drugs potentially on the market to lower lipoprotein(a) levels, the safety of lowering lipoprotein(a) to low levels becomes increasingly important. We tested whether low levels of lipoprotein(a) and corresponding LPA genotypes associate with major disease groups including cancers and infectious disease.
Methods and results
We included 109 440 individuals from the Copenhagen General Population Study. For main World Health Organization International Classification of Diseases 10th edition chapter diseases, the only concordant association of low levels of lipoprotein(a) plasma levels and corresponding LPA genotypes with risk of disease was with low risk of diseases of the circulatory system. Furthermore, no concordant association of low levels of lipoprotein(a) plasma levels and corresponding LPA genotypes with the risk of any cancer (i.e. cancer subtypes combined) or infectious disease was seen. The hazard ratio for the risk of any cancer was 1.06 [95% confidence interval (CI): 0.97-1.15] for the first vs. the fourth quartile of lipoprotein(a), 1.02 (0.97-1.07) for the fourth vs. the first quartile of KIV-2 number of repeats, and 1.01 (0.96-1.07) for rs10455872 non-carriers vs. carriers. The corresponding hazard ratios for the risk of hospitalization for infection were 1.05 (95% CI: 0.99-1.10), 1.02 (0.98-1.07), and 0.97 (0.93-1.03), respectively.
Conclusion
In a large, contemporary, general population cohort, apart from the well-established association with cardiovascular disease, low levels of lipoprotein(a) and corresponding LPA genotypes did not concordantly associate with any major disease groups including cancers and infections. There is no safety signal from our results to indicate that low levels of lipoprotein(a) are harmful.

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Eur Heart J: 20 Mar 2021; 42:1147-1156
Langsted A, Nordestgaard BG, Kamstrup PR
Eur Heart J: 20 Mar 2021; 42:1147-1156 | PMID: 33724357
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Abstract

The management of secondary mitral regurgitation in patients with heart failure: a joint position statement from the Heart Failure Association (HFA), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), and European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Coats AJS, Anker SD, Baumbach A, Alfieri O, ... Seferovic PM, Prendergast B
Secondary (or functional) mitral regurgitation (SMR) occurs frequently in chronic heart failure (HF) with reduced left ventricular (LV) ejection fraction, resulting from LV remodelling that prevents coaptation of the valve leaflets. Secondary mitral regurgitation contributes to progression of the symptoms and signs of HF and confers worse prognosis. The management of HF patients with SMR is complex and requires timely referral to a multidisciplinary Heart Team. Optimization of pharmacological and device therapy according to guideline recommendations is crucial. Further management requires careful clinical and imaging assessment, addressing the anatomical and functional features of the mitral valve and left ventricle, overall HF status, and relevant comorbidities. Evidence concerning surgical correction of SMR is sparse and it is doubtful whether this approach improves prognosis. Transcatheter repair has emerged as a promising alternative, but the conflicting results of current randomized trials require careful interpretation. This collaborative position statement, developed by four key associations of the European Society of Cardiology-the Heart Failure Association (HFA), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association of Cardiovascular Imaging (EACVI), and European Heart Rhythm Association (EHRA)-presents an updated practical approach to the evaluation and management of patients with HF and SMR based upon a Heart Team approach.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 17 Mar 2021; epub ahead of print
Coats AJS, Anker SD, Baumbach A, Alfieri O, ... Seferovic PM, Prendergast B
Eur Heart J: 17 Mar 2021; epub ahead of print | PMID: 33734354
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Abstract

Road traffic noise and cardiovascular disease risk factors in UK Biobank.

Kupcikova Z, Fecht D, Ramakrishnan R, Clark C, Cai YS
Aims
The aim of this study was to investigate the cross-sectional associations of modelled residential road traffic noise with cardiovascular disease risk factors [systolic (SBP) and diastolic blood pressure (DBP), C-reactive protein, triglycerides, glycated haemoglobin, and self-reported hypertension] in UK Biobank.
Methods and results
The UK Biobank recruited 502 651 individuals aged 40-69 years across the UK during 2006-10. Road traffic noise (Lden and Lnight) exposure for 2009 was estimated at baseline address using a simplified version of the Common Noise Assessment Methods model. We used multivariable linear and logistic regression models, adjusting for age, sex, body mass index (BMI), smoking, alcohol intake, area- and individual-level deprivation, season of blood draw, length of time at residence, and nitrogen dioxide (main model), in an analytical sample size of over 370 000 participants. Exposure to road-traffic Lden >65 dB[A], as compared to ≤55 dB[A], was associated with 0.77% [95% confidence interval (CI) 0.60%, 0.95%], 0.49% (95% CI 0.32%, 0.65%), 0.79% (95% CI 0.11%, 1.47%), and 0.12% (95% CI -0.04%, 0.28%) higher SBP, DBP, triglycerides, and glycated haemoglobin, respectively. Removing BMI from the main model yielded significant positive associations with all five markers with elevated percent changes. The associations with SBP or DBP did not appear to be impacted by hypertension medication while a positive association with prevalent self-reported hypertension was seen in the non-medicated group who exposed to a Lden level of 60-65 dB[A] (odds ratio 1.07, 95% CI 1.00, 1.15).
Conclusion
Exposure to road traffic noise >65 dB[A], independent of nitrogen dioxide, was associated with small but adverse changes in blood pressure and cardiovascular biochemistry.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 17 Mar 2021; epub ahead of print
Kupcikova Z, Fecht D, Ramakrishnan R, Clark C, Cai YS
Eur Heart J: 17 Mar 2021; epub ahead of print | PMID: 33733673
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Abstract

Brugada syndrome genetics is associated with phenotype severity.

Ciconte G, Monasky MM, Santinelli V, Micaglio E, ... Petretto E, Pappone C
Aims 
Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS.
Methods and results
Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area.
Conclusion 
In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

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

Eur Heart J: 13 Mar 2021; 42:1082-1090
Ciconte G, Monasky MM, Santinelli V, Micaglio E, ... Petretto E, Pappone C
Eur Heart J: 13 Mar 2021; 42:1082-1090 | PMID: 33221895
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Abstract

Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?

Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM
Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of \'reduced RVOT conduction reserve\'.

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Eur Heart J: 13 Mar 2021; 42:1073-1081
Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AAM
Eur Heart J: 13 Mar 2021; 42:1073-1081 | PMID: 33421051
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Abstract

Polymorphic ventricular tachycardia, ischaemic ventricular fibrillation, and torsade de pointes: importance of the QT and the coupling interval in the differential diagnosis.

Rosso R, Hochstadt A, Viskin D, Chorin E, ... Banai S, Viskin S
Aims
Distinctive types of polymorphic ventricular tachycardia (VT) respond differently to different forms of therapy. We therefore performed the present study to define the electrocardiographic characteristics of different forms of polymorphic VT.
Methods and results
We studied 190 patients for whom the onset of 305 polymorphic VT events was available. The study group included 87 patients with coronary artery disease who had spontaneous polymorphic VT triggered by short-coupled extrasystoles in the absence of myocardial ischaemia. This group included 32 patients who had a long QT interval but nevertheless had their polymorphic VT triggered by ectopic beats with short coupling interval, a subcategory termed \'pseudo-torsade de pointes] (TdP). For comparison, we included 50 patients who had ventricular fibrillation (VF) during acute myocardial infarction (\'ischaemic VF\' group) and 53 patients with drug-induced TdP (\'true TdP\' group). The QT of patients with pseudo-TdP was (by definition) longer than that of patients with polymorphic VT and normal QT (QTc 491.4 ± 25.2 ms vs. 447.3 ± 55.6 ms, P < 0.001). However, their QT was significantly shorter than that of patients with true TdP (QTc 564.6 ± 75.6 ms, P < 0.001). Importantly, the coupling interval of the ectopic beat triggering the arrhythmia was just as short during pseudo-TdP as during polymorphic VT with normal QT (359.1 ± 38.1 ms vs. 356.6 ± 39.4 ms, P = 0.467) but was much shorter than during true TdP (581.2 ± 95.3 ms, P < 0.001).
Conclusions
The coupling interval helps discriminate between polymorphic VT that occurs despite a long QT interval (pseudo-TdP) and polymorphic arrhythmias striking because of a long QT (true TdP).

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 09 Mar 2021; epub ahead of print
Rosso R, Hochstadt A, Viskin D, Chorin E, ... Banai S, Viskin S
Eur Heart J: 09 Mar 2021; epub ahead of print | PMID: 33693589
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Abstract

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

Arnold M, Schweizer J, Nakas CT, Schütz V, ... von Eckardstein A, Katan M
Aims
Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients.
Methods and results
For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48).
Conclusion
Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 07 Mar 2021; epub ahead of print
Arnold M, Schweizer J, Nakas CT, Schütz V, ... von Eckardstein A, Katan M
Eur Heart J: 07 Mar 2021; epub ahead of print | PMID: 33709115
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Abstract

The association between coronary graft patency and clinical status in patients with coronary artery disease.

Gaudino M, Di Franco A, Bhatt DL, Alexander JH, ... Fremes SE, Bangalore S
The concept of a direct association between coronary graft patency and clinical status is generally accepted. However, the relationship is more complex and variable than usually thought. Key issues are the lack of a common definition of graft occlusion and of a standardized imaging protocol for patients undergoing coronary bypass surgery. Factors like the type of graft, the timing of the occlusion, and the amount of myocardium at risk, as well as baseline patients\' characteristics, modulate the patency-to-clinical status association. Available evidence suggests that graft occlusion is more often associated with non-fatal events rather than death. Also, graft failure due to competitive flow is generally a benign event, while graft occlusion in a graft-dependent circulation is associated with clinical symptoms. In this systematic review, we summarize the evidence on the association between graft status and clinical outcomes.

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Eur Heart J: 07 Mar 2021; epub ahead of print
Gaudino M, Di Franco A, Bhatt DL, Alexander JH, ... Fremes SE, Bangalore S
Eur Heart J: 07 Mar 2021; epub ahead of print | PMID: 33709098
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Abstract

Precision Medicine and cardiac channelopathies: when dreams meet reality.

Gnecchi M, Sala L, Schwartz PJ
Precision Medicine (PM) is an innovative approach that, by relying on large populations\' datasets, patients\' genetics and characteristics, and advanced technologies, aims at improving risk stratification and at identifying patient-specific management through targeted diagnostic and therapeutic strategies. Cardiac channelopathies are being progressively involved in the evolution brought by PM and some of them are benefiting from these novel approaches, especially the long QT syndrome. Here, we have explored the main layers that should be considered when developing a PM approach for cardiac channelopathies, with a focus on modern in vitro strategies based on patient-specific human-induced pluripotent stem cells and on in silico models. PM is where scientists and clinicians must meet and integrate their expertise to improve medical care in an innovative way but without losing common sense. We have indeed tried to provide the cardiologist\'s point of view by comparing state-of-the-art techniques and approaches, including revolutionary discoveries, to current practice. This point matters because the new approaches may, or may not, exceed the efficacy and safety of established therapies. Thus, our own eagerness to implement the most recent translational strategies for cardiac channelopathies must be tempered by an objective assessment to verify whether the PM approaches are indeed making a difference for the patients. We believe that PM may shape the diagnosis and treatment of cardiac channelopathies for years to come. Nonetheless, its potential superiority over standard therapies should be constantly monitored and assessed before translating intellectually rewarding new discoveries into clinical practice.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 03 Mar 2021; epub ahead of print
Gnecchi M, Sala L, Schwartz PJ
Eur Heart J: 03 Mar 2021; epub ahead of print | PMID: 33686390
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Abstract

Percutaneous coronary intervention in patients with cancer and readmissions within 90 days for acute myocardial infarction and bleeding in the USA.

Kwok CS, Wong CW, Kontopantelis E, Barac A, ... Bhatt DL, Mamas MA
Aims
The post-discharge outcomes of patients with cancer who undergo PCI are not well understood. This study evaluates the rates of readmissions within 90 days for acute myocardial infarction (AMI) and bleeding among patients with cancer who undergo percutaneous coronary intervention (PCI).
Methods and results
Patients treated with PCI in the years from 2010 to 2014 in the US Nationwide Readmission Database were evaluated for the influence of cancer on 90-day readmissions for AMI and bleeding. A total of 1 933 324 patients were included in the analysis (2.7% active cancer, 6.8% previous history of cancer). The 90-day readmission for AMI after PCI was higher in patients with active cancer (12.1% in lung, 10.8% in colon, 7.5% in breast, 7.0% in prostate, and 9.1% for all cancers) compared to 5.6% among patients with no cancer. The 90-day readmission for bleeding after PCI was higher in patients with active cancer (4.2% in colon, 1.5% in lung, 1.4% in prostate, 0.6% in breast, and 1.6% in all cancer) compared to 0.6% among patients with no cancer. The average time to AMI readmission ranged from 26.7 days for lung cancer to 30.5 days in colon cancer, while the average time to bleeding readmission had a higher range from 38.2 days in colon cancer to 42.7 days in breast cancer.
Conclusions
Following PCI, patients with cancer have increased risk for readmissions for AMI or bleeding, with the magnitude of risk depending on both cancer type and the presence of metastasis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 02 Mar 2021; epub ahead of print
Kwok CS, Wong CW, Kontopantelis E, Barac A, ... Bhatt DL, Mamas MA
Eur Heart J: 02 Mar 2021; epub ahead of print | PMID: 33681960
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Impact:
Abstract

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Garnier S, Harakalova M, Weiss S, Mokry M, ... Trégouët DA, Charron P
Aims 
Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.
Methods and results 
We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.
Conclusion 
This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 02 Mar 2021; epub ahead of print
Garnier S, Harakalova M, Weiss S, Mokry M, ... Trégouët DA, Charron P
Eur Heart J: 02 Mar 2021; epub ahead of print | PMID: 33677556
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Impact:
Abstract

Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms.

Kyaw T, Loveland P, Kanellakis P, Cao A, ... Toh BH, Bobik A
Aims 
Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI.
Methods and results 
We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis.
Conclusion 
Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.

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 Feb 2021; 42:938-947
Kyaw T, Loveland P, Kanellakis P, Cao A, ... Toh BH, Bobik A
Eur Heart J: 28 Feb 2021; 42:938-947 | PMID: 33338208
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Impact:
Abstract

Does a myocardial infarction boost your (B cell) memory?

Monaco C, Cole J
Graphical abstract Establishment of an autoreactive B cell memory after myocardial infarction: a working hypothesis. The demise of cardiac cells leads to the release of cryptoantigens that induce a humoral immune response that leads to accumulation of immunoglobulins in plaques and eventually amplifies atherogenesis at remote sites.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 28 Feb 2021; 42:948-950
Monaco C, Cole J
Eur Heart J: 28 Feb 2021; 42:948-950 | PMID: 33394010
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Abstract

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials.

Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, ... Mehta NN, Ridker PM
Aims
The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy.
Methods and results
Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE. All analyses were performed first in CANTOS, and then externally validated in the other four trials. For the five trials, hazard ratios for major CV events and mortality comparing NLR quartiles were computed using Cox proportional hazards models, and the effect of each randomized intervention on the NLR was evaluated in comparison to placebo. The NLR modestly correlated with interleukin-6, C-reactive protein, and fibrinogen levels but minimally with lipids. In all five randomized trials, baseline NLR predicted incident CV events and death; the per-quartile increase in risk of MACE was 20% in CANTOS [95% confidence interval (CI) 14-25%, P < 0.0001], 31% in SPIRE-1 (95% CI 14-49%, P = 0.00007), 27% in SPIRE-2 (95% CI 12-43%, P = 0.0002), 9% in CIRT (95% CI 0.2-20%, P = 0.045), and 11% in JUPITER (95% CI 1-22%, P = 0.03). While lipid-lowering agents had no significant impact on the NLR, anti-inflammatory therapy with canakinumab lowered the NLR (P < 0.0001).
Conclusion
The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 28 Feb 2021; 42:896-903
Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, ... Mehta NN, Ridker PM
Eur Heart J: 28 Feb 2021; 42:896-903 | PMID: 33417682
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Impact:
Abstract

Learning whether to subtract beta-blockers: it\'s about time.

van Diepen S, Armstrong PW
Proposed framework for foundational and provisional secondary prevention therapy over time in low-risk post-MI patients. Foundational therapies should be considered in all patients without contraindications, while provisional therapies should be considered in selected patients with comorbidities or post-infarction complications. The horizontal time axis proposes duration of therapies and timeframes for pharmacotherapeutic re-assessment, and should be responsive to the temporal evolution of post-MI risk and events. ADP, adenosine diphosphate receptor inhibitors; ASA, acetylsalicylic acid; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension; RAAS, renin-angiotensin-aldosterone system; RCT, randomized controlled trials; TG, triglyceride. *Pending guideline recommendations.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 28 Feb 2021; 42:915-918
van Diepen S, Armstrong PW
Eur Heart J: 28 Feb 2021; 42:915-918 | PMID: 33428708
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Abstract

Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study.

Holt A, Blanche P, Zareini B, Rajan D, ... Gislason GH, Lamberts M
Aims
We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF).
Methods and results
Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%).
Conclusions
In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 28 Feb 2021; 42:907-914
Holt A, Blanche P, Zareini B, Rajan D, ... Gislason GH, Lamberts M
Eur Heart J: 28 Feb 2021; 42:907-914 | PMID: 33428707
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Abstract

The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction.

Ceglarek U, Schellong P, Rosolowski M, Scholz M, ... Pöss J, Thiele H
Background 
Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) still reaches excessively high mortality rates. This analysis is aimed to develop a new easily applicable biomarker-based risk score.
Methods and results 
A biomarker-based risk score for 30-day mortality was developed from 458 patients with CS complicating AMI included in the randomized CULPRIT-SHOCK trial. The selection of relevant predictors and the coefficient estimation for the prognostic model were performed by a penalized multivariate logistic regression analysis. Validation was performed internally, internally externally as well as externally in 163 patients with CS included in the randomized IABP-SHOCK II trial. Blood samples were obtained at randomization. The two trials are registered with ClinicalTrials.gov (NCT01927549 and NCT00491036), are closed to new participants, and follow-up is completed. Out of 58 candidate variables, the four strongest predictors for 30-day mortality were included in the CLIP score (cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide). The score was well calibrated and yielded high c-statistics of 0.82 [95% confidence interval (CI) 0.78-0.86] in internal validation, 0.82 (95% CI 0.75-0.89) in internal-external (temporal) validation, and 0.73 (95% CI 0.65-0.81) in external validation. Notably, it outperformed the Simplified Acute Physiology Score II and IABP-SHOCK II risk score in prognostication (0.83 vs 0.62; P < 0.001 and 0.83 vs. 0.76; P = 0.03, respectively).
Conclusions 
A biomarker-only score for 30-day mortality risk stratification in infarct-related CS was developed, extensively validated and calibrated in a prospective cohort of contemporary patients with CS after AMI. The CLIP score outperformed other clinical scores and may be useful as an early decision tool in CS.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 26 Feb 2021; epub ahead of print
Ceglarek U, Schellong P, Rosolowski M, Scholz M, ... Pöss J, Thiele H
Eur Heart J: 26 Feb 2021; epub ahead of print | PMID: 33647946
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Impact:
Abstract

Long-term outcomes following endovascular and surgical revascularization for peripheral artery disease: a propensity score-matched analysis.

Parvar SL, Ngo L, Dawson J, Nicholls SJ, ... Psaltis PJ, Ranasinghe I
Aims
Peripheral artery disease (PAD) revascularization can be performed by either endovascular or open surgical approach. Despite increasing use of endovascular revascularization, it is still uncertain which strategy yields better long-term outcomes.
Methods and results
This retrospective cohort study evaluated patients hospitalized with PAD in Australia and New Zealand who underwent either endovascular or surgical revascularization between 2008 and 2015, and compared procedures using a propensity score-matched analysis. Hybrid interventions were excluded. The primary endpoint was mortality or major adverse limb events (MALE), defined as a composite endpoint of acute limb ischaemia, urgent surgical or endovascular reintervention, or major amputation, up to 8 years post-hospitalization using time-to-event analyses 75 189 patients fulfilled eligibility (15 239 surgery and 59 950 endovascular), from whom 14 339 matched pairs (mean ± SD age 71 ± 12 years, 73% male) with good covariate balance were identified. Endovascular revascularization was associated with an increase in combined MALE or mortality [hazard ratio (HR) 1.13, 95% confidence interval (CI): 1.09-1.17, P < 0.001]. There was a similar risk of MALE (HR 1.04, 95% CI: 0.99-1.10, P = 0.15), and all-cause urgent rehospitalizations (HR 1.01, 95% CI: 0.98-1.04, P = 0.57), but higher mortality (HR 1.16, 95% CI: 1.11-1.21, P < 0.001) when endovascular repair was compared to surgery. In subgroup analysis, these findings were consistent for both claudication and chronic limb-threatening ischaemia presentations.
Conclusion
Although the long-term risk of MALE was comparable for both approaches, enduring advantages of surgical revascularization included lower long-term mortality. This is at odds with some prior PAD studies and highlights contention in this space.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 23 Feb 2021; epub ahead of print
Parvar SL, Ngo L, Dawson J, Nicholls SJ, ... Psaltis PJ, Ranasinghe I
Eur Heart J: 23 Feb 2021; epub ahead of print | PMID: 33624819
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Abstract

Tilt testing remains a valuable asset.

Sutton R, Fedorowski A, Olshansky B, Gert van Dijk J, ... Thijs RD, Benditt DG
Head-up tilt test (TT) has been used for >50 years to study heart rate/blood pressure adaptation to positional changes, to model responses to haemorrhage, to assess orthostatic hypotension, and to evaluate haemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During these studies, some subjects experienced syncope due to vasovagal reflex. As a result, tilt testing was incorporated into clinical assessment of syncope when the origin was unknown. Subsequently, clinical experience supports the diagnostic value of TT. This is highlighted in evidence-based professional practice guidelines, which provide advice for TT methodology and interpretation, while concurrently identifying its limitations. Thus, TT remains a valuable clinical asset, one that has added importantly to the appreciation of pathophysiology of syncope/collapse and, thereby, has improved care of syncopal patients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 23 Feb 2021; epub ahead of print
Sutton R, Fedorowski A, Olshansky B, Gert van Dijk J, ... Thijs RD, Benditt DG
Eur Heart J: 23 Feb 2021; epub ahead of print | PMID: 33624801
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Impact:
Abstract

All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study.

Butt JH, Fosbøl EL, Gerds TA, Andersson C, ... Køber L, Schou M
Background
On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures.
Methods and results
Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87-0.95; IRR 0.95, 95% CI 0.89-1.02; and IRR 0.87, 95% CI 0.83-0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97-1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88-0.96; out-of-hospital, IRR 1.04, 95% CI1.01-1.08). These trends were consistent irrespective of sex and age.
Conclusions
Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 23 Feb 2021; epub ahead of print
Butt JH, Fosbøl EL, Gerds TA, Andersson C, ... Køber L, Schou M
Eur Heart J: 23 Feb 2021; epub ahead of print | PMID: 33624011
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Impact:
Abstract

Outdoor light at night and risk of coronary heart disease among older adults: a prospective cohort study.

Sun S, Cao W, Ge Y, Ran J, ... Tian L, Wellenius GA
Aims
We estimated the association between outdoor light at night at the residence and risk of coronary heart disease (CHD) within a prospective cohort of older adults in Hong Kong.
Methods and results
Over a median of 11 years of follow-up, we identified 3772 incident CHD hospitalizations and 1695 CHD deaths. Annual levels of outdoor light at night at participants\' residential addresses were estimated using time-varying satellite data for a composite of persistent night-time illumination at ∼1 km2 scale. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between outdoor light at night at the residence and risk of CHD. The association between light at night and incident CHD hospitalization and mortality exhibited a monotonic exposure-response function. An interquartile range (IQR) (60.0 nW/cm2/sr) increase in outdoor light at night was associated with an HR of 1.11 (95% CI: 1.03, 1.18) for CHD hospitalizations and 1.10 (95% CI: 1.00, 1.22) for CHD deaths after adjusting for both individual and area-level risk factors. The association did not vary across strata of hypothesized risk factors.
Conclusion
Among older adults, outdoor light at night at the residence was associated with a higher risk of CHD hospitalizations and deaths. We caution against causal interpretation of these novel findings. Future studies with more detailed information on exposure, individual adaptive behaviours, and potential mediators are warranted to further examine the relationship between light at night and CHD risk.

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: 20 Feb 2021; 42:822-830
Sun S, Cao W, Ge Y, Ran J, ... Tian L, Wellenius GA
Eur Heart J: 20 Feb 2021; 42:822-830 | PMID: 33205210
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Impact:
Abstract

Does night-time aircraft noise trigger mortality? A case-crossover study on 24 886 cardiovascular deaths.

Saucy A, Schäffer B, Tangermann L, Vienneau D, Wunderli JM, Röösli M
Aims
It is unclear whether night-time noise events, including from aeroplanes, could trigger a cardiovascular death. In this study, we investigate the potential acute effects of aircraft noise on mortality and the specific role of different night-time exposure windows by means of a case-crossover study design.
Methods and results
We selected 24 886 cases of death from cardiovascular disease (CVD) from the Swiss National Cohort around Zürich Airport between 2000 and 2015. For night-time deaths, exposure levels 2 h preceding death were significantly associated with mortality for all causes of CVD [OR = 1.44 (1.03-2.04) for the highest exposure group (LAeq > 50 dB vs. <20 dB)]. Most consistent associations were observed for ischaemic heart diseases, myocardial infarction, heart failure, and arrhythmia. Association were more pronounced for females (P = 0.02) and for people living in areas with low road and railway background noise (P = 0.01) and in buildings constructed before 1970 (P = 0.36). We calculated a population attributable fraction of 3% in our study population.
Conclusion
Our findings suggest that night-time aircraft noise can trigger acute cardiovascular mortality. The association was similar to that previously observed for long-term aircraft noise exposure.

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

Eur Heart J: 20 Feb 2021; 42:835-843
Saucy A, Schäffer B, Tangermann L, Vienneau D, Wunderli JM, Röösli M
Eur Heart J: 20 Feb 2021; 42:835-843 | PMID: 33245107
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Impact:
Abstract

Discriminatory cardiac arrest care? Patients with low socioeconomic status receive delayed cardiopulmonary resuscitation and are less likely to survive an in-hospital cardiac arrest.

Agerström J, Carlsson M, Bremer A, Herlitz J, Israelsson J, Årestedt K
Aims 
Individuals with low socioeconomic status (SES) face widespread prejudice in society. Whether SES disparities exist in treatment and survival following in-hospital cardiac arrest (IHCA) is unclear. The aim of the current retrospective registry study was to examine SES disparities in IHCA treatment and survival, assessing SES at the patient level, and adjusting for major demographic, clinical, and contextual factors.
Methods and results 
In total, 24 217 IHCAs from the Swedish Register of Cardiopulmonary Resuscitation were analysed. Education and income constituted SES proxies. Controlling for age, gender, ethnicity, comorbidity, heart rhythm, aetiology, hospital, and year, primary analyses showed that high (vs. low) SES patients were significantly less likely to receive delayed cardiopulmonary resuscitation (CPR) (highly educated: OR = 0.89, and high income: OR = 0.98). Furthermore, patients with high SES were significantly more likely to survive CPR (high income: OR = 1.02), to survive to hospital discharge with good neurological outcome (highly educated: OR = 1.27; high income: OR = 1.06), and to survive to 30 days (highly educated: OR = 1.21; and high income: OR = 1.05). Secondary analyses showed that patients with high SES were also significantly more likely to receive prophylactic heart rhythm monitoring (highly educated: OR = 1.16; high income: OR = 1.02), and this seems to partially explain the observed SES differences in CPR delay.
Conclusion 
There are clear SES differences in IHCA treatment and survival, even when controlling for major sociodemographic, clinical, and contextual factors. This suggests that patients with low SES could be subject to discrimination when suffering IHCA.

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

Eur Heart J: 20 Feb 2021; 42:861-869
Agerström J, Carlsson M, Bremer A, Herlitz J, Israelsson J, Årestedt K
Eur Heart J: 20 Feb 2021; 42:861-869 | PMID: 33345270
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Impact:
Abstract

Paradoxical impact of socioeconomic factors on outcome of atrial fibrillation in Europe: trends in incidence and mortality from atrial fibrillation.

Al-Khayatt BM, Salciccioli JD, Marshall DC, Krahn AD, Shalhoub J, Sikkel MB
Aims
The aim of this study was to understand the changing trends in atrial fibrillation (AF) incidence and mortality across Europe from 1990 to 2017, and how socioeconomic factors and sex differences play a role.
Methods and results
We performed a temporal analysis of data from the 2017 Global Burden of Disease Database for 20 countries across Europe using Joinpoint regression analysis. Age-adjusted incidence, mortality, and mortality-to-incidence ratios (MIRs) to approximate case fatality rate are presented. Incidence and mortality trends were heterogenous throughout Europe, with Austria, Denmark, and Sweden experiencing peaks in incidence in the middle of the study period. Mortality rates were higher in wealthier countries with the highest being Sweden for both men and women (8.83 and 8.88 per 100 000, respectively) in 2017. MIRs were higher in women in all countries studied, with the disparity increasing the most over time in Germany (43.6% higher in women vs. men in 1990 to 74.5% higher in women in 2017).
Conclusion
AF incidence and mortality across Europe did not show a general trend, but unique patterns for some nations were observed. Higher mortality rates were observed in wealthier countries, potentially secondary to a survivor effect where patients survive long enough to suffer from AF and its complications. Outcomes for women with AF were worse than men, represented by higher MIRs. This suggests that there is widespread healthcare inequality between the sexes across Europe, or that there are biological differences between them in terms of their risk of adverse outcomes from AF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 20 Feb 2021; 42:847-857
Al-Khayatt BM, Salciccioli JD, Marshall DC, Krahn AD, Shalhoub J, Sikkel MB
Eur Heart J: 20 Feb 2021; 42:847-857 | PMID: 33495788
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Impact:
Abstract

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Kotecha T, Knight DS, Razvi Y, Kumar K, ... Cole GD, Fontana M
Background
Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.
Methods and results
One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).
Conclusions
During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 17 Feb 2021; epub ahead of print
Kotecha T, Knight DS, Razvi Y, Kumar K, ... Cole GD, Fontana M
Eur Heart J: 17 Feb 2021; epub ahead of print | PMID: 33596594
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Impact:
Abstract

Long-term outcomes in young patients with atrioventricular block of unknown aetiology.

Dideriksen JR, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK
Aims
Atrioventricular block (AVB) of unknown aetiology is rare in the young, and outcome in these patients is unknown. We aimed to assess long-term morbidity and mortality in young patients with AVB of unknown aetiology.
Methods and results
We identified all Danish patients younger than 50 years receiving a first pacemaker due to AVB between January 1996 and December 2015. By reviewing medical records, we included patients with AVB of unknown aetiology. A matched control cohort was established. Follow-up was performed using national registries. The primary outcome was a composite endpoint consisting of death, heart failure hospitalization, ventricular tachyarrhythmia, and cardiac arrest with successful resuscitation. We included 517 patients, and 5170 controls. Median age at first pacemaker implantation was 41.3 years [interquartile range (IQR) 32.7-46.2 years]. After a median follow-up of 9.8 years (IQR 5.7-14.5 years), the primary endpoint had occurred in 14.9% of patients and 3.2% of controls [hazard ratio (HR) 3.8; 95% confidence interval (CI) 2.9-5.1; P < 0.001]. Patients with persistent AVB at time of diagnosis had a higher risk of the primary endpoint (HR 10.6; 95% CI 5.7-20.0; P < 0.001), and risk was highest early in the follow-up period (HR 6.8; 95% CI 4.6-10.0; P < 0.001, during 0-5 years of follow-up).
Conclusion
Atrioventricular block of unknown aetiology presenting before the age of 50 years and treated with pacemaker implantation was associated with a three- to four-fold higher rate of the composite endpoint of death or hospitalization for heart failure, ventricular tachyarrhythmia, or cardiac arrest with successful resuscitation. Patients with persistent AVB were at higher risk. These findings warrant improved follow-up strategies for young patients with AVB of unknown aetiology.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 17 Feb 2021; epub ahead of print
Dideriksen JR, Christiansen MK, Johansen JB, Nielsen JC, Bundgaard H, Jensen HK
Eur Heart J: 17 Feb 2021; epub ahead of print | PMID: 33599276
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Impact:
Abstract

Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study.

Wartolowska KA, Webb AJS
Aims
White matter hyperintensities (WMH) progress with age and hypertension, but the key period of exposure to elevated blood pressure (BP), and the relative role of systolic BP (SBP) vs. diastolic BP (DBP), remains unclear. This study aims to determine the relationship between WMH and concurrent vs. past BP.
Methods and results 
UK Biobank is a prospective community-based cohort of 40-69-year olds from 22 centres, with magnetic resonance imaging in a subgroup of over 40 000 people at 4-12 years after baseline assessment. Standardized associations between WMH load (WMH volume normalized by total white matter volume and logit-transformed) and concurrent vs. past BP were determined using linear models, adjusted for age, sex, cardiovascular risk factors, BP source, assessment centre, and time since baseline. Associations adjusted for regression dilution bias were determined between median WMH and usual SBP or DBP, stratified by age and baseline BP.In 37 041 eligible participants with WMH data and BP measures, WMH were more strongly associated with concurrent SBP [DBP: β = 0.064, 95% confidence interval (CI) 0.050-0.078; SBP: β = 0.076, 95% CI 0.062-0.090], but the strongest association was for past DBP (DBP: β = 0.087, 95% CI 0.064-0.109; SBP: β = 0.045, 95% CI 0.022-0.069), particularly under the age of 50 (DBP: β = 0.103, 95% CI 0.055-0.152; SBP: β = 0.012, 95% CI -0.044 to 0.069). Due to the higher prevalence of elevated SBP, median WMH increased 1.126 (95% CI 1.107-1.146) per 10 mmHg usual SBP and 1.106 (95% CI 1.090-1.122) per 5 mmHg usual DBP, whilst the population attributable fraction of WMH in the top decile was greater for elevated SBP (19.1% for concurrent SBP; 24.4% for past SBP). Any increase in BP, even below 140 for SBP and below 90 mmHg for DBP, and especially if requiring antihypertensive medication, was associated with increased WMH.
Conclusions
WMH were strongly associated with concurrent and past elevated BP with the population burden of severe WMH greatest for SBP. However, before the age of 50, DBP was more strongly associated with WMH. Long-term prevention of WMH may require control of even mildly elevated midlife DBP.

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

Eur Heart J: 13 Feb 2021; 42:750-757
Wartolowska KA, Webb AJS
Eur Heart J: 13 Feb 2021; 42:750-757 | PMID: 33238300
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Abstract

Prognostic value of peak stress cardiac power in patients with normal ejection fraction undergoing exercise stress echocardiography.

Anand V, Kane GC, Scott CG, Pislaru SV, ... Pellikka PA, Pislaru C
Aims 
Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF.
Methods and results 
We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6-8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4-0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results.
Conclusion 
The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

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: 13 Feb 2021; 42:776-785
Anand V, Kane GC, Scott CG, Pislaru SV, ... Pellikka PA, Pislaru C
Eur Heart J: 13 Feb 2021; 42:776-785 | PMID: 33377479
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Abstract

A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans.

Abohashem S, Osborne MT, Dar T, Naddaf N, ... Rajagopalan S, Tawakol A
Aims 
Air pollution [i.e. particulate matter with diameter <2.5 μm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE.
Methods and results 
Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual\'s home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE.
Conclusions 
Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 13 Feb 2021; 42:761-772
Abohashem S, Osborne MT, Dar T, Naddaf N, ... Rajagopalan S, Tawakol A
Eur Heart J: 13 Feb 2021; 42:761-772 | PMID: 33428721
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Abstract

Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo.

Diaz-Rodriguez S, Rasser C, Mesnier J, Chevallier P, ... Mantovani D, Caligiuri G
Aims
The rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leukocyte activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, we have shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leukocyte homeostasis and arterial healing. Furthermore, we have shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The aim of this study was to evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements and the in vivo strut coverage and neointimal growth.
Methods and results
We produced Cobalt Chromium discs and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results. We found that CD31-mimetic discs significantly reduced the extent of primary human coronary artery EC and blood platelet/leukocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/timepoint). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized with no activated platelets/leukocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared to BMS, appearing as a normal arterial media with the absence of thrombosis contrary to DES.
Conclusion
CD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis. Hence, such coatings seem to improve the metal stent biocompatibility.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 12 Feb 2021; epub ahead of print
Diaz-Rodriguez S, Rasser C, Mesnier J, Chevallier P, ... Mantovani D, Caligiuri G
Eur Heart J: 12 Feb 2021; epub ahead of print | PMID: 33580685
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Abstract

Genetic insight into sick sinus syndrome.

Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, ... Holm H, Stefansson K
Aims
The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.
Methods and results
We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05).
Conclusion
We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 12 Feb 2021; epub ahead of print
Thorolfsdottir RB, Sveinbjornsson G, Aegisdottir HM, Benonisdottir S, ... Holm H, Stefansson K
Eur Heart J: 12 Feb 2021; epub ahead of print | PMID: 33580673
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Abstract

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart \'OMics\' in AGEing (HOMAGE) randomized clinical trial.

Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Aims 
To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure.
Methods and results 
Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone.
Conclusions 
Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

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

Eur Heart J: 10 Feb 2021; 42:684-696
Cleland JGF, Ferreira JP, Mariottoni B, Pellicori P, ... Zannad F, HOMAGE Trial Committees and Investigators
Eur Heart J: 10 Feb 2021; 42:684-696 | PMID: 33215209
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Abstract

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Aims
The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF).
Methods and results
HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported.
Conclusion
The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

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: 10 Feb 2021; 42:700-710
Abraham WT, Lindenfeld J, Ponikowski P, Agostoni P, ... Salsali A, Anker SD
Eur Heart J: 10 Feb 2021; 42:700-710 | PMID: 33351892
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Abstract

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Aims
We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction.
Methods and results
The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated.
Conclusion
The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 10 Feb 2021; 42:671-680
Packer M, Anker SD, Butler J, Filippatos G, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Eur Heart J: 10 Feb 2021; 42:671-680 | PMID: 33459776
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Abstract

Cardiac arrest in COVID-19: characteristics and outcomes of in- and out-of-hospital cardiac arrest. A report from the Swedish Registry for Cardiopulmonary Resuscitation.

Sultanian P, Lundgren P, Strömsöe A, Aune S, ... Herlitz J, Rawshani A
Aim
To study the characteristics and outcome among cardiac arrest cases with COVID-19 and differences between the pre-pandemic and the pandemic period in out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA).
Method and results
We included all patients reported to the Swedish Registry for Cardiopulmonary Resuscitation from 1 January to 20 July 2020. We defined 16 March 2020 as the start of the pandemic. We assessed overall and 30-day mortality using Cox regression and logistic regression, respectively. We studied 1946 cases of OHCA and 1080 cases of IHCA during the entire period. During the pandemic, 88 (10.0%) of OHCAs and 72 (16.1%) of IHCAs had ongoing COVID-19. With regards to OHCA during the pandemic, the odds ratio for 30-day mortality in COVID-19-positive cases, compared with COVID-19-negative cases, was 3.40 [95% confidence interval (CI) 1.31-11.64]; the corresponding hazard ratio was 1.45 (95% CI 1.13-1.85). Adjusted 30-day survival was 4.7% for patients with COVID-19, 9.8% for patients without COVID-19, and 7.6% in the pre-pandemic period. With regards to IHCA during the pandemic, the odds ratio for COVID-19-positive cases, compared with COVID-19-negative cases, was 2.27 (95% CI 1.27-4.24); the corresponding hazard ratio was 1.48 (95% CI 1.09-2.01). Adjusted 30-day survival was 23.1% in COVID-19-positive cases, 39.5% in patients without COVID-19, and 36.4% in the pre-pandemic period.
Conclusion
During the pandemic phase, COVID-19 was involved in at least 10% of all OHCAs and 16% of IHCAs, and, among COVID-19 cases, 30-day mortality was increased 3.4-fold in OHCA and 2.3-fold in IHCA.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 04 Feb 2021; epub ahead of print
Sultanian P, Lundgren P, Strömsöe A, Aune S, ... Herlitz J, Rawshani A
Eur Heart J: 04 Feb 2021; epub ahead of print | PMID: 33543259
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Abstract

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

Hartiala JA, Han Y, Jia Q, Hilser JR, ... Hazen SL, Allayee H
Aims
While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.
Methods and results
We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.
Conclusions
A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Eur Heart J: 02 Feb 2021; epub ahead of print
Hartiala JA, Han Y, Jia Q, Hilser JR, ... Hazen SL, Allayee H
Eur Heart J: 02 Feb 2021; epub ahead of print | PMID: 33532862
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Impact:

This program is still in alpha version.