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Cardiovascular Research

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The journal of basic, translational and clinical research

Cardiovascular Research  (CVR) is the international journal of the European Society of Cardiology that deals with basic and translational research across different disciplines and areas.

The journal enhances insights into cardiovascular disease mechanisms and innovation.

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• Editor-in-chief: Tomasz J. Guzik, UK
• Current volume: 120 (year 2024)
• Issues per subscription: 18
• Impact Factor 2022: 10.9

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© 2024 European Society of Cardiology. All rights reserved.

Cardiovascular Ultrasound  strongly encourages that all datasets on which the conclusions of the paper rely should be available to readers. We encourage authors to ensure that their datasets are either deposited in publicly available repositories (where available and appropriate) or presented in the main manuscript or additional supporting files whenever possible. Please see Springer Nature’s  information on recommended repositories .

Authors who need help depositing and curating data may wish to consider contacting our Research Data Support Helpdesk .

Graphical Abstracts

Authors of Research articles are required to submit a graphical abstract (schematic figure) as part of the article, in addition to the text abstract. The graphical abstract should summarize in a visual or conceptual manner the key message of the paper and allow the reader to understand the essence of the study. The graphical abstract may incorporate multiple panels including key figures (numbers, percentages) or graphics, or short text lists summarising key points or variables. The graphical abstract should be submitted for peer review as a separate Additional file. The file should be clearly named, e.g. graphical_abstract.tiff. The graphical abstract should be submitted in a  landscape  format.

Preparing your manuscript

The information below details the section headings that you should include in your manuscript and what information should be within each section.

Please note that your manuscript must include a 'Declarations' section including all of the subheadings (please see below for more information).

The title page should:

• "A versus B in the treatment of C: a randomized controlled trial", "X is a risk factor for Y: a case control study", "What is the impact of factor X on subject Y: A systematic review"
• or for non-clinical or non-research studies a description of what the article reports
• if a collaboration group should be listed as an author, please list the Group name as an author. If you would like the names of the individual members of the Group to be searchable through their individual PubMed records, please include this information in the “Acknowledgements” section in accordance with the instructions below
• Large Language Models (LLMs), such as ChatGPT , do not currently satisfy our authorship criteria . Notably an attribution of authorship carries with it accountability for the work, which cannot be effectively applied to LLMs. Use of an LLM should be properly documented in the Methods section (and if a Methods section is not available, in a suitable alternative part) of the manuscript.
• indicate the corresponding author

The Abstract should not exceed 350 words. Please minimize the use of abbreviations and do not cite references in the abstract. Reports of randomized controlled trials should follow the CONSORT extension for abstracts. The abstract must include the following separate sections:

• Background: the context and purpose of the study
• Methods: how the study was performed and statistical tests used
• Results: the main findings
• Conclusions: brief summary and potential implications
• Trial registration: If your article reports the results of a health care intervention on human participants, it must be registered in an appropriate registry and the registration number and date of registration should be stated in this section. If it was not registered prospectively (before enrollment of the first participant), you should include the words 'retrospectively registered'. See our editorial policies for more information on trial registration

Three to ten keywords representing the main content of the article.

The Background section should explain the background to the study, its aims, a summary of the existing literature and why this study was necessary or its contribution to the field.

The methods section should include:

• the aim, design and setting of the study
• the characteristics of participants or description of materials
• a clear description of all processes, interventions and comparisons. Generic drug names should generally be used. When proprietary brands are used in research, include the brand names in parentheses
• the type of statistical analysis used, including a power calculation if appropriate

This should include the findings of the study including, if appropriate, results of statistical analysis which must be included either in the text or as tables and figures.

This section should discuss the implications of the findings in context of existing research and highlight limitations of the study.

Conclusions

This should state clearly the main conclusions and provide an explanation of the importance and relevance of the study reported.

List of abbreviations

If abbreviations are used in the text they should be defined in the text at first use, and a list of abbreviations should be provided.

Declarations

All manuscripts must contain the following sections under the heading 'Declarations':

Ethics approval and consent to participate

Consent for publication, availability of data and materials, competing interests, authors' contributions, acknowledgements.

• Authors' information (optional)

Please see below for details on the information to be included in these sections.

If any of the sections are not relevant to your manuscript, please include the heading and write 'Not applicable' for that section. 

Manuscripts reporting studies involving human participants, human data or human tissue must:

• include a statement on ethics approval and consent (even where the need for approval was waived)
• include the name of the ethics committee that approved the study and the committee’s reference number if appropriate

Studies involving animals must include a statement on ethics approval and for experimental studies involving client-owned animals, authors must also include a statement on informed consent from the client or owner.

See our editorial policies for more information.

If your manuscript does not report on or involve the use of any animal or human data or tissue, please state “Not applicable” in this section.

If your manuscript contains any individual person’s data in any form (including any individual details, images or videos), consent for publication must be obtained from that person, or in the case of children, their parent or legal guardian. All presentations of case reports must have consent for publication.

You can use your institutional consent form or our consent form if you prefer. You should not send the form to us on submission, but we may request to see a copy at any stage (including after publication).

See our editorial policies for more information on consent for publication.

If your manuscript does not contain data from any individual person, please state “Not applicable” in this section.

All manuscripts must include an ‘Availability of data and materials’ statement. Data availability statements should include information on where data supporting the results reported in the article can be found including, where applicable, hyperlinks to publicly archived datasets analysed or generated during the study. By data we mean the minimal dataset that would be necessary to interpret, replicate and build upon the findings reported in the article. We recognise it is not always possible to share research data publicly, for instance when individual privacy could be compromised, and in such instances data availability should still be stated in the manuscript along with any conditions for access.

Authors are also encouraged to preserve search strings on searchRxiv https://searchrxiv.org/ , an archive to support researchers to report, store and share their searches consistently and to enable them to review and re-use existing searches. searchRxiv enables researchers to obtain a digital object identifier (DOI) for their search, allowing it to be cited. 

Data availability statements can take one of the following forms (or a combination of more than one if required for multiple datasets):

• The datasets generated and/or analysed during the current study are available in the [NAME] repository, [PERSISTENT WEB LINK TO DATASETS]
• The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
• All data generated or analysed during this study are included in this published article [and its supplementary information files].
• The datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.
• Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
• The data that support the findings of this study are available from [third party name] but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of [third party name].
• Not applicable. If your manuscript does not contain any data, please state 'Not applicable' in this section.

More examples of template data availability statements, which include examples of openly available and restricted access datasets, are available here .

BioMed Central strongly encourages the citation of any publicly available data on which the conclusions of the paper rely in the manuscript. Data citations should include a persistent identifier (such as a DOI) and should ideally be included in the reference list. Citations of datasets, when they appear in the reference list, should include the minimum information recommended by DataCite and follow journal style. Dataset identifiers including DOIs should be expressed as full URLs. For example:

Hao Z, AghaKouchak A, Nakhjiri N, Farahmand A. Global integrated drought monitoring and prediction system (GIDMaPS) data sets. figshare. 2014. http://dx.doi.org/10.6084/m9.figshare.853801

With the corresponding text in the Availability of data and materials statement:

The datasets generated during and/or analysed during the current study are available in the [NAME] repository, [PERSISTENT WEB LINK TO DATASETS]. [Reference number]  

If you wish to co-submit a data note describing your data to be published in BMC Research Notes , you can do so by visiting our submission portal . Data notes support open data and help authors to comply with funder policies on data sharing. Co-published data notes will be linked to the research article the data support ( example ).

All financial and non-financial competing interests must be declared in this section.

See our editorial policies for a full explanation of competing interests. If you are unsure whether you or any of your co-authors have a competing interest please contact the editorial office.

Please use the authors initials to refer to each authors' competing interests in this section.

If you do not have any competing interests, please state "The authors declare that they have no competing interests" in this section.

All sources of funding for the research reported should be declared. If the funder has a specific role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript, this should be declared.

The individual contributions of authors to the manuscript should be specified in this section. Guidance and criteria for authorship can be found in our editorial policies .

Please use initials to refer to each author's contribution in this section, for example: "FC analyzed and interpreted the patient data regarding the hematological disease and the transplant. RH performed the histological examination of the kidney, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript."

Please acknowledge anyone who contributed towards the article who does not meet the criteria for authorship including anyone who provided professional writing services or materials.

Authors should obtain permission to acknowledge from all those mentioned in the Acknowledgements section.

See our editorial policies for a full explanation of acknowledgements and authorship criteria.

If you do not have anyone to acknowledge, please write "Not applicable" in this section.

Group authorship (for manuscripts involving a collaboration group): if you would like the names of the individual members of a collaboration Group to be searchable through their individual PubMed records, please ensure that the title of the collaboration Group is included on the title page and in the submission system and also include collaborating author names as the last paragraph of the “Acknowledgements” section. Please add authors in the format First Name, Middle initial(s) (optional), Last Name. You can add institution or country information for each author if you wish, but this should be consistent across all authors.

Please note that individual names may not be present in the PubMed record at the time a published article is initially included in PubMed as it takes PubMed additional time to code this information.

Authors' information

This section is optional.

You may choose to use this section to include any relevant information about the author(s) that may aid the reader's interpretation of the article, and understand the standpoint of the author(s). This may include details about the authors' qualifications, current positions they hold at institutions or societies, or any other relevant background information. Please refer to authors using their initials. Note this section should not be used to describe any competing interests.

Footnotes can be used to give additional information, which may include the citation of a reference included in the reference list. They should not consist solely of a reference citation, and they should never include the bibliographic details of a reference. They should also not contain any figures or tables.

Footnotes to the text are numbered consecutively; those to tables should be indicated by superscript lower-case letters (or asterisks for significance values and other statistical data). Footnotes to the title or the authors of the article are not given reference symbols.

Always use footnotes instead of endnotes.

Examples of the Vancouver reference style are shown below.

See our editorial policies for author guidance on good citation practice

Web links and URLs: All web links and URLs, including links to the authors' own websites, should be given a reference number and included in the reference list rather than within the text of the manuscript. They should be provided in full, including both the title of the site and the URL, as well as the date the site was accessed, in the following format: The Mouse Tumor Biology Database. http://tumor.informatics.jax.org/mtbwi/index.do . Accessed 20 May 2013. If an author or group of authors can clearly be associated with a web link, such as for weblogs, then they should be included in the reference.

Example reference style:

Article within a journal

Smith JJ. The world of science. Am J Sci. 1999;36:234-5.

Article within a journal (no page numbers)

Rohrmann S, Overvad K, Bueno-de-Mesquita HB, Jakobsen MU, Egeberg R, Tjønneland A, et al. Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition. BMC Medicine. 2013;11:63.

Article within a journal by DOI

Slifka MK, Whitton JL. Clinical implications of dysregulated cytokine production. Dig J Mol Med. 2000; doi:10.1007/s801090000086.

Article within a journal supplement

Frumin AM, Nussbaum J, Esposito M. Functional asplenia: demonstration of splenic activity by bone marrow scan. Blood 1979;59 Suppl 1:26-32.

Book chapter, or an article within a book

Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. In: Bourne GH, Danielli JF, Jeon KW, editors. International review of cytology. London: Academic; 1980. p. 251-306.

OnlineFirst chapter in a series (without a volume designation but with a DOI)

Saito Y, Hyuga H. Rate equation approaches to amplification of enantiomeric excess and chiral symmetry breaking. Top Curr Chem. 2007. doi:10.1007/128_2006_108.

Complete book, authored

Blenkinsopp A, Paxton P. Symptoms in the pharmacy: a guide to the management of common illness. 3rd ed. Oxford: Blackwell Science; 1998.

Online document

Doe J. Title of subordinate document. In: The dictionary of substances and their effects. Royal Society of Chemistry. 1999. http://www.rsc.org/dose/title of subordinate document. Accessed 15 Jan 1999.

Online database

Healthwise Knowledgebase. US Pharmacopeia, Rockville. 1998. http://www.healthwise.org. Accessed 21 Sept 1998.

Supplementary material/private homepage

Doe J. Title of supplementary material. 2000. http://www.privatehomepage.com. Accessed 22 Feb 2000.

University site

Doe, J: Title of preprint. http://www.uni-heidelberg.de/mydata.html (1999). Accessed 25 Dec 1999.

Doe, J: Trivial HTTP, RFC2169. ftp://ftp.isi.edu/in-notes/rfc2169.txt (1999). Accessed 12 Nov 1999.

Organization site

ISSN International Centre: The ISSN register. http://www.issn.org (2006). Accessed 20 Feb 2007.

Dataset with persistent identifier

Zheng L-Y, Guo X-S, He B, Sun L-J, Peng Y, Dong S-S, et al. Genome data from sweet and grain sorghum (Sorghum bicolor). GigaScience Database. 2011. http://dx.doi.org/10.5524/100012 .

Figures, tables and additional files

See  General formatting guidelines  for information on how to format figures, tables and additional files.

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Affiliated to the Institute of Clinical Physiology of the Italian National Research Council .

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Annual Journal Metrics

2022 Citation Impact 1.9 - 2-year Impact Factor 2.4 - 5-year Impact Factor 1.052 - SNIP (Source Normalized Impact per Paper) 0.562 - SJR (SCImago Journal Rank)

2023 Speed 11 days submission to first editorial decision for all manuscripts (Median) 115 days submission to accept (Median)

2023 Usage  560,342 downloads 303 Altmetric mentions 

• More about our metrics

Cardiovascular Ultrasound

ISSN: 1476-7120

• General enquiries: [email protected]

Abstracts and Awards – BCVS Scientific Sessions 2024

Abstract submission is now closed for #BCVS24.

To ensure that your abstract receives proper scientific consideration, be sure to submit to the appropriate category.

Abstract Submission

• Review Best Practices for Writing Abstracts on this page.
• All abstracts must be submitted (and if accepted, will be presented) in English, having accurate grammar and spelling suitable for publication.
• Statistical results (including descriptive and inferential statistics) are to be included.
• Author must affirm the work submitted is original and all statements declared as facts are based on thorough examination and investigation for accurateness.
• Authors should not "split" data to create several abstracts from one. If splitting is judged to have occurred, prior scores of related abstracts will be negatively influenced.
• Abstracts containing identical or nearly identical data submitted from the same institution and/or individuals will be disqualified.
• Proofread abstracts carefully to avoid errors before submission. The abstract will be published exactly as submitted.
• Submission of an abstract constitutes a commitment by the author(s) to present if accepted. Failure to present, if not justified, will jeopardize future acceptance of abstracts for American Heart Association meetings/conferences.
• There is no limit to the number of abstracts an investigator may submit. If selected, the presenter must be one of the co-authors listed. If multiple submissions are accepted, the presenting author must resolve schedule conflicts by arranging for a co-author to present.
• The work covered by the abstract must not have been presented at a national or international meeting before presentation at BCVS 2024, unless the submission includes incremental information from the abstract presented elsewhere to justify submission and presentation at the AHA. Each investigator will determine, in good conscience, what constitutes incremental information.
• Abstracts associated with a published manuscript can be presented at an AHA scientific event if the manuscript was published after the time the abstract was submitted to the event, however the abstract will not be published as a part of the journal publication.

Abstract Title

• An abstract must have a short, specific title (containing no abbreviations or inflammatory language) that indicates the nature of the investigation.
• Avoid an abstract title that reveals the results of the study. Explicit titles denoting the findings should be used (not “Investigations of…”, “Studies of…,” etc.)

Abstract Text

• Introduction/Background
• Research Questions/Hypothesis
• Methods/Approach
• Results/Data (descriptive and inferential statistics)
• Conclusion(s)
• Looking for recommendations on how to improve your abstract? We highly recommend you view these recommendations from AHA journals.
• Use generic drug names.
• Avoid beginning sentences with numbers.
• Standard abbreviations may be used without definition. Nonstandard abbreviations (kept to a minimum) must be placed in parentheses after the first use of the word or phrase abbreviated.
• Do not include references, credits or grant support.
• Do not include the names or personal information of any patient participating in the study or trial.

Abstract Character Guidelines

• Abstracts are limited to 1,950 characters (about 300-350 words).
• Spaces do not count as characters .
• Text in the abstract body
• Graphics – addition of an image, whether a figure or a table, deducts 250 characters.
• Title of abstract
• Names of authors
• Spaces in the abstract body
• Caption of graphic
• All graphics (figures) and text-based graphics (tables) should be provided as 72-300—dpi, pre-sized, .BMP, .GIF, .JPG or .PNG images only, with a maximum width of 440 pixels (no limit on length). Black-and-white digital images should be in grayscale mode. Color images should be saved in RGB mode.
• All graphics will require a brief description of the image.
• Please Note: If an abstract is accepted for publication, any images submitted with the abstract are placed after the abstract that will appear in the online-only supplement to Circulation Research , an American Heart Association journal.

Author Name(s)

• The submitting author will be designated as the primary and presenting author unless otherwise specified. The presenting author must be listed on the abstract and can be listed anywhere in the author block.
• Please review the author block carefully. Edits cannot be made after the March 13, 6:00 PM CDT/UTC-5 deadline. Once submission is complete, the author block will be published as submitted. Additions or deletions of author names are not permitted after the submission deadline.

Abstract Revisions

• Abstracts may not be revised in any way or resubmitted.
• Additions or deletions of author names will not be permitted.
• Proofread abstracts carefully to avoid errors before submission.

Abstract Copyright Transfer Agreement

• Your selection of “Yes” will grant permission to publish.
• Your selection of “No” will prohibit publication of the abstract in all formats including the Circulation Research supplement, ePoster site, and the online program planner.

Abstract Review

• Abstracts successfully submitted by the March 13, 2024, 6:00 pm CDT/UTC -5 deadline are posted to a secured web site for blind review. Our intent is to be inclusive of quality science received without compromising scientific integrity. As such, a team of experts, selected by the BCVS Program Committee, independently reviews abstracts in the category that best fits their expertise.
• Scientific merit - direction toward the development of a new or improved diagnostic procedure or idea.
• Organization - well organized, easy to follow and understand.
• Practicality - should be available, logical and feasible.
• Presentation - should be clear, brief, show understanding of the subject matter.
• Technical quality - the idea must stand up to scrutiny. Facts and data have scientific backing.

Abstract Acceptance

• Abstract acceptance/non-acceptance status will be available by mid-May. Please ensure the email provided for the presenting author is accurate as all correspondence will be sent via email, to the presenting author only.
• All communications regarding your abstract will be sent from [email protected] . . Please make sure to add this email address to your email contacts to ensure important program participant related information gets through your spam filters, etc.
• All accepted abstracts will be scheduled either in an oral or poster presentation format. All presentations including question-and-answers will be conducted in English. Presenters may request assistance from the moderator who will repeat or rephrase questions from the audience or may ask a colleague in the audience to assist with translation.
• Guidelines for abstract presentation will be included in the acceptance communication.

Abstract Journal Publication

• Accepted abstracts having selected “Yes” to the Abstract Copyright Transfer Agreement will be published online in the Circulation Research journal supplement.

Embargo Policy

• Non-late breaking abstracts and presentations are embargoed for release at date and time of presentation for oral abstract presentations; and July 22, 2024 at 8:00 am Central Time for all poster presentations, and are therefore prohibited from release until date and time of AHA designated embargo time. You will be contacted by AHA communications if you are selected to participate in an AHA news event. NOTE: If presenting an abstract at the Asian Cardiovascular Symposium held on Sunday, July 21, 2024, the embargo will be lifted on date/time of presentation for oral sessions and July 21, 2024, at 1:00p pm Central Time for poster presentations.
• Written embargoed information cannot be shared with anyone outside of the AHA with the exception of a journal manuscript where one-on-one embargoed media interviews can be conducted as long as the reporter agrees to abide by the embargo policy. Failure to honor embargo policies will result in this abstract being withdrawn and future abstracts also being barred from presentation. Complete AHA Embargo Policy .

Recording Policy

• Unauthorized recording of the AHA Scientific Sessions, scientific conferences, and the AHA/ASA International Stroke Conference is prohibited, whether by video, still or digital photography, audio or any other recording or reproduction mechanism. This includes recording of presentations and supporting audiovisual materials and of poster presentations and supporting poster materials.
• The American Heart Association and American Stroke Association reserve the rights to all recordings or reproductions of presentations at AHA/ASA scientific conferences and meetings.

Use of Automated Assistive Writing Technologies and Tools

• The use of automated assistive writing technologies and tools (commonly referred to as artificial intelligence or machine learning tools) is permitted provided that their use is documented, and authors assume responsibility for the content. As with human-generated content, authors are responsible for the accuracy, validity, and originality of computer-generated content. Automated assistive writing technologies do not qualify for authorship as they are unable to provide approval or consent for submission.
• If the use of these technologies has involved the research design, the tools should be documented in the Methods. For additional information, see the World Association of Medical Editor recommendations .
• For your abstract submission, you will need to indicate the use of these tools.

Cardiac Regeneration, Stem Cells and Tissue Engineering

Cardio-immunology and Inflammation

Cardio-oncology

Cardiovascular Technologies and Therapeutics **NEW**

Cell Death Mechanisms, Apoptosis, Necrosis and Autophagy

Clinical/Translational Research

COVID 19 in the Cardiovascular System

Excitation-Contraction Coupling, Ion Channels and Arrhythmias

Extracellular Vesicles and Exosome Biology

Genetics and Genomics of Cardiovascular Disease

Human Cellular Models of Disease

Inflammation, Thrombosis and Vascular Biology

Mechanisms of Cardiac Remodeling, Hypertrophy and Failure

Mechanisms of Heart Failure Preserved Ejection Fraction

Mechanisms of Myocardial Fibrosis

Mitochondria and Metabolism

Myocardial Ischemia, Oxidative Stress, and Cardioprotection

RNA and Cellular Regulation

Sarcomeric Function and Contractility

Sex-based Differences in Heart Disease

Signal Transduction Pathways

Systems Approach to Cardiovascular Biology

Transcriptional and Epigenetic Regulation of Gene Expression

Cardiovascular Development **NEW**

Interorgan Links in Cardiovascular Disease **NEW**

The suggestions below are intended to provide guidance on abstract writing.

Title To the extent the data permits, make the title dynamic and conclusive, rather than descriptive. For example, “Hypoxia Inhibits Kv1.5 Channels in Rat Pulmonary Artery Smooth Muscle Cells” is preferable to “Effects of Hypoxia on Kv1.5 Channels.” Explicit titles denoting the findings should be used (not “Investigations of…,” “Studies of…,” etc.)

Structure Abstracts may have the following identifiable sections, but they are not mandatory: Introduction, Hypothesis, Methods, Results and Conclusions.

Abbreviations Abbreviations may be used after they are spelled out or defined. Use generic, not commercial, names for all therapeutic agents.

Category Be sure to select up to three abstract categories that best describes your work. Category selection determines which team grades the abstract. If you select the appropriate category, your abstract will be blindly graded by experts familiar with the science of the category.

Common mistakes

• Failure to state the hypothesis. We advise a formal statement such as, “We assessed the hypothesis that…”
• Failure to state a conclusion. We encourage a final sentence that says: “In conclusion…”
• Failure to state sample size. The reviewers want to assess the quality of the data – they need a mean SEM and a sample size.
• Excessive use of abbreviations. All but the most standard abbreviations should be defined, and most abstracts should have less than 3 abbreviations.

Traps to avoid

• Typographical errors
• References cited in the abstract
• Not providing context or a statement of relevance that provides the rationale for your study.
• Complex graphics. Simple line or bar graphs are most appropriate. Ensure the font size is adequately large on each axis to be visible. Check a printed version of the abstract before submitting.
• Duplicative work

Remember: Make sure your abstract is clear, concise, and follows all rules. Show your abstract to a colleague prior to submission and modify accordingly. A fresh pair of eyes will help spot any errors and will ensure the final package is ready for submission.

Apply for BCVS 2024 Awards

• BCVS Cardiovascular Outreach Award
• BCVS Outstanding Early Career Award
• BCVS New Investigator Travel Award

Important Message to Abstract Submitters

The AHA has moved to a single sign-on process for submitting abstracts and disclosures through our website, Professional Heart Daily .

• Abstract submitters must have a username and password on Professional Heart Daily to complete their abstract submission when submitting to any AHA scientific meeting.
• If you do not remember your Professional Heart Daily login information or need to update your personal profile, do not create a new account. Please reach out to AHA Customer Service for assistance: AHA Customer Service: 1-888-242-2453 (Inside U.S.) 1-214-570-5935 (Outside U.S.) Email: [email protected] Hours of Operation: Monday-Friday (8 a.m. – 5 p.m.) CT Hours of Operation: Monday-Friday, 8 a.m. – 5 p.m. CT
• As the submitting author, please be prepared to provide all co-author emails.
• Co-authors without a complete disclosure will receive separate correspondence to submit this information.

Submission guidelines

Article types, online submission guidelines, graphical abstracts, scientific style, artwork and illustrations guidelines, supplementary information (si), ethical responsibilities of authors, authorship principles, compliance with ethical standards, disclosure of potential conflicts of interest, research involving human participants, their data or biological material, informed consent, editing services, research data policy and data availability statements, after acceptance.

Open Choice

Open access publishing

• Mistakes to avoid during manuscript preparation

Instructions for Authors

Review – limited to 6000 words and 6 figures.

Original Article – original research limited to 6000 words and 6 figures.

Short Communication – limited to 800 words, 1 figure and 5 references, no abstract, no extensive author list with detailed affiliations.

Methods Articles – limited to 6000 words and 6 figures

Letter to the Editor – Opinion pieces. Criterion includes interest in the field, and providing sufficient evidence to support.

Case Study – the Journal does not accept Case Studies.

Editorial Note – limited to 1 ½ pages or less, 1 figure and 5 references, no abstract, no extensive author list with detailed affiliations. Editorial Notes comment on one or more articles in the same issue of the Journal.

1. Manuscript Submission

• Submission of a manuscript implies that the work described has not been published before; that it is not under consideration for publication anywhere else; that its publication has been approved by all co-authors, if any, as well as by the responsible authorities – tacitly or explicitly – at the institute where the work has been carried out. The publisher will not be held legally responsible should there be any claims for compensation.

• Authors wishing to include figures, tables, or text passages that have already been published elsewhere are required to obtain permission from the copyright owner(s) for both the print and online format and to include evidence that such permission has been granted when submitting their papers. Any material received without such evidence will be assumed to originate from the authors.

• Authors are required to submit manuscripts online. Please follow the hyperlink “Submit online” on the right and upload all of your manuscript files following the instructions given on the screen.

• Authors are required to submit a cover letter stating the novelty of the work as well as the work has not been published before and is not being considered for publication elsewhere.

• Upload all information as supplemental files that is in preparation, or submitted, or is in press, or any abstracts related to the work.

• Organize manuscripts in this order:

o Title Page should include: Title, lead author’s first & last name, short title (50 characters including spaces), total word count of manuscript (includes references, figures, and tables), and corresponding author’s name, phone, and email. Please also include full names, academic/medical degrees and affiliations of all authors including lead and corresponding authors.

o Abbreviations

o Abstract (150 words or less), do not cite references in the abstract.

o Key words (10 or less)

o Introduction

o Discussion

o Acknowledgments

o Sources of Funding

o Disclosures

o Human subjects/informed consent statement

o If the authors did not carry out human studies they must state “No human studies were carried out by the authors for this article” in the manuscript immediately before the References section.

o If the authors did carry out human studies they must state something similar to, “All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.” immediately before the References section.

o Any experimental protocol must be approved, and owing to US regulations (the recent Health Insurance Portability and Accountability Act - HIPAA) even studies without any experimental protocol merely reporting patients or patient material require approval; these regulations require review for any studies involving patient identity, including retrospective chart, radiographic reviews, or removed tissues or materials.

o If any identifying information about patients is included in the article, the following sentence must also be included, “Additional informed consent was obtained from all patients for whom identifying information is included in this article.”

o Animal Studies

o If the authors did not carry out animal studies as part of their article they must include this statement, No animal studies were carried out by the authors for this article.” in the manuscript immediately before the References section.

o If the authors did use studies involving animals a statement indicating that the work was conducted with the approval and in accordance with the guidelines of the institution(s) where it was performed is needed. A statement to this effect must be included in the manuscript immediately before the References section. The following is recommended sample text, “All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

o The editors reserve the right to reject manuscripts that do not comply with the above-mentioned requirements. The author will be held responsible for false statements or failure to fulfill the above-mentioned requirements.

• Sources of Funding need to be stated after the human and animal subject statement and should include all sources of research support, including public and private entities, commercial or institutional support, and any substantial contributions by individuals.

• All grant funding agency abbreviations should be completely spelled out.

• References

• References are included in the word count.

• The list of references should only include works that are cited in the text and that have been published or accepted for publication.

• Personal communications need an accompanying letter verifying the personal communication.

• Do not use footnotes or endnotes as a substitute for a reference list.

• The entries in the list should be numbered consecutively.

• Journal article: Gamelin FX, Baquet G, Berthoin S, Thevenet D, Nourry C, Nottin S, Bosquet L (2009) Effect of high intensity intermittent training on heart rate variability in prepubescent children. Eur J Appl Physiol 105:731-738. doi: 10.1007/s00421-008-0955-8

• Ideally, the names of all authors should be provided, but the usage of “et al” in long author lists will also be accepted: Smith J, Jones M Jr, Houghton L et al (1999) Future of health insurance. N Engl J Med 965:325–329

• Article by DOI: Slifka MK, Whitton JL (2000) Clinical implications of dysregulated cytokine production. J Mol Med. doi:10.1007/s001090000086

• Book: South J, Blass B (2001) The future of modern genomics. Blackwell, London

• Book chapter: Brown B, Aaron M (2001) The politics of nature. In: Smith J (ed) The rise of modern genomics, 3rd edn. Wiley, New York, pp 230-257

• Online document: Cartwright J (2007) Big stars have weather too. IOP Publishing PhysicsWeb. http://physicsweb.org/articles/news/11/6/16/1. Accessed 26 June 2007

• Dissertation: Trent JW (1975) Experimental acute renal failure. Dissertation, University of California

• Always use the standard abbreviation of a journal’s name according to the ISSN List of Title Word Abbreviations, see

• www.issn.org/2-22661-LTWA-online.php

• For authors using EndNote, Springer provides an output style that supports the formatting of in-text citations and reference list.

• EndNote style (zip, 2 kB)

• Authors preparing their manuscript in LaTeX can use the bibtex file spbasic.bst which is included in Springer’s LaTeX macro package

• All tables are to be numbered using Arabic numerals.

• Tables should always be cited in text in consecutive numerical order.

• For each table, please supply a table caption (title) explaining the components of the table.

• Identify any previously published material by giving the original source in the form of a reference at the end of the table caption.

• Footnotes to tables should be indicated by superscript lower-case letters (or asterisks for significance values and other statistical data) and included beneath the table body

• Electronic Figures with Figure Legends

• All figures are to be numbered using Arabic numerals.

• Figures should always be cited in text in consecutive numerical order.

• Figure parts should be denoted by lowercase letters (a, b, c, etc.)

• If any magnification is used in the photographs, indicate this by using scale bars within the figures themselves.

• Color art is free of charge for online publication.

• If black and white will be shown in the print version, make sure that the main information will still be visible. If the figures will be printed in black and white, do not refer to color in the captions.

• Color illustrations should be submitted as RGB (8 bits per channel).

• Each figure should have a concise caption describing accurately what the figure depicts. Include the captions in the text file of the manuscript, not in the figure file.

• Figure captions begin with the term Fig. In bold type, followed by the figure number, also in bold type.

• No punctuation is to be included after the number, nor is any punctuation to be placed at the end of the caption.

• Identify all elements found in the figure in the figure caption; and use boxes, circles, etc., as coordinate points in graphs.

• Identify previously published material by giving the original source in the form of a reference citation at the end of the figure caption.

• If you include figures that have already been published elsewhere, you must obtain permission from the copyright owner(s) for both the print and online format. Please be aware that some publishers do not grant electronic rights for free and that Springer will not be able to refund any costs that may have occurred to receive these permissions. In such cases, material from other sources should be used.

Online abstract of published article requires an accompanying graphic (graphical abstract) that will be visible to all readers of the online edition. Therefore, if your manuscript has an abstract, we ask you to kindly submit an attractive, eye-catching image for the graphical online abstract. This image should be colored and must be submitted in a separate file, preferably in one of the following formats: jpeg, png, svg, tiff, bmp, doc, ppt (acceptable size: 920x300px, 150KB max).

Please label the figure ‘Online Abstract Figure’. The file designation is ‘figure’. Please make sure that you are the owner of the copyright or have the permission to reprint the image.

A short sentence is also required (140-200 characters) that summarizes the key message of the article, to be used as a legend for the graphical abstract.

Professionally produced Visual Abstracts

Springer Nature provide a service to produce high quality and affordable visual abstracts. Click here[ https://solutions.springernature.com/discount/JCTRTWENTY?redirect=%2Fproducts%2Fvisual-abstract ] to find out more about the service. As an author submitting to the Journal of Cardiovascular Translational Research you are entitled to a 20% discount on this service, which will automatically be applied at checkout when using the link above.

• Please always use internationally accepted signs and symbols for units ( SI units ).

Reference citations in the text should be identified by numbers in square brackets. Some examples:

1. Negotiation research spans many disciplines [3].

2. This result was later contradicted by Becker and Seligman [5].

3. This effect has been widely studied [1-3, 7].

Reference list

The list of references should only include works that are cited in the text and that have been published or accepted for publication. Personal communications and unpublished works should only be mentioned in the text.

The entries in the list should be numbered consecutively.

If available, please always include DOIs as full DOI links in your reference list (e.g. “https://doi.org/abc”).

Smith JJ. The world of science. Am J Sci. 1999;36:234–5.

Slifka MK, Whitton JL. Clinical implications of dysregulated cytokine production. J Mol Med. 2000; https://doi.org/10.1007/s001090000086

Blenkinsopp A, Paxton P. Symptoms in the pharmacy: a guide to the management of common illness. 3rd ed. Oxford: Blackwell Science; 1998.

Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. In: Bourne GH, Danielli JF, Jeon KW, editors. International review of cytology. London: Academic; 1980. pp. 251–306.

Doe J. Title of subordinate document. In: The dictionary of substances and their effects. Royal Society of Chemistry. 1999. http://www.rsc.org/dose/title of subordinate document. Accessed 15 Jan 1999.

Always use the standard abbreviation of a journal’s name according to the ISSN List of Title Word Abbreviations, see

ISSN.org LTWA

If you are unsure, please use the full journal title.

• All tables are to be numbered using Arabic numerals.
• Tables should always be cited in text in consecutive numerical order.
• For each table, please supply a table caption (title) explaining the components of the table.
• Identify any previously published material by giving the original source in the form of a reference at the end of the table caption.
• Footnotes to tables should be indicated by superscript lower-case letters (or asterisks for significance values and other statistical data) and included beneath the table body.

Electronic Figure Submission

• Supply all figures electronically.
• Indicate what graphics program was used to create the artwork.
• For vector graphics, the preferred format is EPS; for halftones, please use TIFF format. MSOffice files are also acceptable.
• Vector graphics containing fonts must have the fonts embedded in the files.
• Name your figure files with "Fig" and the figure number, e.g., Fig1.eps.
• Definition: Black and white graphic with no shading.
• Do not use faint lines and/or lettering and check that all lines and lettering within the figures are legible at final size.
• All lines should be at least 0.1 mm (0.3 pt) wide.
• Scanned line drawings and line drawings in bitmap format should have a minimum resolution of 1200 dpi.

Halftone Art

• Definition: Photographs, drawings, or paintings with fine shading, etc.
• If any magnification is used in the photographs, indicate this by using scale bars within the figures themselves.
• Halftones should have a minimum resolution of 300 dpi.

Combination Art

• Definition: a combination of halftone and line art, e.g., halftones containing line drawing, extensive lettering, color diagrams, etc.
• Combination artwork should have a minimum resolution of 600 dpi.
• Color art is free of charge for online publication.
• If black and white will be shown in the print version, make sure that the main information will still be visible. Many colors are not distinguishable from one another when converted to black and white. A simple way to check this is to make a xerographic copy to see if the necessary distinctions between the different colors are still apparent.
• If the figures will be printed in black and white, do not refer to color in the captions.
• Color illustrations should be submitted as RGB (8 bits per channel).

Figure Lettering

• To add lettering, it is best to use Helvetica or Arial (sans serif fonts).
• Keep lettering consistently sized throughout your final-sized artwork, usually about 2–3 mm (8–12 pt).
• Variance of type size within an illustration should be minimal, e.g., do not use 8-pt type on an axis and 20-pt type for the axis label.
• Avoid effects such as shading, outline letters, etc.
• Do not include titles or captions within your illustrations.

Figure Numbering

• All figures are to be numbered using Arabic numerals.
• Figures should always be cited in text in consecutive numerical order.
• Figure parts should be denoted by lowercase letters (a, b, c, etc.).
• If an appendix appears in your article and it contains one or more figures, continue the consecutive numbering of the main text. Do not number the appendix figures,"A1, A2, A3, etc." Figures in online appendices [Supplementary Information (SI)] should, however, be numbered separately.

Figure Captions

• Each figure should have a concise caption describing accurately what the figure depicts. Include the captions in the text file of the manuscript, not in the figure file.
• Figure captions begin with the term Fig. in bold type, followed by the figure number, also in bold type.
• No punctuation is to be included after the number, nor is any punctuation to be placed at the end of the caption.
• Identify all elements found in the figure in the figure caption; and use boxes, circles, etc., as coordinate points in graphs.
• Identify previously published material by giving the original source in the form of a reference citation at the end of the figure caption.

Figure Placement and Size

• Figures should be submitted within the body of the text. Only if the file size of the manuscript causes problems in uploading it, the large figures should be submitted separately from the text.
• When preparing your figures, size figures to fit in the column width.
• For large-sized journals the figures should be 84 mm (for double-column text areas), or 174 mm (for single-column text areas) wide and not higher than 234 mm.
• For small-sized journals, the figures should be 119 mm wide and not higher than 195 mm.

Permissions

If you include figures that have already been published elsewhere, you must obtain permission from the copyright owner(s) for both the print and online format. Please be aware that some publishers do not grant electronic rights for free and that Springer will not be able to refund any costs that may have occurred to receive these permissions. In such cases, material from other sources should be used.

Accessibility

In order to give people of all abilities and disabilities access to the content of your figures, please make sure that

• All figures have descriptive captions (blind users could then use a text-to-speech software or a text-to-Braille hardware)
• Patterns are used instead of or in addition to colors for conveying information (colorblind users would then be able to distinguish the visual elements)
• Any figure lettering has a contrast ratio of at least 4.5:1

Generative AI Images

Please check Springer’s policy on generative AI images and make sure your work adheres to the principles described therein.

Springer accepts electronic multimedia files (animations, movies, audio, etc.) and other supplementary files to be published online along with an article or a book chapter. This feature can add dimension to the author's article, as certain information cannot be printed or is more convenient in electronic form.

Before submitting research datasets as Supplementary Information, authors should read the journal’s Research data policy. We encourage research data to be archived in data repositories wherever possible.

• Supply all supplementary material in standard file formats.
• Please include in each file the following information: article title, journal name, author names; affiliation and e-mail address of the corresponding author.
• To accommodate user downloads, please keep in mind that larger-sized files may require very long download times and that some users may experience other problems during downloading.
• High resolution (streamable quality) videos can be submitted up to a maximum of 25GB; low resolution videos should not be larger than 5GB.

Audio, Video, and Animations

• Aspect ratio: 16:9 or 4:3
• Maximum file size: 25 GB for high resolution files; 5 GB for low resolution files
• Minimum video duration: 1 sec
• Supported file formats: avi, wmv, mp4, mov, m2p, mp2, mpg, mpeg, flv, mxf, mts, m4v, 3gp

Text and Presentations

• Submit your material in PDF format; .doc or .ppt files are not suitable for long-term viability.
• A collection of figures may also be combined in a PDF file.

Spreadsheets

• Spreadsheets should be submitted as .csv or .xlsx files (MS Excel).

Specialized Formats

• Specialized format such as .pdb (chemical), .wrl (VRML), .nb (Mathematica notebook), and .tex can also be supplied.

Collecting Multiple Files

• It is possible to collect multiple files in a .zip or .gz file.
• If supplying any supplementary material, the text must make specific mention of the material as a citation, similar to that of figures and tables.
• Refer to the supplementary files as “Online Resource”, e.g., "... as shown in the animation (Online Resource 3)", “... additional data are given in Online Resource 4”.
• Name the files consecutively, e.g. “ESM_3.mpg”, “ESM_4.pdf”.
• For each supplementary material, please supply a concise caption describing the content of the file.

Processing of supplementary files

• Supplementary Information (SI) will be published as received from the author without any conversion, editing, or reformatting.

In order to give people of all abilities and disabilities access to the content of your supplementary files, please make sure that

• The manuscript contains a descriptive caption for each supplementary material
• Video files do not contain anything that flashes more than three times per second (so that users prone to seizures caused by such effects are not put at risk)

This journal is committed to upholding the integrity of the scientific record. As a member of the Committee on Publication Ethics ( COPE ) the journal will follow the COPE guidelines on how to deal with potential acts of misconduct.

Authors should refrain from misrepresenting research results which could damage the trust in the journal, the professionalism of scientific authorship, and ultimately the entire scientific endeavour. Maintaining integrity of the research and its presentation is helped by following the rules of good scientific practice, which include*:

• The manuscript should not be submitted to more than one journal for simultaneous consideration.
• The submitted work should be original and should not have been published elsewhere in any form or language (partially or in full), unless the new work concerns an expansion of previous work. (Please provide transparency on the re-use of material to avoid the concerns about text-recycling (‘self-plagiarism’).
• A single study should not be split up into several parts to increase the quantity of submissions and submitted to various journals or to one journal over time (i.e. ‘salami-slicing/publishing’).
• Concurrent or secondary publication is sometimes justifiable, provided certain conditions are met. Examples include: translations or a manuscript that is intended for a different group of readers.
• Results should be presented clearly, honestly, and without fabrication, falsification or inappropriate data manipulation (including image based manipulation). Authors should adhere to discipline-specific rules for acquiring, selecting and processing data.
• No data, text, or theories by others are presented as if they were the author’s own (‘plagiarism’). Proper acknowledgements to other works must be given (this includes material that is closely copied (near verbatim), summarized and/or paraphrased), quotation marks (to indicate words taken from another source) are used for verbatim copying of material, and permissions secured for material that is copyrighted.

Important note: the journal may use software to screen for plagiarism.

• Authors should make sure they have permissions for the use of software, questionnaires/(web) surveys and scales in their studies (if appropriate).
• Research articles and non-research articles (e.g. Opinion, Review, and Commentary articles) must cite appropriate and relevant literature in support of the claims made. Excessive and inappropriate self-citation or coordinated efforts among several authors to collectively self-cite is strongly discouraged.
• Authors should avoid untrue statements about an entity (who can be an individual person or a company) or descriptions of their behavior or actions that could potentially be seen as personal attacks or allegations about that person.
• Research that may be misapplied to pose a threat to public health or national security should be clearly identified in the manuscript (e.g. dual use of research). Examples include creation of harmful consequences of biological agents or toxins, disruption of immunity of vaccines, unusual hazards in the use of chemicals, weaponization of research/technology (amongst others).
• Authors are strongly advised to ensure the author group, the Corresponding Author, and the order of authors are all correct at submission. Adding and/or deleting authors during the revision stages is generally not permitted, but in some cases may be warranted. Reasons for changes in authorship should be explained in detail. Please note that changes to authorship cannot be made after acceptance of a manuscript.

*All of the above are guidelines and authors need to make sure to respect third parties rights such as copyright and/or moral rights.

Upon request authors should be prepared to send relevant documentation or data in order to verify the validity of the results presented. This could be in the form of raw data, samples, records, etc. Sensitive information in the form of confidential or proprietary data is excluded.

If there is suspicion of misbehavior or alleged fraud the Journal and/or Publisher will carry out an investigation following COPE guidelines. If, after investigation, there are valid concerns, the author(s) concerned will be contacted under their given e-mail address and given an opportunity to address the issue. Depending on the situation, this may result in the Journal’s and/or Publisher’s implementation of the following measures, including, but not limited to:

• If the manuscript is still under consideration, it may be rejected and returned to the author.

- an erratum/correction may be placed with the article

- an expression of concern may be placed with the article

- or in severe cases retraction of the article may occur.

The reason will be given in the published erratum/correction, expression of concern or retraction note. Please note that retraction means that the article is maintained on the platform , watermarked “retracted” and the explanation for the retraction is provided in a note linked to the watermarked article.

• The author’s institution may be informed
• A notice of suspected transgression of ethical standards in the peer review system may be included as part of the author’s and article’s bibliographic record.

Fundamental errors

Authors have an obligation to correct mistakes once they discover a significant error or inaccuracy in their published article. The author(s) is/are requested to contact the journal and explain in what sense the error is impacting the article. A decision on how to correct the literature will depend on the nature of the error. This may be a correction or retraction. The retraction note should provide transparency which parts of the article are impacted by the error.

Suggesting / excluding reviewers

Authors are welcome to suggest suitable reviewers and/or request the exclusion of certain individuals when they submit their manuscripts. When suggesting reviewers, authors should make sure they are totally independent and not connected to the work in any way. It is strongly recommended to suggest a mix of reviewers from different countries and different institutions. When suggesting reviewers, the Corresponding Author must provide an institutional email address for each suggested reviewer, or, if this is not possible to include other means of verifying the identity such as a link to a personal homepage, a link to the publication record or a researcher or author ID in the submission letter. Please note that the Journal may not use the suggestions, but suggestions are appreciated and may help facilitate the peer review process.

These guidelines describe authorship principles and good authorship practices to which prospective authors should adhere to.

Authorship clarified

The Journal and Publisher assume all authors agreed with the content and that all gave explicit consent to submit and that they obtained consent from the responsible authorities at the institute/organization where the work has been carried out, before the work is submitted.

The Publisher does not prescribe the kinds of contributions that warrant authorship. It is recommended that authors adhere to the guidelines for authorship that are applicable in their specific research field. In absence of specific guidelines it is recommended to adhere to the following guidelines*:

All authors whose names appear on the submission

1) made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;

2) drafted the work or revised it critically for important intellectual content;

3) approved the version to be published; and

4) agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

* Based on/adapted from:

ICMJE, Defining the Role of Authors and Contributors,

Transparency in authors’ contributions and responsibilities to promote integrity in scientific publication, McNutt at all, PNAS February 27, 2018

Disclosures and declarations

All authors are requested to include information regarding sources of funding, financial or non-financial interests, study-specific approval by the appropriate ethics committee for research involving humans and/or animals, informed consent if the research involved human participants, and a statement on welfare of animals if the research involved animals (as appropriate).

The decision whether such information should be included is not only dependent on the scope of the journal, but also the scope of the article. Work submitted for publication may have implications for public health or general welfare and in those cases it is the responsibility of all authors to include the appropriate disclosures and declarations.

Data transparency

All authors are requested to make sure that all data and materials as well as software application or custom code support their published claims and comply with field standards. Please note that journals may have individual policies on (sharing) research data in concordance with disciplinary norms and expectations.

Role of the Corresponding Author

One author is assigned as Corresponding Author and acts on behalf of all co-authors and ensures that questions related to the accuracy or integrity of any part of the work are appropriately addressed.

The Corresponding Author is responsible for the following requirements:

• ensuring that all listed authors have approved the manuscript before submission, including the names and order of authors;
• managing all communication between the Journal and all co-authors, before and after publication;*
• providing transparency on re-use of material and mention any unpublished material (for example manuscripts in press) included in the manuscript in a cover letter to the Editor;
• making sure disclosures, declarations and transparency on data statements from all authors are included in the manuscript as appropriate (see above).

* The requirement of managing all communication between the journal and all co-authors during submission and proofing may be delegated to a Contact or Submitting Author. In this case please make sure the Corresponding Author is clearly indicated in the manuscript.

Author contributions

In absence of specific instructions and in research fields where it is possible to describe discrete efforts, the Publisher recommends authors to include contribution statements in the work that specifies the contribution of every author in order to promote transparency. These contributions should be listed at the separate title page.

Examples of such statement(s) are shown below:

• Free text:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [full name], [full name] and [full name]. The first draft of the manuscript was written by [full name] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Example: CRediT taxonomy:

• Conceptualization: [full name], …; Methodology: [full name], …; Formal analysis and investigation: [full name], …; Writing - original draft preparation: [full name, …]; Writing - review and editing: [full name], …; Funding acquisition: [full name], …; Resources: [full name], …; Supervision: [full name],….

For review articles where discrete statements are less applicable a statement should be included who had the idea for the article, who performed the literature search and data analysis, and who drafted and/or critically revised the work.

For articles that are based primarily on the student’s dissertation or thesis , it is recommended that the student is usually listed as principal author:

A Graduate Student’s Guide to Determining Authorship Credit and Authorship Order, APA Science Student Council 2006

Affiliation

The primary affiliation for each author should be the institution where the majority of their work was done. If an author has subsequently moved, the current address may additionally be stated. Addresses will not be updated or changed after publication of the article.

Changes to authorship

Authors are strongly advised to ensure the correct author group, the Corresponding Author, and the order of authors at submission. Changes of authorship by adding or deleting authors, and/or changes in Corresponding Author, and/or changes in the sequence of authors are not accepted after acceptance of a manuscript.

• Please note that author names will be published exactly as they appear on the accepted submission!

Please make sure that the names of all authors are present and correctly spelled, and that addresses and affiliations are current.

Adding and/or deleting authors at revision stage are generally not permitted, but in some cases it may be warranted. Reasons for these changes in authorship should be explained. Approval of the change during revision is at the discretion of the Editor-in-Chief. Please note that journals may have individual policies on adding and/or deleting authors during revision stage.

Author identification

Authors are recommended to use their ORCID ID when submitting an article for consideration or acquire an ORCID ID via the submission process.

Deceased or incapacitated authors

For cases in which a co-author dies or is incapacitated during the writing, submission, or peer-review process, and the co-authors feel it is appropriate to include the author, co-authors should obtain approval from a (legal) representative which could be a direct relative.

Authorship issues or disputes

In the case of an authorship dispute during peer review or after acceptance and publication, the Journal will not be in a position to investigate or adjudicate. Authors will be asked to resolve the dispute themselves. If they are unable the Journal reserves the right to withdraw a manuscript from the editorial process or in case of a published paper raise the issue with the authors’ institution(s) and abide by its guidelines.

Confidentiality

Authors should treat all communication with the Journal as confidential which includes correspondence with direct representatives from the Journal such as Editors-in-Chief and/or Handling Editors and reviewers’ reports unless explicit consent has been received to share information.

To ensure objectivity and transparency in research and to ensure that accepted principles of ethical and professional conduct have been followed, authors should include information regarding sources of funding, potential conflicts of interest (financial or non-financial), informed consent if the research involved human participants, and a statement on welfare of animals if the research involved animals.

Authors should include the following statements (if applicable) in a separate section entitled “Compliance with Ethical Standards” when submitting a paper:

• Research involving Human Participants and/or Animals

Please note that standards could vary slightly per journal dependent on their peer review policies (i.e. single or double blind peer review) as well as per journal subject discipline. Before submitting your article check the instructions following this section carefully.

The corresponding author should be prepared to collect documentation of compliance with ethical standards and send if requested during peer review or after publication.

The Editors reserve the right to reject manuscripts that do not comply with the above-mentioned guidelines. The author will be held responsible for false statements or failure to fulfill the above-mentioned guidelines.

Authors must disclose all relationships or interests that could have direct or potential influence or impart bias on the work. Although an author may not feel there is any conflict, disclosure of relationships and interests provides a more complete and transparent process, leading to an accurate and objective assessment of the work. Awareness of a real or perceived conflicts of interest is a perspective to which the readers are entitled. This is not meant to imply that a financial relationship with an organization that sponsored the research or compensation received for consultancy work is inappropriate. Examples of potential conflicts of interests that are directly or indirectly related to the research may include but are not limited to the following:

• Research grants from funding agencies (please give the research funder and the grant number)
• Honoraria for speaking at symposia
• Financial support for attending symposia
• Financial support for educational programs
• Employment or consultation
• Support from a project sponsor
• Position on advisory board or board of directors or other type of management relationships
• Multiple affiliations
• Financial relationships, for example equity ownership or investment interest
• Intellectual property rights (e.g. patents, copyrights and royalties from such rights)
• Holdings of spouse and/or children that may have financial interest in the work

In addition, interests that go beyond financial interests and compensation (non-financial interests) that may be important to readers should be disclosed. These may include but are not limited to personal relationships or competing interests directly or indirectly tied to this research, or professional interests or personal beliefs that may influence your research.

The corresponding author collects the conflict of interest disclosure forms from all authors. In author collaborations where formal agreements for representation allow it, it is sufficient for the corresponding author to sign the disclosure form on behalf of all authors. Examples of forms can be found

The corresponding author will include a summary statement in the text of the manuscript in a separate section before the reference list, that reflects what is recorded in the potential conflict of interest disclosure form(s).

Please make sure to submit all Conflict of Interest disclosure forms together with the manuscript.

See below examples of disclosures:

Funding: This study was funded by X (grant number X).

Conflict of Interest: Author A has received research grants from Company A. Author B has received a speaker honorarium from Company X and owns stock in Company Y. Author C is a member of committee Z.

If no conflict exists, the authors should state:

Conflict of Interest: The authors declare that they have no conflict of interest.

Ethics approval

When reporting a study that involved human participants, their data or biological material, authors should include a statement that confirms that the study was approved (or granted exemption) by the appropriate institutional and/or national research ethics committee (including the name of the ethics committee) and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. If doubt exists whether the research was conducted in accordance with the 1964 Helsinki Declaration or comparable standards, the authors must explain the reasons for their approach, and demonstrate that an independent ethics committee or institutional review board explicitly approved the doubtful aspects of the study. If a study was granted exemption from requiring ethics approval, this should also be detailed in the manuscript (including the reasons for the exemption).

Retrospective ethics approval

If a study has not been granted ethics committee approval prior to commencing, retrospective ethics approval usually cannot be obtained and it may not be possible to consider the manuscript for peer review. The decision on whether to proceed to peer review in such cases is at the Editor's discretion.

Ethics approval for retrospective studies

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• Review Article
• Published: 21 May 2024

The pig as an optimal animal model for cardiovascular research

• Hao Jia   ORCID: orcid.org/0000-0002-4736-0957 1   na1 ,
• Yuan Chang   ORCID: orcid.org/0000-0002-0966-7966 1   na1 &
• Jiangping Song   ORCID: orcid.org/0000-0002-9782-3323 1 , 2  

Lab Animal volume  53 ,  pages 136–147 ( 2024 ) Cite this article

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• Cardiovascular models
• Genetic engineering

Cardiovascular disease is a worldwide health problem and a leading cause of morbidity and mortality. Preclinical cardiovascular research using animals is needed to explore potential targets and therapeutic options. Compared with rodents, pigs have many advantages, with their anatomy, physiology, metabolism and immune system being more similar to humans. Here we present an overview of the available pig models for cardiovascular diseases, discuss their advantages over other models and propose the concept of standardized models to improve translation to the clinical setting and control research costs.

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Acknowledgements

This work was supported by the National Natural Science Fund for Distinguished Young Scholars of China (82125004; to J.S.) and the Frontier Biotechnology Key Project of National Key R & D Program of the Ministry of Science and Technology of China (2023YFC3404300; to J.S.).

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These authors contributed equally: Hao Jia, Yuan Chang.

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Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, National Centre for Cardiovascular Disease, Department of Cardiac Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Hao Jia, Yuan Chang & Jiangping Song

Sanya Institute of China Agricultural University, Sanya, China

Jiangping Song

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Jia, H., Chang, Y. & Song, J. The pig as an optimal animal model for cardiovascular research. Lab Anim 53 , 136–147 (2024). https://doi.org/10.1038/s41684-024-01377-4

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The year in cardiovascular medicine 2022: the top 10 papers in heart failure and cardiomyopathies

Rudolf a de boer.

Department of Cardiology, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands

Johann Bauersachs

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany

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Graphical Abstract

Panel A. Primary endpoint of DELIVER [cardiovascular (CV) death or heart failure (HF) hospitalization] in the entire population (left) and in the population with LVEF <60%. Reprinted with permission. 2 Panel B. A pooled analysis of patients enrolled in the DAPA-HF and DELIVER trials reveals a consistent benefit of dapagliflozin on the primary endpoint (CV death or HF hospitalization) across the entire spectrum of LVEF, with no signs of attenuation of the effect in the higher LVEF range. Reprinted with permission. 3 Panel C. Effect of acetazolamide on congestion in the ADVOR trial. From Day 1 onwards, the use of acetazolamide on top of regular loop diuretics resulted in accelerated decongestion. Reprinted with permission. 6 Panel D. Kaplan–Meier estimates of all-cause mortality or HF hospitalization for patients receiving PCI or optimal medical therapy in the REVIVED trial. LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention. Reprinted with permission. 8

The year of 2022 has been an exciting year in heart failure (HF). In this brief report, we will highlight some of the most provocative and impactful papers in the field.

Sodium–glucose co-transporter 2 (SGLT2) inhibitors are becoming one of the main treatments for patients with cardiorenal disease. Some uncertainties remained, e.g. if SGLT2 inhibitors were effective in patients with acute HF (AHF), or in HF with a left ventricular ejection fraction (LVEF) > 40%, or in patients with improved LVEF. The Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure (EMPULSE; {"type":"clinical-trial","attrs":{"text":"NCT04157751","term_id":"NCT04157751"}} NCT04157751 ) trial enrolled 530 patients with acute de novo or decompensated HF to receive empagliflozin 10 mg once daily or placebo. 1 The unique aspect of EMPULSE was that patients were randomized in hospital, when clinically stabilized (median time to randomization: 3 days), and were treated for up to 90 days. More patients treated with empagliflozin had clinical benefits compared with placebo (this was assessed by a ‘win’ ratio). Mortality and HF readmissions were also reduced.

The Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER, {"type":"clinical-trial","attrs":{"text":"NCT03619213","term_id":"NCT03619213"}} NCT03619213 ) study was a randomized double-blind clinical trial in 6263 patients with chronic symptomatic HF, LVEF > 40%, and elevated natriuretic peptides comparing the effect of dapagliflozin 10 mg once daily vs. placebo, in addition to standard of care. 2 After a median follow-up of 28 months, the primary outcome [death from cardiovascular (CV) causes or HF hospital admissions] occurred in 16.4% in the dapagliflozin group and in 19.5% in the placebo group [hazard ratio (HR) 0.82; 95% confidence interval (95% CI): 0.73–0.92; P < 0.001, Panel A ]. Findings were similar in prespecified subgroups. The frequency of adverse events leading to treatment discontinuation, related to volume depletion, and hypoglycaemia were similar between groups.

A prespecified patient-level pooled analysis ( n = 11 007) of the DAPA-HF ( {"type":"clinical-trial","attrs":{"text":"NCT03036124","term_id":"NCT03036124"}} NCT03036124 ) and DELIVER trials 3 found that the benefits of dapagliflozin were similar regardless of LVEF. Dapagliflozin reduced the risk of the composite of HF hospitalizations or CV death ( Panel B ), and of CV death alone (HR 0.86; 95% CI: 0.76–0.97; P = 0.01), death from any cause (HR 0.90; 95% CI: 0.82–0.99; P = 0.03), total hospitalizations for HF (HR 0.71; 95% CI: 0.65–0.78; P < 0.001), and MACE (HR 0.89; 95% CI: 0.80–0.99; P = 0.02). In this patient-level meta-analysis, there was no evidence that the effects of dapagliflozin differed by LVEF.

Several papers addressed the issue of diuresis, renal function, sodium, and potassium.

The issue of sodium restriction in HF has been disputed for long, and the study of dietary intervention under 100 mmol in heart failure (SODIUM-HF) was designed to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. 4 SODIUM-HF enrolled 806 patients with chronic HF receiving guideline-directed medical treatment, and randomized them to either usual care according to local guidelines or a low sodium diet (LSD) of <100 mmol (this is <1500 mg/day). The median sodium intake decreased from 2286 mg/day (interquartile range 1653–3005) to 1658 mg/day (1301–2189) in the low sodium group and from 2119 mg/day (1673–2804) to 2073 mg/day (1541–2900) in the usual care group. By 12 months, the primary composite endpoint of CV-related admission to hospital, CV-related emergency department visit, or all-cause death had occurred in 15% of patients in the LSD group and 17% in the usual care group (HR 0.89; 95% CI: 0.63–1.26; P = 0.53). So, a dietary intervention to reduce sodium intake does not reduce clinical events.

Patiromer is a potassium lowering agent, and the Patiromer for the Management of Hyperkalemia in Participants Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND, {"type":"clinical-trial","attrs":{"text":"NCT03888066","term_id":"NCT03888066"}} NCT03888066 ) trial investigated the effects of patiromer on serum potassium level, and if its use would enable target doses of renin–angiotensin–aldosterone system inhibitors (RAASi) use in patients with HFrEF. 5 A total of 1195 patients were enrolled during the run-in phase with patiromer and optimization of RAASi therapy [≥50% recommended dose of RAASi and 50 mg of mineralocorticoid receptor antagonist (MRA)]; this was achieved in 878 (84.6%) of the patients who were 1:1 randomized. At the end of the treatment, the adjusted mean change in potassium was +0.03 mmol/L in the patiromer group and +0.13 mmol/L in the placebo group [difference: −0.10 (95% CI −0.13, −0.07), P < 0.001]. This was accompanied by lower risk of hyperkalaemia (>5.5 mmol/L) and less reductions in MRA dose. Strikingly, a large proportion of the patients with hyperkalaemia in the past whose RAASi or MRA was downtitrated could tolerate adequate dosages of RAASi and/or MRA during the run-in phase of the DIAMOND trial. In any way, patiromer enables adequate titration of RAASi and MRA in patients with hyperkalaemia, although the number needed to treat to prevent hard clinical outcomes by this strategy appears to be rather high.

Diuretic resistance is another clinical dilemma which was addressed by two interesting trials. The Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial 6 evaluated if acetazolamide, a carbonic anhydrase inhibitor, reduces proximal tubular sodium reabsorption, on top of loop diuretics in patients with AHF; 519 AHF patients and clinical signs of volume overload and an NT-proBNP level of more than 1000 pg/mL were randomized to either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics. Successful decongestion was more often achieved in the acetazolamide group compared with the placebo group [risk ratio (RR) 1.46, 95% CI: 1.17–1.82; P < 0.001; Panel C ]. Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. However, neither changes in symptoms, nor weight, nor the EuroQoL outcomes were reported and may complement the published data. The incidence of worsening kidney function, hypokalaemia, hypotension, and adverse events was similar in the two groups. These data likely will shift the standard diuretic regimen in AHF.

The Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC trial; {"type":"clinical-trial","attrs":{"text":"NCT01647932","term_id":"NCT01647932"}} NCT01647932 ) 7 evaluated if addition of hydrochlorothiazide (HCT) to intravenous furosemide is a safe and effective strategy for improving diuretic response in patients with AHF. In total, 230 patients (48% women, 83 years) were randomized to HCT or placebo; those on HCT lost more weight at 72 h [−2.3 vs. −1.5 kg; −1.14 (95% CI −1.84 to −0.42); P = 0.002], but there were no significant differences in patient-reported dyspnoea. Mortality or HF rehospitalization rates were similar between HCT and placebo. Patients with HCT more often had a significant increase in creatinine (46.5% vs. 17.2%; P < 0.001).

Several other interesting articles were published.

First, the long-standing dispute about whether or not patients with ischaemic cardiomyopathy may benefit from revascularization by percutaneous coronary intervention (PCI), when compared with optimal medical therapy (OMT) (i.e. individually adjusted pharmacologic and device therapy for HF), was addressed by the Study of Efficacy and Safety of Percutaneous Coronary Intervention to Improve Survival in Heart Failure (REVIVED-BCIS2; {"type":"clinical-trial","attrs":{"text":"NCT01920048","term_id":"NCT01920048"}} NCT01920048 ). 8 Patients with an LVEF of 35% or less, extensive coronary artery disease that could be treated by PCI, and demonstrable myocardial viability were randomized to either PCI plus OMT (PCI group) or OMT alone. Totally, 347 were assigned to the PCI group and 353 to the OMT group. Over a median of 41 months, a primary outcome (death from any cause or HF hospitalization) occurred in 37.2% in the PCI group and in 38.0% in the OMT group (HR 0.99; 95% CI: 0.78–1.27; P = 0.96; Panel D ). The LVEF was similar in the two groups at 6 and 12 months. So, revascularization by PCI has no benefit in these patients on top of medical therapy.

Finally, two interesting articles addressed how drug titration in patients with HF may be handled. Until recently, the guidelines recommended initiating therapy in patients with HF in a historical sequence, with slow and controlled up-titration of individual classes of drugs. However, the newest guidelines state that four classes of drugs should be titrated on a faster schedule; however, the order and speed of titration remained unaddressed.

A first study 9 to address this was a retrospective study analysing data from six major mortality trials in HF: the SOLVD-Treatment trial (angiotensin-converting enzyme inhibition, enalapril), the MERIT-HF trial (beta-blockade, metoprolol), EMPHASIS-HF (MRA, eplerenone), the PARADIGM-HF trial (angiotensin receptor–neprilysin inhibition), DAPA-HF (SGLT2 inhibition, dapagliflozin), and CHARM (angiotensin receptor blocker, candesartan). The authors modelled the potential reductions in CV events that might be expected from more rapid up-titration in the conventional order (based on a chronology of trials), and compared this to accelerated up-titration, using treatments in different orders than currently is conventional. Indeed, a rapid up-titration schedule was associated with fewer HF hospitalization or CV death. Furthermore, an optimal ‘alternative’ sequence of drugs was identified, which proposed SGLT2i and an MRA as the first two therapies.

A second study addressing this pressing issue was the Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies (STRONG-HF; {"type":"clinical-trial","attrs":{"text":"NCT03412201","term_id":"NCT03412201"}} NCT03412201 ). 10 STRONG-HF randomized patients who were admitted to the hospital with AHF, who were not treated with full doses of guideline-directed drug treatment, to usual care or high-intensity care (HIC). HIC was defined by the up-titration of treatments to 100% of recommended doses within 2 weeks of discharge, with four scheduled outpatient visits over the 2 months after discharge, to closely monitor clinical status, laboratory values, and biomarkers. The primary endpoint was 180-day readmission for HF or all-cause death. In total, 1078 patients were randomized to HIC ( n = 542) or usual care ( n = 536). The study was stopped prematurely by the DSMB because of greater than expected between-group differences. A higher proportion of HIC patients had been up-titrated to full doses of prescribed drugs. HF readmission or all-cause death up to day 180 occurred in 74 (15.2%) of 506 patients in the HIC group and 109 (23.3%) of 502 patients in the usual care group (difference: 8.1%; RR 0.66, 95% CI: 0.50–0.86). Patients receiving HIC thus ended up having both more medical attention and visits as well as higher dosages of drugs—it remains uncertain what part of the benefit is explained by what element. More adverse events by 90 days occurred in the HIC group (41%) than in the usual care group (29%), but similar incidences of serious adverse events were reported in each group.

Overall, these two trials provide strong support for accelerated titration of guideline-directed drug treatment, while the order of drugs installed does not need to be based on historical grounds.

Contributor Information

Rudolf A de Boer, Department of Cardiology, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.

Johann Bauersachs, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.

All authors declare no funding for this contribution.

Data availability

Advancements in risk stratification and management strategies in primary cardiovascular prevention

Affiliations.

• 1 Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. Electronic address: [email protected].
• 2 Department of Internal Medicine, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
• 3 The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
• 4 Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
• 5 Division of Cardiology, Department of Medicine, Department of Physiology, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
• 6 2(nd) Department of Internal Medicine, St. Anne's University Hospital in Brno and Faculty of Medicine of Masaryk University, Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
• 7 Genomics Medicine Unit, Navarra Institute for Health Research - IdiSNA, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain.
• 8 Centre for Academic Primary Care, School of Medicine, University of Nottingham, United Kingdom.
• 9 Department of Medicine and Surgery, University of Perugia, Italy.
• 10 Internal Medicine Department, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania.
• 11 Department of Endocrinology, Tan Tock Seng Hospital, Singapore.
• 12 Cardiology Department, Institute of Endocrinology and Metabolism, Kyiv, Ukraine.
• 13 Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; Universidade de Lisboa, Faculdade de Ciências, BioISI - Biosystems & Integrative Sciences Institute, Lisboa, Portugal.
• 14 Division of Vascular and Endovascular Surgery, Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy.
• 15 Sumy State University, Sumy, Ukraine; Tallinn University of Technology, Tallinn, Estonia.
• 16 Cardiology Clinic, Ankara Bilkent City Hospital, Ankara, Turkey.
• 17 Nantes Université, CNRS, INSERM, l'institut du Thorax, Nantes, France.
• 18 Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy.
• 19 Centre for Cardiovascular Medicine and Devices, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; Barts Interventional Group, Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom.
• 20 Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
• 21 Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Petrovsky National Research Centre of Surgery, Moscow, Russia.
• 22 "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania; Institute of Cardiovascular Diseases Timisoara, Timisoara, Romania.
• 23 Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
• 24 Cardiovascular Center Aalst, OLV Clinic, Aalst, Belgium; Department of Prevention and Treatment of Emergency Conditions, L.T. Malaya Therapy National Institute NAMSU, Kharkiv, Ukraine.
• 25 Republican Specialized Scientific Practical Medical Center of Therapy and Medical Rehabilitation, Tashkent, Uzbekistan.
• 26 Department of Medicine, University of Padova, Italy.
• 27 Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074, Aachen, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336, Munich, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074, Aachen, Germany.
• 28 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
• PMID: 38824844
• DOI: 10.1016/j.atherosclerosis.2024.117579

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk assessment and management strategies. Although significant progress has been made recently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health.

Keywords: Atherosclerosis; Cardiovascular disease; Plaque regression; Primary prevention; Risk stratification.

Copyright © 2024 Elsevier B.V. All rights reserved.

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• Volume 3, Issue 1
• Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study
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• Ge Chen 1 ,
• Zhengmin (Min) Qian 2 ,
• Junguo Zhang 1 ,
• Shiyu Zhang 1 ,
• http://orcid.org/0000-0002-7003-6565 Zilong Zhang 1 ,
• Michael G Vaughn 3 ,
• Hannah E Aaron 2 ,
• Chuangshi Wang 4 ,
• Gregory YH Lip 5 , 6 and
• http://orcid.org/0000-0002-3643-9408 Hualiang Lin 1
• 1 Department of Epidemiology , Sun Yat-Sen University , Guangzhou , China
• 2 Department of Epidemiology and Biostatistics, College for Public Health and Social Justice , Saint Louis University , Saint Louis , Missouri , USA
• 3 School of Social Work, College for Public Health and Social Justice , Saint Louis University , Saint Louis , Missouri , USA
• 4 Medical Research and Biometrics Centre , Fuwai Hospital, National Centre for Cardiovascular Diseases, Peking Union Medical College , Beijing , China
• 5 Liverpool Centre for Cardiovascular Science , University of Liverpool and Liverpool Heart and Chest Hospital , Liverpool , UK
• 6 Department of Clinical Medicine , Aalborg University , Aalborg , Denmark
• Correspondence to Dr Hualiang Lin, Department of Epidemiology, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; linhualiang{at}mail.sysu.edu.cn

Objective To examine the effects of fish oil supplements on the clinical course of cardiovascular disease, from a healthy state to atrial fibrillation, major adverse cardiovascular events, and subsequently death.

Design Prospective cohort study.

Setting UK Biobank study, 1 January 2006 to 31 December 2010, with follow-up to 31 March 2021 (median follow-up 11.9 years).

Participants 415 737 participants, aged 40-69 years, enrolled in the UK Biobank study.

Main outcome measures Incident cases of atrial fibrillation, major adverse cardiovascular events, and death, identified by linkage to hospital inpatient records and death registries. Role of fish oil supplements in different progressive stages of cardiovascular diseases, from healthy status (primary stage), to atrial fibrillation (secondary stage), major adverse cardiovascular events (tertiary stage), and death (end stage).

Results Among 415 737 participants free of cardiovascular diseases, 18 367 patients with incident atrial fibrillation, 22 636 with major adverse cardiovascular events, and 22 140 deaths during follow-up were identified. Regular use of fish oil supplements had different roles in the transitions from healthy status to atrial fibrillation, to major adverse cardiovascular events, and then to death. For people without cardiovascular disease, hazard ratios were 1.13 (95% confidence interval 1.10 to 1.17) for the transition from healthy status to atrial fibrillation and 1.05 (1.00 to 1.11) from healthy status to stroke. For participants with a diagnosis of a known cardiovascular disease, regular use of fish oil supplements was beneficial for transitions from atrial fibrillation to major adverse cardiovascular events (hazard ratio 0.92, 0.87 to 0.98), atrial fibrillation to myocardial infarction (0.85, 0.76 to 0.96), and heart failure to death (0.91, 0.84 to 0.99).

Conclusions Regular use of fish oil supplements might be a risk factor for atrial fibrillation and stroke among the general population but could be beneficial for progression of cardiovascular disease from atrial fibrillation to major adverse cardiovascular events, and from atrial fibrillation to death. Further studies are needed to determine the precise mechanisms for the development and prognosis of cardiovascular disease events with regular use of fish oil supplements.

• Health policy
• Nutritional sciences
• Public health

Data availability statement

Data are available upon reasonable request. UK Biobank is an open access resource. Bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/ .

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/ .

https://doi.org/10.1136/bmjmed-2022-000451

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Findings of the effects of omega 3 fatty acids or fish oil on the risk of cardiovascular disease are controversial

Most previous studies focused on one health outcome and did not characterise specific cardiovascular disease outcomes (eg, atrial fibrillation, myocardial infarction, stroke, heart failure, and major adverse cardiovascular events)

Whether fish oil could differentially affect the dynamic course of cardiovascular diseases, from atrial fibrillation to major adverse cardiovascular events, to other specific cardiovascular disease outcomes, or even to death, is unclear

WHAT THIS STUDY ADDS

In people with no known cardiovascular disease, regular use of fish oil supplements was associated with an increased relative risk of atrial fibrillation and stroke

In people with known cardiovascular disease, the beneficial effects of fish oil supplements were seen on transitions from atrial fibrillation to major adverse cardiovascular events, atrial fibrillation to myocardial infarction, and heart failure to death

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

Regular use of fish oil supplements might have different roles in the progression of cardiovascular disease

Further studies are needed to determine the precise mechanisms for the development and prognosis of cardiovascular disease events with regular use of fish oil supplements

Introduction

Cardiovascular disease is the leading cause of death worldwide, accounting for about one sixth of overall mortality in the UK. 1 2 Fish oil, a rich source of omega 3 fatty acids, containing eicosapentaenoic acid and docosahexaenoic acid, has been recommended as a dietary measure to prevent cardiovascular disease. 3 The UK National Institute for Health and Care Excellence recommends that people with or at high risk of cardiovascular disease consume at least one portion of oily fish a week, and the use of fish oil supplements has become popular in the UK and other western countries in recent years. 4 5

Although some epidemiological and clinical studies have assessed the effect of omega 3 fatty acids or fish oil on cardiovascular disease and its risk factors, the findings are controversial. The Agency for Healthcare Research and Quality systematically reviewed 37 observational studies and 61 randomised controlled trials, and found evidence indicating the beneficial effects of higher consumption of fish oil supplements on ischaemic stroke, whereas no beneficial effect was found for atrial fibrillation, major adverse cardiovascular events, myocardial infarction, total stroke, or all cause death. 6 In contrast, the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) reported a decreased risk of major adverse cardiovascular events with icosapent ethyl in patients with raised levels of triglycerides, regardless of the use of statins. 7 Most of these findings, however, tended to assess the role of fish oil at a certain stage of cardiovascular disease. For example, some studies restricted the study population to people with a specific cardiovascular disease or at a high risk of cardiovascular disease, 8 9 whereas others evaluated databases of generally healthy populations. 10 All of these factors might preclude direct comparison of the effects of omega 3 fatty acids on atrial fibrillation events or on further deterioration of cardiovascular disease. Few studies have fully characterised specific cardiovascular disease outcomes or accounted for differential effects based on the complex disease characteristics of participants. Hence, in this study, we hypothesised that fish oil supplements might have harmful, beneficial, or no effect on different cardiovascular disease events in patients with varying health conditions.

Most previous studies on the association between fish oil and cardiovascular diseases generally focused on one health outcome. Also, no study highlighted the dynamic progressive course of cardiovascular diseases, from healthy status (primary stage), to atrial fibrillation (secondary stage), major adverse cardiovascular events (tertiary stage), and death (end stage). Clarifying this complex pathway in relation to the detailed progression of cardiovascular diseases would provide substantial insights into the prevention or treatment of future disease at critical stages. Whether fish oil could differentially affect the dynamic course of cardiovascular disease (ie, from atrial fibrillation to major adverse cardiovascular events, to other specific cardiovascular disease outcomes, or even to death) is unclear.

To deal with this evidence gap, we conducted a longitudinal cohort study to estimate the associations between fish oil supplements and specific clinical cardiovascular disease outcomes, including atrial fibrillation, major adverse cardiovascular events, and all cause death in people with no known cardiovascular disease or at high risk of cardiovascular disease for the purpose of primary prevention. We also assessed the modifying effects of fish oil supplements on the disease process, from atrial fibrillation to other outcomes, in people with known cardiovascular disease for the purpose of secondary prevention.

The UK Biobank is a community based cohort study with more than half a million UK inhabitants aged 40-69 years at recruitment. 11–13 Participants were invited to participate in this study if they were registered with the NHS and lived within 35 km of one of 22 Biobank assessment centres. Between 1 March 2006 and 31 July 2010, a baseline survey was conducted, based on a touch screen questionnaire and face-to-face interviews, to collect detailed personal, socioeconomic, and lifestyle characteristics, and information on diseases. 11–13

We excluded patients who had a diagnosis of atrial fibrillation (n=8326), heart failure (n=2748), myocardial infarction (n=11 949), stroke (n=7943), or cancer (n=48 624) at baseline; who withdrew from the study during follow-up (n=1299); or who had incomplete or outlier data for the main information (n=11 748). Because we focused only on a specific sequence of progression of cardiovascular disease (ie, from healthy status to atrial fibrillation, to major adverse cardiovascular events, and then to death), we excluded 1983 participants with other transition patterns. The remaining 415 737 participants were included in this analysis ( figure 1 ).

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Flowchart of selection of participants in study. The count of diagnosed diseases does not equate to the total number of individuals, because each person could have multiple diagnoses

Determining use of fish oil supplements

Information on regular use of fish oil supplements was collected from a self-reported touchscreen questionnaire during the baseline survey. 14 15 Each participant was asked whether they regularly used any fish oil supplement. Trained staff conducted a verbal interview with participants, asking if they were currently receiving treatments or taking any medicines, including omega 3 or fish oil supplements. Based on this information, we classified participants as regular users of fish oil supplements and non-users.

Follow-up and outcomes

Participants were followed up from the time of recruitment to death, loss to follow-up, or the end date of follow-up (31 March 2021), whichever came first. Incident cases of interest, including atrial fibrillation, heart failure, stroke, and myocardial infarction, were identified by linkage to death registries, primary care records, and hospital inpatient records. 11 Information on deaths was obtained from death registries of the NHS Information Centre, for participants in England and Wales, and from the NHS Central Register Scotland, for participants in Scotland. 11 Outcomes were defined by a three character ICD-10 (international classification of diseases, 10th revision) code. In this study, atrial fibrillation was defined by ICD-10 code I48, and major adverse cardiovascular events was determined by a combination of heart failure (I50, I11.0, I13.0, and I13.2), stroke (I60-I64), and myocardial infarction (I21, I22, I23, I24.1, and I25.2) codes.

We collected baseline data on age (<65 years and ≥65 years), sex (men and women), ethnic group (white and non-white), Townsend deprivation index (with a higher score indicating higher levels of deprivation), smoking status (never, previous, and current smokers), and alcohol consumption (never, previous, and current drinkers). Data for sex were taken from information in UK Biobank rather than from patient reported gender. Baseline dietary data were obtained from a dietary questionnaire completed by the patient or by an interviewer. The questionnaire was established for each nation (ie, England, Scotland, and Wales) to assess an individual's usual food intake (oily fish, non-oily fish, vegetables, fruit, and red meat). Diabetes mellitus was defined by ICD-10 codes E10-E14, self-reported physician's diagnosis, self-reported use of antidiabetic drugs, or haemoglobin A1c level ≥6.5% at baseline. Hypertension was defined by ICD-10 code I10 or I15, self-reported physician's diagnosis, self-reported use of antihypertensive drugs, or measured systolic and diastolic blood pressure ≥130/85 mm Hg at baseline. Information on other comorbidities (obesity (ICD-10 code E66), chronic obstructive pulmonary disease (J44), and chronic renal failure (N18)) was extracted from the first occurrence (UKB category ID 1712). Information on the use of drugs, including antihypertensive drugs, antidiabetic drug, and statins, was extracted from treatment and drug use records. Biochemistry markers were measured immediately at the central laboratory from serum samples collected at baseline. Binge drinking was defined as consumption of ≥6 standard drinks/day for women or ≥8 standard drinks/day for men. Detailed information on alcohol consumption and binge drinking in the UK Biobank was reported previously. 16

Statistical analysis

Characteristics of participants are summarised as number (percentages) for categorical variables and mean (standard deviation (SD)) for continuous variables. Comparisons between regular users of fish oil supplements and non-users were made with the χ 2 test or Student's t test.

We used a multi-state regression model to assess the role of regular use of fish oil supplements in the temporal disease progression from healthy status to atrial fibrillation, to major adverse cardiovascular events, and subsequently to death. The multi-state model is an extension of competing risks survival analysis. 17–19 The model allows simultaneous estimation of the role of risk factors in transitions from a healthy state to atrial fibrillation (transition A), healthy state to major adverse cardiovascular events (transition B), healthy state to death (transition C), atrial fibrillation to major adverse cardiovascular events (transition D), atrial fibrillation to death (transition E), and major adverse cardiovascular events to death (transition F) (transition pattern I, figure 2 ). The focus on these six transitions rather than on all possible health state transitions was preplanned and evidence based. If participants entered different states on the same date, we used the date of the theoretically previous state as the entry date of the latter state minus 0.5 days.

Numbers of participants in transition pattern I, from baseline to atrial fibrillation, major adverse cardiovascular events, and death

We further examined the effects of regular use of fish oil supplements on other pathways. For example, we divided major adverse cardiovascular events into three individual diseases (heart failure, stroke, and myocardial infarction), resulting in three independent pathways (transition patterns II, III, and IV, online supplemental figures S1–S3 ). All models were adjusted for age, sex, ethnic group, Townsend deprivation index, consumption of oily fish, consumption of non-oily fish, smoking status, alcohol consumption, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic renal failure, and use of statins, antidiabetic drugs, and antihypertensive drugs.

Supplemental material

We conducted several sensitivity analyses for the multi-state analyses of transition pattern A: additionally adjusting for setting (urban and rural), body mass index (underweight, normal, overweight, and obese), and physical activity (low, moderate, and high) in the model; adjusting for binge drinking rather than alcohol consumption; additionally adjusting for other variables of dietary intake (consumption of vegetables, fruit, and red meat); calculating participants' entry date into the previous state with different time intervals (0.5 years, one year, and two years); excluding participants who entered different states on the same date; excluding events occurring in the first two years of follow-up; restricting the follow-up date to 31 March 2020 to evaluate the influence of the covid-19 pandemic; and the use of the inverse probability weighted method to deal with biases between the regular users and non-users of fish oil supplements. Also, we conducted grouped analyses for sex, age group, ethnic group, smoking status, consumption of oily fish, consumption of non-oily fish, hypertension, and drug use, to examine effect modification. The interactions were tested with the likelihood ratio test. All analyses were carried out with R software (version 4.0.3), and the multi-model analysis was performed with the mstate package. A two tailed P value <0.05 was considered significant.

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Participants were involved in developing the ethics and governance framework for UK Biobank and have been engaged in the progress of UK Biobank through follow-up questionnaires and additional assessment visits. UK Biobank keeps participants informed of all research output through the study website ( https://www.ukbiobank.ac.uk/explore-your-participation ), participant events, and newsletters.

A total of 415 737 participants (mean age 55.9 (SD 8.1) years; 55% women), aged 40-69 years, were analysed, and 31.4% (n=1 30 365) of participants reported regular use of fish oil supplements at baseline ( figure 1 ). Table 1 shows the characteristics of regular users (n=130 365) and non-users (n=285 372) of fish oil supplements. In the group of regular users of fish oil supplements, we found higher proportions of elderly people (22.6% v 13.9%), white people (95.1% v 94.2%), and women (57.6% v 53.9%), and higher consumption of alcohol (93.1% v 92.0%), oily fish (22.1% v 15.4%), and non-oily fish (18.0% v 15.4%) than non-users. The Townsend deprivation index (mean −1.5 (SD 3.0) v −1.3 (3.0)) and the proportion of current smokers (8.1% v 11.4%) were lower in regular users of fish oil supplements. Online supplemental table S1 provides more details on patient characteristics and online supplemental table S2 compares the basic characteristics of included and excluded people.

• View inline

Baseline characteristics of study participants grouped by use of fish oil supplements

Over a median follow-up time of of 11.9 years, 18 367 participants had atrial fibrillation (transition A) and 17 826 participants had major adverse cardiovascular events (transition B); 14 902 participants died without having atrial fibrillation or major adverse cardiovascular events (transition C). Among patients with incident atrial fibrillation, 4810 developed major adverse cardiovascular events (transition D) and 1653 died (transition E). Among patients with incident major adverse cardiovascular events, 5585 died during follow-up (transition F, figure 2 ). In separate analyses for individual diseases (transition patterns II, III, and IV, online supplemental figures S1–S3 ), in patients with atrial fibrillation, 3085 developed heart failure, 1180 had a stroke, and 1415 had a myocardial infarction. During follow-up, 2436, 2088, and 2098 deaths occurred in patients with heart failure, stroke, and myocardial infarction, respectively.

Multi-state regression results

Table 2 shows the different roles of regular use of fish oil supplements in transitions from healthy status to atrial fibrillation, to major adverse cardiovascular events, and then to death. For individuals in the primary stage (healthy status), we found that the use of fish oil supplements had a harmful effect on the transition from health to atrial fibrillation, with an adjusted hazard ratio of 1.13 (95% CI 1.10 to 1.17, transition A). The hazard ratio for transition B (from health to major adverse cardiovascular events) was 1.00 (95% CI 0.97 to 1.04) and for transition C (from health to death) was 0.98 (0.95 to 1.02).

Hazard ratios (95% confidence intervals) for each transition, for different transition patterns for progressive cardiovascular disease by regular use of fish oil supplements

For individuals in the secondary stage (atrial fibrillation) at the beginning of the study, regular use of fish oil supplements decreased the risk of major adverse cardiovascular events (transition D, hazard ratio 0.92, 95% CI 0.87 to 0.98), and had a borderline protective effect on the transition from atrial fibrillation to death (transition E, 0.91, 0.82 to 1.01). For transition F, from major adverse cardiovascular events to death, after adjusting for covariates, the hazard ratio was 0.99 (0.94 to 1.06, transition pattern I, table 2 ).

We divided major adverse cardiovascular events into three individual diseases (ie, heart failure, stroke, and myocardial infarction) and found that regular use of fish oil supplements was marginally associated with an increased risk of stroke in people with a healthy cardiovascular state (hazard ratio 1.05, 95% CI 1.00 to 1.11), whereas a protective effect was found in transitions from healthy cardiovascular states to heart failure (0.92, 0.86 to 0.98). For patients with atrial fibrillation, we found that the beneficial effects of regular use of fish oil supplements were for transitions from atrial fibrillation to myocardial infarction (0.85, 0.76 to 0.96), and from atrial fibrillation to death (0.88, 0.81 to 0.95) for transition pattern IV. For patients with heart failure, we found a protective effect of regular use of fish oil supplements on the risk of mortality (0.91, 0.84 to 0.99) (transition patterns II, III, and IV, table 2 ).

Stratified and sensitivity analyses

We found that age, sex, smoking, consumption of non-oily fish, prevalent hypertension, and use of statins and antihypertensive drugs modified the associations between regular use of fish oil supplements and the transition from healthy states to atrial fibrillation ( online supplemental figure S4 ). We found that the association between regular use of fish oil supplements and risk of transition from healthy states to major adverse cardiovascular events was greater in women (hazard ratio 1.06, 95% CI 1.00 to 1.11, P value for interaction=0.005) and non-smoking participants (1.06, 1.06 to 1.11, P value for interaction=0.001) ( online supplemental figure S4 ). The protective effect of regular use of fish oil supplements on the transition from healthy states to death was greater in men (hazard ratio 0.93, 95% CI 0.89 to 0.98, P value for interaction=0.003) and older participants (0.91, 0.86 to o 0.96, P value for interaction=0.002) ( online supplemental figures S5 and S6 ). The results were not substantially changed in the sensitivity analyses ( online supplemental table S3 ).

Principal findings

Our study characterised the regular use of fish oil supplements on the progressive course of cardiovascular disease, from a healthy state (primary stage), to atrial fibrillation (secondary stage), major adverse cardiovascular events (tertiary stage), and death (end stage). In this prospective analysis of more than 400 000 UK adults, we found that regular use of fish oil supplements could have a differential role in the progression of cardiovascular disease. For people with a healthy cardiovascular profile, regular use of fish oil supplements, a choice of primary prevention, was associated with an increased risk of atrial fibrillation. For participants with a diagnosis of atrial fibrillation, however, regular use of fish oil supplements, as secondary prevention, had a protective effect or no effect on transitions from atrial fibrillation to major adverse cardiovascular events, atrial fibrillation to death, and major adverse cardiovascular events to death. When we divided major adverse cardiovascular events into three individual diseases (ie, heart failure, stroke, and myocardial infarction), we found associations that could suggest a mildly harmful effect between regular use of fish oil supplements and transitions from a healthy cardiovascular state to stroke, whereas potential beneficial associations were found between regular use of fish oil supplements and transitions from atrial fibrillation to myocardial infarction, atrial fibrillation to death, and heart failure to death.

Comparison with other studies

Primary prevention.

The cardiovascular benefits of regular use of fish oil supplements have been examined in numerous studies but the results are controversial. Extending previous reports, our study estimated the associations between regular use of fish oil supplements and specific clinical cardiovascular disease outcomes in people with no known cardiovascular disease. Our findings are in agreement with the results of several previous randomised controlled trials and meta-analyses. The Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH) reported that consumption of 4 g/day of marine omega 3 fatty acids was associated with a 69% higher risk of new onset atrial fibrillation in people at high risk of cardiovascular disease. 20 A meta-analysis of seven randomised controlled trials showed that users of marine omega 3 fatty acids supplements had a higher risk of atrial fibrillation events, with a hazard ratio of 1.25 (95% CI 1.07 to 1.46, P=0.013). 21 The Vitamin D and Omega-3 Trial (VITAL Rhythm study), a large trial of omega 3 fatty acids for the primary prevention of cardiovascular disease in adults aged ≥50 years, however, found no effects on incident atrial fibrillation, major adverse cardiovascular events, or cardiovascular disease mortality among those treated with 840 mg/day of marine omega 3 fatty acids compared with placebo. 10 22

One possible explanation for the inconsistent results in these studies is that adverse effects might be related to dose and composition. Higher doses of omega 3 fatty acids used in previous studies might have had an important role in causing an adverse effect on atrial fibrillation. 21 One study found that high concentrations of fish oil altered cell membrane properties and inhibited Na-K-ATPase pump activity, whereas a low concentration of fish oil minimised peroxidation potential and optimised activity. 23 In another study, individuals with atrial fibrillation or flutter had higher percentages of total polyunsaturated fatty acids, and n-3 and n-6 polyunsaturated fatty acids, on red blood cell membranes than healthy controls. 24

In terms of composition of omega 3 fatty acids, a recent meta-analysis showed that eicosapentaenoic acid alone can be more effective at reducing the risk of cardiovascular disease than the combined effect of eicosapentaenoic acid and docosahexaenoic acid. 25 Similar outcomes were reported in the INSPIRE study, which showed that higher levels of docosahexaenoic acid reduced the cardiovascular benefits of eicosapentaenoic acid when given as a combination. 26 Another possible explanation is that age, sex, ethnic group, smoking status, dietary patterns, and use of statins and antidiabetic drugs by participants might modify the effects of regular use of fish oil supplements on cardiovascular disease events. Despite these differences in risk estimates, our findings do not support the use of fish oil or omega 3 fatty acid supplements for the primary prevention of incident atrial fibrillation or other specific clinical cardiovascular disease events in generally healthy individuals. Caution might be warranted when fish oil supplements are used for primary prevention because of the uncertain cardiovascular benefits.

Secondary prevention

Our large scale cohort study assessed the role of regular use of fish oil supplements on the disease process, from atrial fibrillation to more serious cardiovascular disease stages, to death, in people with known cardiovascular disease. Contrary to the observations for primary prevention, we found associations that could suggest beneficial effects between regular use of fish oil supplements and most cardiovascular disease transitions. No associations were found between regular use of fish oil supplements and transitions from atrial fibrillation to death, or from major adverse cardiovascular events to death.

Consistent with our hypothesis, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) Prevenzione study reported an association between administration of low dose prescriptions of n-3 polyunsaturated fatty acids and reduced cardiovascular events in patients with recent myocardial infarction. 27 A meta-analysis of 16 randomised controlled trials also reported a tendency towards a greater beneficial effect for secondary prevention in patients with cardiovascular disease. 28 Why patients with previous atrial fibrillation benefit is unclear. These findings indicate that triglyceride independent effects of omega 3 fatty acids might in part be responsible for the benefits in cardiovascular disease seen in previous trials. 29–31 No proven biological mechanism for this explanation exists, however, and the dose and formulation of omega 3 fatty acids used in clinical practice are not known.

For the disease process, from cardiovascular disease to death, our findings are consistent with the results of secondary prevention trials of omega 3 fatty acids, which have mostly shown a weak or neutral preventive effect in all cause mortality with oil fish supplements. The GISSI heart failure trial (GISSI-HF), conducted in 6975 patients with chronic heart failure, reported that supplemental omega 3 fatty acids reduced the risk of all cause mortality by 9% (hazard ratio 0.91, 95% CI 0.833 to 0.998, P=0.041). 32 Zelniker et al showed that omega 3 fatty acids were inversely associated with a lower incidence of sudden cardiac death in patients with non-ST segment elevation acute coronary syndrome. 33 A meta-analysis found that use of omega 3 supplements of ≤1 capsule/day was not associated with all cause mortality, but among participants with a risk of cardiovascular disease, taking a higher dose was associated with a reduction in cardiac death and sudden death. 28 Individuals who might benefit the most from fish oil or omega 3 fatty acid supplements are possibly more vulnerable individuals, such as those with previous cardiovascular diseases and those who can no longer live in the community. How fish oil supplements stop further deterioration of cardiovascular disease is unclear, but the theory that supplemental omega 3 fatty acids might protect the coronary artery is biologically plausible, suggesting that omega 3 fatty acids have anti-inflammatory and anti-hypertriglyceridaemia effects, contributing to a reduction in thrombosis and improvement in endothelial function. 34–41 Nevertheless, the effects of omega 3 fatty acids vary according to an individual's previous use of statins, which might partly explain the different effects of fish oil supplements in people with and without cardiovascular disease.

Many studies of omega 3 fatty acids, including large scale clinical trials and meta-analyses, have not produced entirely consistent results. 21 25 42 Our study mainly explored the varied potential effects of regular use of fish oil supplements on progression of cardiovascular disease, offering an initial overview of this ongoing discussion. Our findings suggest caution in the use of fish oil supplements for primary prevention because of the uncertain cardiovascular benefits and adverse effects. Further studies are needed to determine whether potential confounders modify the effects of oil fish supplements and the precise mechanisms related to the development and prognosis of cardiovascular disease events.

Strengths and limitations of this study

The strengths of our study were the large sample size, long follow-up period, which allowed us to analyse clinically diagnosed incident diseases, and complete data on health outcomes. Another strength was our analytical strategy. The multi-state model gives less biased estimates than the conventional Cox model, and distinguished the effect of regular use of fish oil supplements on each transition in the course of cardiovascular disease.

Our study had some limitations. Firstly, as an observational study, no causal relations can be drawn from our findings. Secondly, although we adjusted for multiple covariates, residual confounding could still exist. Thirdly, information on dose and formulation of the fish oil supplements was not available in this study, so we could not evaluate potential dose dependent effects or differentiate between the effects of different fish oil formulations. Fourthly, the use of hospital inpatient data for determining atrial fibrillation events could have excluded some events triggered by acute episodes, such as surgery, trauma, and similar conditions, resulting in underestimation of the true risk because undiagnosed atrial fibrillation is a common occurrence. 43 Fifthly, most of the participants in this study were from the white ethnic group and whether the findings can be generalised to other ethnic groups is not known. Finally, our study did not consider behavioural changes in populations with different cardiovascular profiles because of limited information, and variations in outcomes for different cardiovascular states merits further exploration.

Conclusions

This large scale prospective study of a UK cohort suggested that regular use of fish oil supplements might have differential roles in the course of cardiovascular diseases. Regular use of fish oil supplements might be a risk factor for atrial fibrillation and stroke among the general population but could be beneficial for disease progression, from atrial fibrillation to major adverse cardiovascular events, and from atrial fibrillation to death. Further studies are needed to determine whether potential confounders modify the effects of oil fish supplements and the precise mechanisms for the development and prognosis of cardiovascular disease events.

Ethics statements

Patient consent for publication.

Consent obtained directly from patients.

Ethics approval

The UK Biobank study obtained ethical approval from the North West Multicentre Research ethics committee, Information Advisory Group, and the Community Health Index Advisory Group (REC reference for UK Biobank 11/NW/0382). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

This study was conducted with UK Biobank Resource (application No: 69550). We appreciate all participants and professionals contributing to UK Biobank.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1
• Data supplement 2

GYL and HL are joint senior authors.

Contributors HL supervised the whole project and designed the work. GC and HL directly accessed and verified the underlying data reported in the manuscript. GC contributed to data interpretation and writing of the report. ZQ, SZ, JZ, ZZ, MGV, HEA, CW, and GYHL contributed to the discussion and data interpretation, and revised the manuscript. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. HL is the guarantor. Transparency: The lead author (guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Funding This work was supported by the Bill and Melinda Gates Foundation (grant No INV-016826). Under the grant conditions of the foundation, a creative commons attribution 4.0 generic license has already been assigned to the author accepted manuscript version that might arise from this submission. The funder had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Bill and Melinda Gates Foundation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Volume 120, Issue 7, May 2024

Cardiovascular research onlife, clinical commentaries, cardiac magnetic resonance or computed tomography: are we ready for a change of gold standard before transcatheter aortic valve replacement.

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Protein discovery could help prevent cancer treatment-related heart damage

B locking a protein known as CDK7 could prevent heart damage associated with a commonly used cancer chemotherapy medication, according to a study led by scientists at Washington State University. Importantly, the researchers also found that inhibiting CDK7 could help enhance the medication's cancer-killing capability.

Based on an animal model, the study findings could provide a foundation for future treatment strategies to reduce chemotherapy-related heart toxicity and increase treatment effectiveness. This could ultimately help increase the lifespan of people with cancer. Heart damage related to chemotherapy treatment can surface decades after treatment and can result in heart attacks, heart failure, cardiomyopathy and other types of heart disease.

Published in the journal Cardiovascular Research , the WSU study focused on doxorubicin, a chemotherapy drug used to treat breast cancer, lymphoma, leukemia and other cancers. Capable of killing a wide range of cancer cells, doxorubicin and other similar chemotherapy medications are known to be toxic to the heart. Despite this toxicity, the drug still sees a lot of use.

"Doxorubicin remains the mainstay treatment for certain cancer types for which targeted therapies or other better treatments are not available," said senior study author Zhaokang Cheng, an associate professor in the WSU College of Pharmacy and Pharmaceutical Sciences.

Cheng has been working to unravel the underlying mechanisms of doxorubicin-induced heart toxicity to make the use of doxorubicin safer for patients who rely on the drug. This new study builds on findings from earlier research that showed that doxorubicin activates a protein known as CDK2 . That protein then activates another known as FOXO1, which causes heart cells to die. Cheng's team collaborated with WSU cancer biology researcher Boyang (Jason) Wu to take a closer look at CDK7, a protein that helps fuel cell growth and has been shown to play a role in the development of cancer.

The researchers found that CDK7 activated CDK2, which set off the chain of molecular signals that eventually led to heart cell death. They also showed that mice that lacked the CDK7 gene were protected from doxorubicin-induced heart toxicity.

Next, they used a CDK7 inhibitor drug known as THZ1 to block the protein's activity and examine the impact on heart health and cancer growth. A similar inhibitor is currently being tested as an anticancer drug in clinical trials, but its effect on the heart is still not clear.

"We are the first to study the effect of THZ1 on the heart and on tumor growth in the same model," said study first author Jingrui Chen, a WSU research associate. "And what we found is that this CDK7 inhibitor drug can increase heart function and at the same time inhibit tumor growth."

Though more research is needed, the researchers said their findings suggest that combining doxorubicin and THZ1 could help prevent heart damage and increase the effectiveness of chemotherapy treatment.

The researchers' next step is to test the effect of THZ1 on heart damage and cancer growth in younger mice and follow them longer. This would more closely mimic long-term doxorubicin-induced heart toxicity seen in childhood cancer survivors. They also plan to look at other proteins that may somehow be involved in the signaling pathway that underlies doxorubicin-related heart damage.

More information: Jingrui Chen et al, Inhibition of cyclin-dependent kinase 7 mitigates doxorubicin cardiotoxicity and enhances anticancer efficacy, Cardiovascular Research (2024). DOI: 10.1093/cvr/cvae084

Provided by Washington State University

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All manuscripts must include an ‘Availability of data and materials’ statement. Data availability statements should include information on where data supporting the results reported in the article can be found including, where applicable, hyperlinks to publicly archived datasets analysed or generated during the study. By data we mean the minimal dataset that would be necessary to interpret, replicate and build upon the findings reported in the article. We recognise it is not always possible to share research data publicly, for instance when individual privacy could be compromised, and in such instances data availability should still be stated in the manuscript along with any conditions for access.

Authors are also encouraged to preserve search strings on searchRxiv https://searchrxiv.org/ , an archive to support researchers to report, store and share their searches consistently and to enable them to review and re-use existing searches. searchRxiv enables researchers to obtain a digital object identifier (DOI) for their search, allowing it to be cited. 

Data availability statements can take one of the following forms (or a combination of more than one if required for multiple datasets):

• The datasets generated and/or analysed during the current study are available in the [NAME] repository, [PERSISTENT WEB LINK TO DATASETS]
• The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
• All data generated or analysed during this study are included in this published article [and its supplementary information files].
• The datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.
• Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
• The data that support the findings of this study are available from [third party name] but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of [third party name].
• Not applicable. If your manuscript does not contain any data, please state 'Not applicable' in this section.

More examples of template data availability statements, which include examples of openly available and restricted access datasets, are available here .

BioMed Central strongly encourages the citation of any publicly available data on which the conclusions of the paper rely in the manuscript. Data citations should include a persistent identifier (such as a DOI) and should ideally be included in the reference list. Citations of datasets, when they appear in the reference list, should include the minimum information recommended by DataCite and follow journal style. Dataset identifiers including DOIs should be expressed as full URLs. For example:

Hao Z, AghaKouchak A, Nakhjiri N, Farahmand A. Global integrated drought monitoring and prediction system (GIDMaPS) data sets. figshare. 2014. http://dx.doi.org/10.6084/m9.figshare.853801

With the corresponding text in the Availability of data and materials statement:

The datasets generated during and/or analysed during the current study are available in the [NAME] repository, [PERSISTENT WEB LINK TO DATASETS]. [Reference number]  

If you wish to co-submit a data note describing your data to be published in BMC Research Notes , you can do so by visiting our submission portal . Data notes support open data and help authors to comply with funder policies on data sharing. Co-published data notes will be linked to the research article the data support ( example ).

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All sources of funding for the research reported should be declared. If the funder has a specific role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript, this should be declared.

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Please use initials to refer to each author's contribution in this section, for example: "FC analyzed and interpreted the patient data regarding the hematological disease and the transplant. RH performed the histological examination of the kidney, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript."

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You may choose to use this section to include any relevant information about the author(s) that may aid the reader's interpretation of the article, and understand the standpoint of the author(s). This may include details about the authors' qualifications, current positions they hold at institutions or societies, or any other relevant background information. Please refer to authors using their initials. Note this section should not be used to describe any competing interests.

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Always use footnotes instead of endnotes.

Examples of the Vancouver reference style are shown below.

See our editorial policies for author guidance on good citation practice

Web links and URLs: All web links and URLs, including links to the authors' own websites, should be given a reference number and included in the reference list rather than within the text of the manuscript. They should be provided in full, including both the title of the site and the URL, as well as the date the site was accessed, in the following format: The Mouse Tumor Biology Database. http://tumor.informatics.jax.org/mtbwi/index.do . Accessed 20 May 2013. If an author or group of authors can clearly be associated with a web link, such as for weblogs, then they should be included in the reference.

Example reference style:

Article within a journal

Smith JJ. The world of science. Am J Sci. 1999;36:234-5.

Article within a journal (no page numbers)

Rohrmann S, Overvad K, Bueno-de-Mesquita HB, Jakobsen MU, Egeberg R, Tjønneland A, et al. Meat consumption and mortality - results from the European Prospective Investigation into Cancer and Nutrition. BMC Medicine. 2013;11:63.

Article within a journal by DOI

Slifka MK, Whitton JL. Clinical implications of dysregulated cytokine production. Dig J Mol Med. 2000; doi:10.1007/s801090000086.

Article within a journal supplement

Frumin AM, Nussbaum J, Esposito M. Functional asplenia: demonstration of splenic activity by bone marrow scan. Blood 1979;59 Suppl 1:26-32.

Book chapter, or an article within a book

Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. In: Bourne GH, Danielli JF, Jeon KW, editors. International review of cytology. London: Academic; 1980. p. 251-306.

OnlineFirst chapter in a series (without a volume designation but with a DOI)

Saito Y, Hyuga H. Rate equation approaches to amplification of enantiomeric excess and chiral symmetry breaking. Top Curr Chem. 2007. doi:10.1007/128_2006_108.

Complete book, authored

Blenkinsopp A, Paxton P. Symptoms in the pharmacy: a guide to the management of common illness. 3rd ed. Oxford: Blackwell Science; 1998.

Online document

Doe J. Title of subordinate document. In: The dictionary of substances and their effects. Royal Society of Chemistry. 1999. http://www.rsc.org/dose/title of subordinate document. Accessed 15 Jan 1999.

Online database

Healthwise Knowledgebase. US Pharmacopeia, Rockville. 1998. http://www.healthwise.org. Accessed 21 Sept 1998.

Supplementary material/private homepage

Doe J. Title of supplementary material. 2000. http://www.privatehomepage.com. Accessed 22 Feb 2000.

University site

Doe, J: Title of preprint. http://www.uni-heidelberg.de/mydata.html (1999). Accessed 25 Dec 1999.

Doe, J: Trivial HTTP, RFC2169. ftp://ftp.isi.edu/in-notes/rfc2169.txt (1999). Accessed 12 Nov 1999.

Organization site

ISSN International Centre: The ISSN register. http://www.issn.org (2006). Accessed 20 Feb 2007.

Dataset with persistent identifier

Zheng L-Y, Guo X-S, He B, Sun L-J, Peng Y, Dong S-S, et al. Genome data from sweet and grain sorghum (Sorghum bicolor). GigaScience Database. 2011. http://dx.doi.org/10.5524/100012 .

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