European Heart Journal

doi: 10.1093/eurheartj/ehy663pmid: 30428034

With the European Heart Journal continuing to hold the number one spot among global cardiology journals, Editor-in-Chief Thomas F. Lüscher outlined the performance and trends over the last 12 months at the publication’s annual editorial board meeting with an impressive attendance of cardiologists from around the world. Held in the grand setting of the Bayerischer Hof Hotel in Munich on the eve of the final day of the 2018 ESC Congress in the city, he also pointed to areas where the journal needed to grow into—particularly the realms of social media—in order to maintain and evolve its influence as a global publication. Performance and impact During the meeting Professor Lüscher recapped on the 5 year strategic goals of the journal in the area of impact, influence, reach, and sustainability and growth, and in particular to be known as the number one journal for cardiovascular medicine globally with continued growth and influence. But he also emphasised the need for it to be a journal with a user-friendly author submission process and a publication renowned for quality reviewers. Submissions in 2017 were 3173, compared with 3578 in 2012, and a forecast of 3100 for 2018, with an acceptance rate of around 8%. He considered the decline to be related to the increasing impact factor and, in turn, the declining acceptance rate over the last few years. Submissions for 2018 so far are 54.3% from Europe, 20.1% from east and south-east Asia, 17.8% from North America, and the remainder from Africa, central Asia, and south and central America and Oceania. Thomas Lüscher said: ‘I am particularly pleased with our US colleagues as they submit a lot of excellent papers and their acceptance is the highest, followed by the UK and Germany’. He further announced the launch of a Japanese edition of the EHJ under the editorship of Hiroaki Shimokawa, associate editor of the EHJ. Manuscript transfer within the ESC journal family Manuscript transfer is an important feature of the ESC journal family. ‘Sometimes we have papers that are not suitable for us, maybe they are too specific, or maybe more suited to European Journal of Heart Failure, for example’, he said. ‘We transfer about 350–400 papers a year to other journals in the ESC journal family but not all authors will accept the offer’. Impact factor A crucial marker remains the Impact Factor, what Prof. Lüscher described to the board as ‘measuring the unmeasurable’, as pointed out in a recent editorial. ‘Every good scientific paper is good on its own and we don’t just consider the role of numbers—though we do love numbers—most readers and scientists want to know who is first, second and third’, he said. ‘But when you compare the currently used factors you get slightly different results as they measure impact in different ways. At the end, good science is a piece of art and we should consider it as such’. But when it comes down to numbers, the EHJ tops the Impact Factor table with 2017 figures of 23.425, up 3.213 from 20.212 in 2016. That compares with 2017 figures for Circulation of 18.880 and Journal of the American College of Cardiology of 16.834. In terms of Cardiac and Cardiovascular Systems ranking, the European Heart Journal is number one out of 128 journals with the European Journal of Heart Failure in sixth place with 10.683 and EHJ Cardiovascular Imaging in 10th with an Impact Factor of 8.366. ‘Articles contributing most to the impact factor’, he continued, ‘are primarily reviews and original research papers but guidelines are important too and we are glad to have them as they are of interest to our readers, particularly for downloads and citations’. Surprisingly, the ESC Guidelines make up 16.78% of citations of the EHJ, compared with 11.7% for Circulation and 9.8% for JACC for the US Guidelines. He said: ‘The Impact Factor increase in 2017 was largely due to an increase in the number of papers contributing more than 200 citations supported by an increase in the number of papers receiving more than 50 citations and a decrease on total source items’. Source items decreased from 560 in 2016 to 532 in 2017; 29 papers received more than 100 citations in 2017 compared with 24 the previous year; and eight papers received more than 200 citations compared with three in 2016. EHJ also leads the Immediacy Index, which while similar to the Impact Factor, measures the activity within a single calendar year (7.055 compared with 5.982 for Circulation in 2017). However, in terms of the CiteScore—which considers the number of citations in 1 year to items published in a previous window—EHJ with 8.66 sits second to JACC on 8.81. In terms of who was citing the journal, in 2017 that was 60.2% from Europe, 21% from North America, and 9.8% from east and southeast Asia. The Altimetric score of social media impact measures visibility, attention, media echo. Here, Prof. Lüscher noted that the US-based publishers lead the way with an Altimetric score of 75.09 for Circulation in top spot and JACC in second (71.13) compared with EHJ in fifth on 30.45. ‘We Europeans are still behind the others, particularly JACC and Circulation. Why is that? It is because the culture of social media is far more developed in the US… and because they have a very active role model in Washington! Perhaps we try to be more modest’. Influence and downloads Downloads of articles from the EHJ platform differ from citations. ‘What is important for a journal is not just impact but influence and what we offer from our experts to our readers on what to do in their daily practice’. He spoke of the importance of impact in terms of citations, interest for scientists, and influence on clinical practice. Unlike impact, downloads reflect the interest of clinicians for published material as it has importance for their daily cardiology practice. ‘Our usage report looked good last year with eight million downloads—HTML and pdf—and this year I suspect we are going to get even higher, particularly with all the hotlines published from this year’s congress’. The top downloading countries in 2017 were Europe (43.7%), North America (24%), and east and south-east Asia at 14.3% and the leading downloaded article in 2017 was Understanding Heart Failure: Pathophysiology and Diagnosis by Alexandre Mebazza as first author with 8830 downloads. Journal features He drew attention to regular features of the journal such as Issues@aGlance, summarising the content and importance of each EHJ issue, and the popularity of the CardioPulse news section which reports on people, institutions, societies and cardiology at large. Furthermore, the EHJ regularly published the Year in Cardiology in different fields such as acute coronary syndromes, arrhythmias, imaging, heart failure, and the like. Consensus papers and the ESC Guidelines are obviously also very important features of the journal. Reviewers and editors The peer review system relies on expert reviewers. ‘The journal would not run well without them’, he said, ‘we need reviewers with good judgement and commitment. Overwhelmingly, they provide balanced reviews and appropriate assessments about what a good paper is. Because we can only accept around 6–8% of the submitted papers, decision making becomes very difficult. Our reviewers have done a marvellous job over the years. What do they get? Recognition and Prestige—and every year a free dinner… all are volunteers and work for the good of science. We highly appreciate this academic spirit’. In honouring the reviewers, he presented the Reviewer of the Year award to Professor Allan Jaffe from the Mayo Clinic in Rochester, MN, USA and honoured the leading elite reviewers with a certificate of special recognition. These were Professors Johann Auer from Austria, Thomas Bartel from the Cleveland Clinic, Abu Dhabi, Bernard Lung from Paris, and Jurgen Prochaska from Mainz, Germany. The EHJ Editor of the year was Basic Science Editor Christian Matter. Conflict of interest: M.N. received expenses to attend ESC Congress by EHJ CardioPulse. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Santema, Bernadet T; Kloosterman, Mariëlle; Van Gelder, Isabelle C; Mordi, Ify; Lang, Chim C; Lam, Carolyn S P; Anker, Stefan D; Cleland, John G; Dickstein, Kenneth; Filippatos, Gerasimos; Van der Harst, Pim; Hillege, Hans L; Ter Maaten, Jozine M; Metra, Marco;

Mosqueira, Diogo; Mannhardt, Ingra; Bhagwan, Jamie R; Lis-Slimak, Katarzyna; Katili, Puspita; Scott, Elizabeth; Hassan, Mustafa; Prondzynski, Maksymilian; Harmer, Stephen C; Tinker, Andrew; Smith, James G W; Carrier, Lucie; Williams, Philip M; Gaffney, Daniel; Eschenhagen, Thomas; Hansen, Arne; Denning, Chris

Lam, Chi Keung; Wu, Joseph C

doi: 10.1093/eurheartj/ehy388pmid: 30010924

Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy’†, by D. Mosqueira et al., on page 3879. Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease. Characterized by left ventricular wall thickening, severe HCM cases are associated with left ventricular outflow tract obstruction, diastolic dysfunction, and sudden cardiac death in adolescents and young adults.1 It is disappointing that after being studied for more than six decades, no effective and targeted HCM pharmacotherapies currently exist.2 Thus, there is a crucial need to expedite therapeutic discovery to improve clinical outcomes, especially in terms of early disease management, to reduce sudden cardiac death in young individuals. In most HCM cases, disease-causing mutations can be isolated by studying the family pedigrees. Decades of research studying familial HCM cases have revealed >1400 mutations, with the majority of mutations located in genes encoding proteins in the sarcomere.3 Theoretically, we should be able to identify HCM patients early through family history and genetic testing. Targeted treatment can then be developed based on the mutation in question to manage the disease at its early stages. However, disease modelling and drug discovery in HCM continue to be hindered by a lack of appropriate experimental animal or cell models. For example, the majority of HCM mutations are found in the MYH7 gene coding for β-myosin heavy chain,2,3 the dominant isoform in human heart. However, mutation studies using rodent models can be misinterpreted as this is not their major cardiac myosin heavy chain isoform.4 This pitfall can now be addressed using a human-based cell/tissue platform, which was made possible by Shinya Yamanaka’s seminal discovery of human induced pluripotent stem cells (iPSCs).5 This new technology enables researchers to differentiate cells into virtually any cell types of interest for disease modelling,6–8 drug discovery and screening,9,10 and regenerative medicine.11,12 However, several challenges must be met before we can fully unleash the potential of iPSCs. First, the differences in genetic background among the iPSC lines may conceal the true phenotype induced by a single mutation. In this regard, the introduction of genome editing technology, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, allows researchers to generate isogenic iPSC lines and study the precise effect of an HCM mutation while avoiding the genetic confounding factors.13 Secondly, we currently lack the technological wherewithal to describe an HCM phenotype in cells comprehensively in an unbiased manner. The development of high-resolution tools and high-throughput quantitative assays is particularly needed to detect the diverse molecular, functional, and morphological features present in iPSC-derived cardiomyocytes (iPSC-CMs).7 Perhaps the biggest question is whether this platform can reliably mirror the true phenotype in HCM patients. It has been hotly debated whether these foetal-like cells derived from iPSCs can reflect molecular or functional alteration in an adult disease. This immaturity can be partially attributed to our current inability to simulate the complex 3-D organ structure that is essential for cardiomyocyte maturation and function.14 Moreover, it is not yet possible for the cell-based system to imitate the structural and geometrical defects in HCM hearts. Concerted efforts from bioengineering are required to improve the current 2-D system or construct the optimal 3-D tissue platform for HCM research. In the current issue of the journal, Mosqueira and colleagues describe an integrative approach to study HCM using a pluripotent stem cell platform.15 The investigators introduced a c.C9123T-MYH7 mutation both heterozygously and homozygously into two iPSC lines and one embryonic stem cell (ESC) line to create three isogenic experimental sets. Using high-throughput flow cytometry and high-content imaging, they were able to detect an enlarged cell size, increased brain natriuretic peptide (BNP) expression, bi-/multinucleation, and sarcomeric disarray in heterozygotes across all three isogenic sets. In terms of cellular function, the investigators detected an elevated maximal respiration in both heterozygous and homozygous mutation lines from two isogenic sets, without changes in mitochondrial content. They were also able to simulate the arrhythmia observed in c.C9123T-MYH7 HCM patients. Using human engineered heart tissues (hEHTs), they revealed hypocontractility and negative clinotropy in the presence of the MYH7 mutation. Utilizing various high-volume and high-throughput phenotypic assays, they examined the effectiveness of several small molecules for this HCM mutation. Overall, this study is a prime example of how HCM can be comprehensively modelled in a relatively high-throughput fashion using both 2-D cell-based and 3-D hEHT-based platforms. However, Mosqueira and colleagues also underscored some limitations in their work. First, it was a huge task to integrate all the findings effectively after a comprehensive characterization. Owing to the descriptive nature of their work, it remains to be explained how one mutation in MHY7 can simultaneously affect several aspects of the cardiomyocyte function. Secondly, they highlighted the challenges in deciding on 2-D cell-based vs. 3-D tissue systems, as these two platforms showed different results in the transcriptomic analysis. Thirdly, cardiomyocyte maturation remains an important issue as in the control lines because the 3-D tissue platform did not demonstrate a positive force–frequency relationship, an important response observed in an adult myocardium.16 It would be valuable to see how their platform could benefit from a more recent protocol for inducing cardiac maturation.17 In summary, Mosqueira et al. provided an intriguing glimpse of the potential for comprehensive HCM disease modelling and drug testing using patient-specific iPSCs, genome editing, and tissue engineering. While more research is needed to improve the robustness and translational relevance of the current system, this study represents a possible direction to advance our current HCM modelling and drug discovery paradigm (Take home figure). Take home figure View largeDownload slide HCM disease modelling and drug discovery using the iPSC platform. Genome editing enables the generation of isogenic cell pairs that can limit the variations in genetic background. Cardiomyocytes and/or other stromal cell types in the heart can be differentiated from iPSCs, which can be engineered into various tissues or ‘organ chips’ for integrative disease modelling and drug screening purposes. Take home figure View largeDownload slide HCM disease modelling and drug discovery using the iPSC platform. Genome editing enables the generation of isogenic cell pairs that can limit the variations in genetic background. Cardiomyocytes and/or other stromal cell types in the heart can be differentiated from iPSCs, which can be engineered into various tissues or ‘organ chips’ for integrative disease modelling and drug screening purposes. Funding This publication was supported in part by research grants from the National Institutes of Health (NIH) R01 HL130020, R01 HL128170, and R01 HL126527, the American Heart Association (AHA) 17MERIT3361009, and Burroughs Welcome Fund 1015009 (J.C.W.). Conflict of interest: none declared. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi: 10.1093/eurheartj/ehy249. References 1 Marian AJ , Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy . Circ Res 2017 ; 121 : 749 – 770 . 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Advanced maturation of human cardiac tissue grown from pluripotent stem cells . Nature 2018 ; 556 : 239 – 243 . Google Scholar Crossref Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)