Instructions for Authors — Korean Circulation Journal

To enhance the journal’s quality and ensure its sustainable advancement, KCJ will introduce an Article Processing Charge (APC), which has previously been waived.

Please refer to the details below regarding future manuscript submissions and publications in KCJ.

The APC is USD 1,000 for Original Research articles which are submitted after 00:00 on July 6, 2026 (Based on the site time of the KCJ submission website). Articles supported by a grant from the Korean Society of Cardiology or the Korean Cardiac Research Foundation are exempt from APC.

Instructions for payment will be provided upon manuscript acceptance. Please note that the publication process will proceed only after the APC payment has been confirmed and the APC must be paid prior to publication.

We deeply appreciate your contribution of high-quality articles to KCJ and kindly ask for your understanding and cooperation for the journal’s advancement.

If you have any questions, please feel free to contact the KCJ Editorial Office at herz1@circulation.or.kr.

KCJ는 본 학회지의 질적 향상과 지속 가능한 발전을 도모하고자, 그동안 면제해왔던 논문 출판 비용(Article Processing Charge, APC)을 신설하게 되었습니다.

이에 아래와 같이 관련 사항을 안내 드리오니, 향후 KCJ 논문 투고 및 게재에 참고 부탁 드립니다.

부과 대상: 2026년 7월 6일 00:00 이후 투고된 Original Research Articles (KCJ 투고 사이트 하단 Site Time 기준)

*면제 대상: 대한심장학회/심장학연구재단 연구비 수혜 논문

APC 비용: USD 1,000

결제 방법: 논문 게재 승인 (Accept) 후 안내에 따라 결제 진행.

항상 수준 높은 논문을 투고해주시는 회원 여러분께 깊은 감사를 드리며, 학회지의 발전을 위한 너른 이해와 협조를 부탁 드립니다.

관련하여 문의사항이 있으시면 KCJ Editorial Office (herz1@circulation.or.kr)로 연락해 주시기 바랍니다.

감사합니다.

Instructions for authors

Revised as of July 2026

The

Korean Circulation Journal (KCJ)is the official journal of the Korean Society of Cardiology, the Korean Pediatric Heart Society, the Korean Society of Interventional Cardiology, and the Korean Society of Heart Failure. It is an open-access journal publishing monthly in English (https://www.e-kcj.org). It is a professional, international, peer-reviewed journal covering all aspects of cardiovascular medicine, including original researches of preclinical and clinical findings, state of the art reviews, perspectives for outbreaking issues, editorials, images in cardiovascular medicine, and letters to the editor. The journal aims to publish highly qualified and novel researches which improve our understanding of cardiovascular disease, educate students and health professionals, give scientific data to researchers and policy makers, and give benefits in clinical practice to general practitioners. KCJ adheres to COPE’sPrinciples of Transparency and Best Practice in Scholarly Publishingand COPE’sCore Practicesfor the overall publication process.

MANUSCRIPT SUBMISSION

The KCJ has an online submission and peer review system and manuscripts must be submitted electronically at

https://kcj.edmgr.com. Please first log in as an author and follow the directions. Manuscripts should be submitted by the corresponding author, who must indicate the contact address, phone number, and e-mail for correspondence on the title page of the manuscript. All articles submitted to the Journal must abide by these instructions. Failure to do so will result in return of the manuscript and possible delay in publication. For assistance, please contact us via e-mail, telephone, or fax. Revised manuscripts should be submitted through the same web system under the same manuscript number.In-Ho Chae, MD, PhD

Editor-in-chief, Korean Circulation Journal

101-1704, Lotte Castle President, 109 Mapo-daero, Mapo-gu, Seoul 04146, Korea

Tel: 82-2-3275-5258, Fax: 82-2-3275-5259

E-mail:

herz1@circulation.or.kr

EDITORIAL and PEER REVIEW PROCESS

2.1. Peer Review Process

All manuscripts are pre-examined for the format and ethical requirements by managing and ethical consultants, and then decide whether to request external peer review by experts and associate editors in related topics. The authors are blinded when the manuscript is requested for external review. External peer review will be done by at least 2 or more experts in the corresponding field. If needed, editorial staff may request a review from statisticians. The acceptance criteria for all papers are based on the quality and originality of the research and their clinical and scientific contributions in cardiovascular medicine. After request for external review, the initial decision is typically made within 4 weeks with the categories of “accept”, “minor revision”, “major revision”, or “reject”. The results of review and the reviewers’ comments will be sent to the corresponding author via e-mail. After revision according to the comments and recommendations, the corresponding author must submit the revised manuscript in the same E-submission system.

If manuscripts from Editorial Boards of KCJ are submitted, it is also treated through same process with other manuscripts. However, those authors are not involved in the peer reviewer selection, review process, or final decision.

Expedited reviewis available for the Original Researches unless otherwise requested. Authors wishing to expedite the review process should include a request and reasons in the cover letter. Reasons for expedited review may include the relevance of the research results and/or the potential simultaneous publication with a congress presentation. Handling editors will decide on expedited review within 3 working days, and provide an initial decision within 2 weeks. Authors should be aware that the expedited review process does not guarantee acceptance. Manuscripts not selected for expedited review can be submitted as regular manuscripts.

2.2. Revision and Acceptance

When you organize a

revised manuscript, you should carefully follow the instructions given in the editor's letter. With each revision, KCJ requires two versions of the manuscript to be resubmitted: one with changes tracked or highlighted and one clean version of the revised manuscript. In your response to the reviewers’ comments, authors have to address each reviewer comment point-by-point and provide the exact page number(s) and line number(s) where each revision was made in the final clean version of the revised manuscript. Failure to do so will cause a delay in the review of your revision. If references, figures or tables are moved, added, or deleted during the revision process, renumber them to reflect the changes so that all references, figures or tables are cited in numeric order.Failure to resubmit the revised manuscript within 8 weeks without notification to KCJ is considered to be a withdrawal of the manuscript.

2.3. After Decision

Acceptance

The finally accepted manuscript will be reviewed by a manuscript editor for consistency of format and the completeness of references. The manuscript may be revised according to the style guides of the journal. Before publication, the galley proof will be sent via e-mail to the corresponding author for approval.

※ Article Processing Charge

An article processing charge (APC) is required for all Original Research articles accepted for publication in the

Korean Circulation Journal.The APC is USD 1,000 for Original Research articles. Articles supported by a grant from the Korean Society of Cardiology or the Korean Cardiac Research Foundation are exempt from the APC. Instructions for payment will be provided upon manuscript acceptance. Please note that the publication process will proceed only after the APC payment has been confirmed and the APC must be paid prior to publication.

Article Type	APC (USD)
Original Research	1,000
State of the Art Reviews, Perspectives for Outbreaking Issues, Editorials, Images, Letters to the Editor, Research Letters	No charge

Complaints or Appeals

Authors, reviewers, readers, and submitters may issue complaints or appeals in cases including follows: falsification, fabrication, plagiarism, duplicate publication, authorship dispute, conflict of interest, ethical treatment of animals, informed consent, bias or unfair/inappropriate competitive acts, copyright, stolen data, defamation, and legal problem.

For the complaints or appeals, concrete data with answers to all factual questions (who, when, where, what, how, why) should be provided.

The Editor, Editorial Board Members including Ethics Consultant, and Editorial Office is responsible for the handling and resolving the submitted complaints and appeals. A Legal Consultant or Ethics Consultant will be involved with the decision making.

The consequence of resolution will depend on the type or degree of the misconduct and will follow the guidelines of the Committee of Publication Ethics (COPE). If not described above, the process of handling complaints and appeals follows the guidelines of the Committee of Publication Ethics available from:

https://publicationethics.org/appeals.

ETHICS from RESEARCH to PUBLICATION

All manuscripts should be prepared in strict observation of the research and publication ethics guideline recommended by the International Committee of Medical Journal Editors (ICMJE, available at

http://www.icmje.org), Council of Science Editors (https://www.councilscienceeditors.org/), World Association of Medical Editors (WAME,http://www.wame.org/), and the Korean Association of Medical Journal Editors (KAMJE,https://www.kamje.or.kr/en/main_en).All researchers involving animal, cellular, or molecular experiments should record a research note detailing the research process and achievements and follow the research note guidelines of their research institute. If the author’s affiliation is different from the institution that conducts the research, the institution that conducted the research should be marked first, and the original affiliation should be marked separately. KCJ will follow the guideline by the Committee on Publication Ethics (COPE,

http://publicationethics.org/) for settlement of any misconduct.3.1. Statement of Human and Animal Rights

All clinical research must be performed according to the principles embodied in the Declaration of Helsinki: (

https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects).Patients have a right to privacy. Therefore, when publishing identifiable images from human research participants, authors must include a statement in the published paper affirming that they have obtained informed consent for publication of the images (unless the consent has waived by an appropriate institutional review board). Images may be cropped to remove nonessential identifying details to protect anonymity but should not be otherwise altered.

Any identifying information, such as patients’ names, initials, hospital numbers, or dates of birth should not be included in images, written descriptions, videos, photographs, and pedigrees unless they are essential for scientific purposes. If identifying characteristics are altered to protect anonymity, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.

Research using animals also should be reviewed by an appropriate committee following the guidelines of the Institutional Animal Care and Use Committee (IACUC). Studies using pathogens requiring a high degree of biosafety should receive permission from a relevant committee such as the Institution Biosafety Committee (IBC).

Authors may be required to provide evidence that they obtained ethical and /or legal approval prior to conducting the research.

3.2. Statement of informed Consents and Institutional Review Board Approval

All researches involving human subjects, human material, or human data must be approved by an appropriate institutional review board.

For all research involving human subjects, informed consent to participate in the study should be obtained from the subjects (or their legally authorized representative), if not waived by the institutional review board.

A statement about this, including the name of the ethics committee and the reference number, must be stated in the methods of manuscript. If a study has been granted an exemption from requiring ethics approval, this should also be detailed in the manuscript (including the name of the ethics committee that granted the exemption).

In the process of submitting the manuscript, authors will be asked if they have obtained the IRB approval and the reference number need to be provided. The editor of the KCJ may request copies of the informed consent and documents of permission from IRB or related committees.

3.3. Authorship and Contribution

KCJ follows the recommendations for authorship by the ICMJE, 2019 (

http://icmje.org/icmje-recommendations.pdf) and Good Publication Practice Guidelines for Medical Journals 3rdEdition (KAMJE, 2019,https://www.kamje.or.kr/board/view?b_name=bo_publication&bo_id=13&per_page=).Authorship credits should be based on 1) substantial contributions to conception or design, acquisition of data, or analysis and interpretation of the data; AND 2) drafting of the manuscript or revising it critically for important intellectual contents; AND 3) final approval of the version to be published; AND 4) agreement to be accountable for all aspects of the work and ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Authors must meet all of these criteria. In addition, an author should be accountable for the parts of the work he or she has done and should be able to identify which co-authors are responsible for specific other parts of the work. Authors should have confidence in the integrity of the contributions of their co-authors. All those designated as authors should meet all four criteria for authorship, and all who meet the four criteria should be identified as authors. Those who do not meet all four criteria should be acknowledged as contributors not be authors. These authorship criteria are intended to reserve the status of authorship for those who deserve credit and can take responsibility for the work. The criteria are not intended for use as a means to disqualify colleagues from authorship who otherwise meet authorship criteria by denying them the opportunity to meet criterion #2 or 3. Therefore, all individuals who meet the first criterion should have the opportunity to participate in the review, drafting, and final approval of the manuscript.

The corresponding author can be only an author(s) who meets all four criteria and cannot be an author who did not meet any one or more of the criteria. The corresponding author should be available throughout the full processes even after publication. When a study is conducted by a large and multicenter group, the group should identify the individual authors who accept responsibility for the manuscript before submission. When submitting a manuscript authored by a group, the corresponding author should clearly indicate the preferred citation and identify all individual authors as well as group name. Contributors to the study can be listed in an acknowledgment section. Acquisition of funding, collection of data, or general supervision of the research does not meet the authorship criteria, and such parties should not be listed as authors. If the corresponding author requests the addition or removal of authors after submission, the editor will assess the reason and a written document regarding agreement from all co-authors. The KCJ has no responsibility for changes in authorship.

3.4. Redundant Publication and Plagiarism

Redundant publication is defined as “reporting (publishing or attempting to publish) substantially the same work more than once, without attribution of the original source(s)”. Characteristics of reports that are substantially similar include the following: (a) “at least one of the authors must be common to all reports (if there are no common authors, it is more likely plagiarism than redundant publication),” (b) “the subjects or study populations are the same or overlapped,” (c) “the methodology is typically identical or nearly so,” and (d) “the results and their interpretation generally vary little, if at all.”

When submitting a manuscript, authors should include a letter informing the editor of any potential overlap with other material already published or material being evaluated for publication and should also state how the manuscript submitted to KCJ differs substantially from other materials. If all or part of your patient population was previously reported, this should be mentioned in the Methods, with citation of the appropriate reference(s).

3.4.1 Handling of Misconduct –Corrections & Retractions

KCJ takes all cases of publication misconduct seriously. All reviewers share a responsibility to report any suspected issues with the manuscript to the editor.

If a reviewer or editor raises a concern about suspected cases of research and publication misconduct, such as a redundant publication, plagiarism, fabricated data, changes in authorship, undisclosed conflicts of interests, or an ethical problem, that person should be informed that the Journal editors will perform an investigation. The investigation process will follow the flowchart provided by the Committee on Publication Ethics [COPE] (

https://publicationethics.org/resources/flowcharts).If the investigation confirms any scientific misconduct, a retraction of the article will be published. If warranted, the authors will be invited to prepare the retraction, which should be submitted with an assignment of copyright statement that has been signed by all authors. If the paper has not been published, then the editor can always reject the paper.

Instances of misconduct will be shared with the editorial board of the KCJ. The editor may wish to impose sanctions, notify editors of other biomedical journals, and depending on the severity of the allegation, notify the author’s institution.

KCJ will not hesitate to publish errata, corrigenda, clarifications, retractions, and apologies when any misconduct is founded.

3.5. Clinical Trials

1) Obligation to register

Clinical trial defined as “any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome” should be registered to the primary registry to be prior publication. KCJ accepts the registration in any of the primary registries that participate in the WHO International Clinical Trials Portal (

http://www.who.int/ictrp/en/), NIH ClinicalTrials.gov (http://www.clinicaltrials.gov/), ISRCTN Resister (www.ISRCTN.org), or the Clinical Research Information Service (CRIS), Korea CDC (https://cris.hih.go.kr/cris/index.jsp). The clinical trial registration number shall be published at the end of the abstract.2) Data sharing statement

KCJ accepts the ICMJE Recommendations for data sharing statement policy (

http://icmje.org/icmje-recommendations.pdf). All manuscripts reporting clinical trial results should submit a data sharing statement following the ICMJE guidelines from 1 July 2018.When the manuscript is submitted, authors should specify the methods of data sharing if it is possible for sharing, otherwise, specify the reason of unable.

Authors may refer to the editorial, “Data Sharing statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors,” in JKMS Vol. 32, No. 7:1051-1053 (

http://crossmark.crossref.org/dialog/?doi=10.3346/jkms.2017.32.7.1051&domain=pdf&date_stamp=2017-06-05).3.6. Conflict of Interest

At manuscript submission, the KCJ requires the corresponding author to summarize all author conflicts of interest disclosures. The conflicts of interest can exist when an author (or author’s institution or employer) has financial or personal relationship or affiliations that could have influence on or bias the authors’ decisions, works, or the manuscript. Such conflicts can be financial support or private connection to pharmaceutical companies, potential pressure from interest groups, or academic benefits.

The KCJ requires complete disclosure of all relevant financial relationships and potential financial conflicts of interest regardless of amount of value. The corresponding author is asked to inform the Editor of all author conflicts of interest that could influence their interpretation of the data.

At manuscript acceptance, the KCJ can ask the authors to confirm and update their disclosure of conflicts of interest online. At the time of publication, the final status of conflicts of interest will be disclosed to the readers on https://www.e-kcj.org. If any author’s disclosure of conflicts of interest is determined to be inaccurate or incomplete after publication, a correction will be published to rectify the original published disclosure statement, and additional action can be taken as necessary.

3.7. Funding

All sources of funding for the study should be listed explicitly and declared under the title of ‘Funding’. The roles of funders were stated in the manuscript including study design, data collection, analysis, any decisions in publication, or preparation of manuscript.

All forms are now signed and submitted electronically. Once the revision manuscript is submitted, the authors will be sent links to complete the electronic Relationship with Industry form and all authors are required to electronically sign a relationship with industry form. Once completed, the further process will be started. Only authors appearing on the final title page will be sent a form.

EDITORIAL POLICY

The editorial staffs assume that all authors agreed with the KCJ policies of manuscript submission. Except for the preapproved secondary publication by editor-in-chief, all manuscripts submitted to KCJ must not be previously published in all languages and not be under consideration for submission or publication in other journals. The identities of decision makers will not be disclosed in any circumstances.

MANUSCRIPT PREPARATION AND FORMAT

The manuscript should be prepared according to “Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals (ICMJE Recommendations, formerly the Uniform Requirements for Manuscripts)” (

http://www.icmje.org).All materials must be written in clear, appropriate English using Microsoft Word (doc) or other major word-processing programs.

The manuscript must be double-spaced in 12-point font with 1-inch margin on both sides, top, and bottom on A4 sized paper or North American letter-sized paper.

Author’s summary

The authors of original researches, state of the art reviews, perspectives of the outbreaking issues have to summarize the articles consisting of; what are the unmet needs, important findings for the unmet needs and scientific and clinical meanings of the article. Avoid copying the part of abstract and exceeding 100 words.

Representative image

Select one figure which is representing the finding of the articles of state of the art reviews, perspectives of the outbreaking issues, images of cardiovascular medicine.

5.1. Original Researches

• Clinical Investigation and Reports: Studies conducted in humans or analysis of human data

• Basic Science Reports: Studies conducted in animals and in vitro experiments

• Word count: ≤ 5000 words excluding the title page, abstract, and tables

• Structured abstract: ≤ 250 words with the following sections: Background and Objectives, Methods, Results, Conclusions. Use complete sentences. All data in the abstract also must appear in the manuscript text or tables

• Keywords: Three to five keywords from the Medical Subject Headings (MeSH) list of Index Medicus

• Number of references: ≤ 30

• Number of figures and tables: ≤ 8

• Graphic abstract: Pictorial form designed image representing the finding of the articles of the research should be included.

The manuscript should be arranged in the following sequence: 1) Title Page, 2) Abstract, 3) Keywords, 4) Text, 5) Acknowledgements (if applicable), 6) Funding, 7) Disclosures 8) References, 9) Figure Legends, 10) Figures, 11) Tables, and 12) Supplemental Materials. Page numbering should begin with the Title Page.

Title Page

The title page should appear as follows; the title of the manuscript, a short title, names of all authors with their academic degrees and ORCID IDs, total word count of the manuscript, conflict of interests, and funding statement.

Full title
Short title (not to exceed 45 characters including spaces)
Authors’ names including academic degrees and ORCID iDs.
The contact information for correspondence and reprints, including name, academic degree(s), address (institutional affiliation, city, zip code, and country), telephone and fax numbers, and e-mail address. The corresponding author will be the sole contact for all submission queries.
Total word count: Include main text, acknowledgement, references, and figure legends. Exclude the title page, abstract, and tables.
Funding statements: Describe the sources of funding that have supported the work with relevant grant numbers. Please also describe the role of any sponsors or funders and if they had no role, include the following statement at the end of your statement: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”
Conflict of Interest: Any potential conflicts of interest relevant to the manuscript should be described. If there are no conflicts of interest, authors should state that none exists.

Abstract

Do not cite references in the abstract.
Limit use of acronyms and abbreviations. Define acronym or abbreviation at its first use in parentheses.
A structured abstract of no more than 250 words for Original Researches
Use the following four headings in Original Researches

• Background and Objectives: Rationale for study

• Methods: Brief presentation of study design and key methods

• Results: Succinct presentation of key results; please include sample sizes

• Conclusions: Succinct statement of data interpretation

All data in the abstract also must appear in the manuscript text or tables.
The clinical trial registration number shall be published at the end of the abstract.

Keywords

Provide three to five keywords from the Medical Subject Headings (MeSH) list of Index Medicus:

http://www.nlm.nih.gov/meshText

The text of Original Researches should be structured using the main headings of Introduction, Methods, Results, and Discussion.
Abbreviations must be defined at first mention in the text and each table and figure.
Every reference, figure, and table should be cited in the text in numerical order according to order of mention.
Ethical Approval (required): Please denote that your study received the proper ethical oversight

in both your cover letter and your Methods section. For manuscripts reporting data on human subjects, note institutional review board/ethics committee approval (or formal review and exemption), includingthe specific name of the board or committee and the reference number. For studies involving animal experiments, note that the study complied with all institutional and national requirements for the care and use of laboratory animals and, if applicable, received animal care and use committee approval.• Experimental animals: State the species, strain, number used, and pertinent descriptive characteristics. When describing surgical procedures, identify the preanesthetic and anesthetic agents used and the amounts, concentrations, routes, and frequency of administration of each. Paralytic agents are not considered acceptable substitutes for anesthetics. For other invasive procedures on animals, report the analgesic or tranquilizing drug used. If none were used, provide justification for exclusion.

• Human studies: Indicate that the study was approved by an institutional review board along with the name of the IRB, and that the participants gave written informed consent (or that no informed consent was required).

• Studies of medications, biologics, and devices: Generic rather than trademark names of all therapeutics should be used.

Acknowledgments

All non-author contributors who did not meet the criteria of author by ICMJE can be listed in the acknowledgments section.

Funding

Describe the sources of funding that have supported the work with relevant grant numbers. Please also describe the role of any sponsors or funders and if they had no role, include the following statement at the end of your statement: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

Disclosure of conflicts of interest

Any potential conflicts of interest relevant to the manuscript should be described. If there are no conflicts of interest, authors should state that none exists.

References

The description of a journal reference follows the below description. Otherwise, it follows the NLM Style Guide for Authors, Editors, and Publishers: Patrias, K. Citing medicine: the NLM style guide for authors, editors, and publishers [Internet]. 2nd ed. Wendling, DL, technical editor. Bethesda (MD): National Library of Medicine (US); 2007 [updated 2009 Jan 14; cited 2009 June 25]. Available from: http://www.nlm.nih.gov/citingmedicine
Accuracy of reference data is the responsibility of the author.
Verify all references against original sources.
The reference list should be typed double-spaced on pages separate from the text; references must be numbered consecutively in the order in which they are mentioned in the text. List all authors if 6 or fewer; otherwise, list the first 3 and add “et al.”
Names of journals should be abbreviated in the style used in Index Medicus.
Overall format of references is as follows:

Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterol-emia.

N Engl J Med1995;20:1301-7.- Books can be cited as follows:

Hinohara T, Robertson CG, Simpson JB. Directional coronary atherectomy. In: Topol EJ, editor.

Textbook of Interventional Cardiology. 2nd ed. Philadelphia: W.B. Saunders Company; 1994. p.645-57.- Do not cite abstracts older than 2 years. Abstracts can be cited as follows:

Sweeney RJ, Gill RM, Reid PR. Increased action potential prolongation by low voltage biphasic versus monophasic field stimulation.

J Am Coll Cardiol1995;86A. Abstract- Personal communications, unpublished observations, and submitted manuscripts are not legitimate references. They must be cited in the text only (not the reference list).

If an article has been published online but has not yet been given an issue or pages, the digital object identifier (DOI) should be supplied.

Figure Legends

All figures must have a number, title, and caption.
Figures should be cited in numerical order in the text.
Figure titles should be short and followed by a 2 to 3 sentence caption.
Figure Legends should be typed double-spaced on pages separate from the text.
All abbreviations should be identified in alphabetical order at the end of each legend.

Figures

Figures and graphs should be provided in GIF, TIFF, EPS, or JPG format.
Color and Gray scale images must be at least 300 DPI. The smallest parts of a figure should be legible when they are reduced to the final print size.
If the number of files is more than five, one PowerPoint file is acceptable.
Figure numbers must correspond with the order in which they are mentioned in the text.
All abbreviations used in the figure should be identified in alphabetical order at the end of each legend.
All symbols used (arrows, circles, etc.) must be explained.
If previously published figures are used, written permission from the original publisher is required. See STM Guidelines for details:

http://www.stm-assoc.org/copyright-legal-affairs/permissions/permissions-guidelines.- Symbols, arrows, or letters used in photographs should contrast the background visually. The legend for each light microscopic image should indicate the stain used and the level of magnification. Electron micrographs should have an internal magnification scale marker. All types of figure can be reduced, enlarged, or trimmed for publication by the editor.

Supply a scale bar with photomicrographs.

Tables

Begin each table on a separate page, double-spaced.
The table number should be Arabic, followed by a period and brief title.
Table numbers must correspond with the order cited in the text.
Tables should be self-explanatory, and the data presented in them should not be duplicated in the text or figures.
Do not use vertical lines between columns. Use horizontal lines above and below the column headings and at the bottom of the table only. Use extra spaces to delineate sections within the table.
Abbreviations used in the table must be defined in a footnote to the table.
Indicate footnotes in this order: , †, ‡, §, ∥, ¶, #, *.

Supplemental Materials

Supplemental materials will be provided in the online version only. Such materials can consist of 1) Information that cannot be printed, such as animations, video clips, and sound recordings, 2) Information that can be presented more conveniently in electronic form, AND 3) Large original data, e.g., additional tables or illustrations.

Submission

• Submit all supplemental materials in standard file formats.

• All submitted supplemental materials must be mentioned in the manuscript.

• All supplemental materials can be submitted with your article in the E-Submission System.

Multimedia files

• Multimedia files should be accompanied by brief relevant information explaining the content of the audio, video, or animation files.

• Please ensure that all researchers featured in the multimedia files have given permission for publication. Written consent must be submitted.

• Audio material should preferably be submitted as an MP3 file, no larger than 10 MB.

• Video material should be submitted in a standard format such as MPEG-2, MPEG-4, H.264, WMV, QuickTime codec with QuickTime (MOV), AVI, or MP4 and be no larger than 10 MB.

• The URL address will be provided in the offline journal and will link to the video in the online journal. Videos should be numbered in the order they appear in the text.

• If your files are larger than 10 MB, please contact the Korean Circulation Journal's editorial office.

Text and Presentations

• Submit your material as a PDF, DOC, or PPT file.

• A collection of figures can also be combined in a single file.

5.2. State of the Art Reviews

Concise and comprehensive articles devoted to review a topic from basic mechanisms to clinical manifestations and interventional approaches to global health implications comprise this category. Most review articles are invited by the Editors; however, unsolicited material might also be considered for publication. If you wish to submit a review article to the journal, please do so via

https://e-kcj.orgour submission site.• Word count: ≤ 10,000 words excluding tables

• Unstructured abstract: ≤ 250 words

• Reference limit: None

Clinical Practice Guideline submissions must be proposed to and approved by the Editor-in-Chief prior to submission. Please submit proposals to

herz1@circulation.or.kr. After the approval, the editorial office will contact the corresponding author(s) to proceed further steps.Papers that contain contents in such areas as policy, ethics, education and any special interest among the medical community can be published as Special Issues with the outside the scope of the other article types listed. These papers must be proposed to and approved by the Editor-in-Chief prior to submission. Please submit proposals to

herz1@circulation.or.kr. After the approval, the editorial office will contact the corresponding author(s) to proceed further steps.5.3. Perspectives for Outbreaking Issues

Perspectives for outbreaking issues are brief and timely articles for the newly emerging or debating issues in cardiovascular medicine. Both invited and unsolicited articles can be published after peer-review by experts and editor on related fields.

• Word count: ≤ 2,000 words excluding tables and figures

• Keywords: three to five words from the Medical Subject Headings (MeSH) list of Index Medicus

• Reference limit: ≤ 25

• Number of figures and tables: ≤ 4

5.4. Editorials

Editorials are commentaries on articles that appear in the journal and are invited by the editors. Editorial topics could include active areas of research, fresh insights, and debates in all fields of cardiovascular medicine. If you are invited to write an editorial, specific requirements will be sent to you. Please do not submit unsolicited editorials.

• Number of references: ≤ 10

5.5. Images in Cardiovascular Medicine

Clinical images illustrate either important or novel findings and provide insight into diagnosis and mechanisms responsible for cardiovascular medicine. The maximum number of authors for images in cardiovascular medicine is 8.

• Word count: ≤ 250 words

• Number of references: ≤ 5

5.6. Letters to the Editor

Letters to the Editor focus on a specific article published in KCJ within 6 months of the issue date. We will seek a reply to your letter from the authors of the original paper and publish both together.

• Word count: ≤ 500 words including references

• Number of Authors: ≤ 3

• Number of figures and tables: ≤ 1

The decision will be made by the reviewers who reviewed the original articles.

5.7. Research Letter

Research Letter is the original investigations of a focused nature.

• Word count: ≤ 800

• Number of Authors: ≤ 10 (Co-first author, Co-corresponding authors are not allowed)

• Supplementary Materials are not allowed

REVISED MANUSCRIPTS

When you organize a revised version of your manuscript, you should carefully follow the instructions given in the editor’s letter. Please submit both a clean copy of your manuscript and an annotated copy describing the changes you have made. Failure to do so will cause a delay in the review of your revision. If references, figures or tables are moved, added, or deleted during the revision process, renumber them to reflect the changes so that all references, figures or tables are cited in numeric order.

The annotated copy should have changes by red or highlighted (either using the Track Changes function in MS Word), with notes in the text referring to the editor or reviewer queries.

All published papers will become the permanent property of the Korean Society of Cardiology and must not be published elsewhere without written permission from the Society. A copyright transfer agreement form should be submitted electronically on the submission website. This form is identical to the Creative Commons (Attribution-Noncommercial) at:

https://creativecommons.org/licenses/by-nc/4.0/legalcode.

AUTHOR REPRINTS

Inquiries for reprints for educational, commercial, or promotional use can be directed to:

Korean Circulation Journal Editorial office

herz1@circulation.or.kr##

Revision history

Revised as of August 2023

Revised as of March 2023

Revised as of November 2022

Revised as of July 2022

Revised as of September 2021

Revised as of March 2021

Revised as of December 2020

Revised as of February 2020

Revised as of July 2018

Revised as of September 2017

Revised as of November 2015

Revised as of January 2014

Journal Information

Journal Title:

Korean Circulation Journal

Journal Abbreviation:

Korean Circ J

Acronym:

Publication Date:

Vol. 35, no. 1 (2005) -

Frequency:

Monthly

Publisher:

Korean Society of Cardiology

Language:

English

pISSN:

1738-5520

eISSN:

1738-5555

DOI Prefix:

10.4070/kcj

Current Format Status:

Electronic only

Continues:

Broad Subject Term(s):

Cardiology

Vascular Diseases

MeSH (NLM):

Blood Circulation

Cardiovascular Diseases/physiopathology

Cardiovascular Physiological Phenomena

SC (SCI):

Cardiac & Cardiovascular Systems

Hematology

Open Access:

Electronic Links:

Indexed/Tracked/Covered By:

Google Scholar

Guidelines

Korean Circ J. 2026;56:e40. Published online Jan 02, 2026.

Korean Circ J. 2026 Jan;56(1):9-32. Published online Dec 11, 2025.

Korean Circ J. 2023 Jul;53(7):452-471. Published online July 7, 2023.

Korean Circ J. 2023 Jul;53(7):425-451. Published online July 13, 2023.

Korean Circ J. 2023 Apr;53(4):217-238. Published online April 11, 2023.

Korean Circ J. 2023 Apr;53(4):195-216. Published online April 11, 2023.

Korean Circ J. 2022 Jan;52(1):1-33. Published online November 26, 2021.

Korean Circ J. 2021 Apr;51(4):289-307. Published online March 25, 2021.

Korean Circ J. 2020 Nov;50(11):974-983. Published online October 19, 2020.

Korean Circ J. 2020 Oct;50(10):845-866. Published online August 25, 2020.

Korean Circ J. 2020 Jun;50(6):476-484. Published online February 29, 2020.

Korean Circ J. 2020 Jun;50(6):485-498. Published online February 18, 2020.

Self-Reported Diet Management and Adherence to Dietary Guidelines in Korean Adults with Hypertension

Korean Circ J. 2020 May;50(5):432-440. Published online January 20, 2020.

Korean Circ J. 2019 Dec;49(12):1123-1135. Published online October 21, 2019.

Korean Circ J. 2019 Nov;49(11):1066-1111. Published online August 29, 2019.

Korean Circ J. 2019 Oct;49(10):883-907. Published online August 8, 2019.

Korean Circ J. 2019 Mar;49(3):249-251. Published online January 7, 2019.

Korean Circ J. 2019 Jan;49(1):46-68. Published online December 24, 2018.

KSHF Guidelines for the Management of Acute Heart Failure: Part II. Treatment of Acute Heart Failure

Korean Circ J. 2019 Jan;49(1):22-45. Published online December 27, 2018.

Korean Circ J. 2019 Jan;49(1):1-21. Published online December 27, 2018.

Korean Circ J. 2018 Dec;48(12):1033-1080. Published online October 31, 2018.

Korean Circ J. 2018 Jun;48(6):492-504. Published online March 12, 2018.

Korean Circ J. 2017 Nov;47(6):877-887. Published online October 17, 2017.

Korean Circ J. 2017 Nov;47(6):861-863. Published online November 9, 2017.

Korean Circ J. 2017 Sep;47(5):555-643. Published online September 18, 2017.

Korean Circ J. 2017 Sep;47(5):543-554. Published online August 21, 2017.

Korean Circ J. 2016 May;46(3):275-306. Published online May 27, 2016.

Korean Circ J. 2015 Mar;45(2):96-105. Published online March 24, 2015.

Korean Circ J. 2014 Nov;44(6):359-385. Published online November 25, 2014.

Korean Circ J. 2008 Sep;38(9):483-490.Korean. Published online September 30, 2008.

Korean Circ J. 2006 Sep;36(9):644-651.Korean. Published online September 30, 2006.

Korean Circ J. 2006 Jun;36(6):405-410.English. Published online June 30, 2006.

Korean Circ J. 2001 Aug;31(8):767-772.Korean. Published online August 31, 2001.

Published online May 20, 2020.

https://doi.org/10.4070/kcj.2020.0171

Cardiovascular Research Using the Korean National Health Information Database

Eue-Keun Choi

, MD, PhD

Abstract

The Korean National Health Information Database (NHID) contains nationwide claims data, including sociodemographic data, health care utilization, health screening data, and healthcare provider information. To compensate for the limitations of randomized clinical trials, real-world observational studies using claims data have emerged as a novel research tool. We summarized the structure of the Korean NHID and the recent researches conducted in the field of cardiovascular science. Epidemiological studies, prescription patterns, temporal trends, comparison of effectiveness and safety of treatments, variability index using laboratory data, and rare intractable disease constitute interesting topics of research in cardiovascular science using the NHID. The operational definition of covariates and clinical outcomes is important for researchers interested in using the NHID data as new tools to prove their hypothesis. A step-by-step approach adopted by a team of data scientists, epidemiologists, statisticians, and clinical researchers may be most effective while designing research studies. The ultimate direction of research using the NHID should aim to improve the welfare of the public by promoting public health, reducing medical costs, and guiding healthcare policies.

INTRODUCTION

Since the beginning of medical science, observation of the “real-world” experience has been a common traditional method to develop new medical therapies. The use of randomized clinical trials (RCTs) has now become the gold standard for proving the efficacy and safety of novel treatments. The evidence generated by this clinical trial model has replaced real-world evidence (RWE) and practice-based observations. The data acquired from RCTs have many advantages, including high internal and external validity, completeness of data, and adjudication of events predefined on study protocols. However, in reality, we frequently encounter diverse and heterogeneous patients in clinical practice, who are not included in RCTs. Patients who are very old, having extreme bodyweight, concomitant medications, and multimorbidities pose a challenge due to a lack of evidence to guide clinical practice. Limited representativeness, high costs, long study duration, and risk of failure pose further challenges for RCTs. Non-randomized observational studies would complement the weaknesses of RCT by providing supplementary data. Moreover, these comprehensive datasets represent large populations, thus, including participants otherwise excluded from RCTs. ‘Real-world’ observation studies use several types of data sources, including regulatory sponsored studies, registries sponsored by learned societies, nationwide cohorts, claims data, investigator-initiated and industry-sponsored studies, and hospital cohorts.1) Electronic medical records have now become the standard method to collect patient data and for administrative work regarding reimbursement and payment. This exponential growth of data is gaining tremendous interest as a novel research tool.

Furthermore, the 21st Century Cures Act (Cures Act) requires the Food and Drug Administration (FDA) to develop programs aimed at accelerating the development of drugs and medical devices. This will also guide the evaluation of RWE to support the approval of previously approved drugs or to fulfill the post-approval study requirements. The FDA is now working on generating evidence supporting the effectiveness and safety of RWE, supporting the findings of RCTs in real-world settings, and developing programs using electronic health records. Appropriate use of the data requires adequate knowledge of the characteristics of the database. Therefore, we sought to summarize the structure of the Korean National Health Information Database (NHID). We also aimed to summarize the findings of recent studies in the field of cardiovascular science, which would be of particular interest to researchers interested in using the NHID data as a new tool to prove their hypotheses.

BASICS OF THE KOREAN NATIONWIDE CLAIMS DATABASE

South Korea (hereafter, Korea) implements a single-payer, universal, mostly fee-for-service, and compulsory healthcare insurance system. The National Health Insurance (NHI) system includes the insured, the healthcare providers, and the regulators of the healthcare system, constituting the National Health Insurance Service (NHIS), Health Insurance Review Agency (HIRA), and Ministry of Health and Welfare (Figure 1).2) Those insured by NHI pay monthly insurance contributions for medical services provided by health care providers. The medical aid program covers low-income households with a minimum livelihood. The NHI program managed by NHIS, Medical Aid for low income groups, and long-term care insurance cover 100% of the Korean population, which was approximately 52 million in 2019. Since the NHIS pays costs based on the billing records of health care providers, the NHIS created a database to collect the required information on insurance eligibility, insurance contributions, medical history, and medical institutions. The NHI program provides health care benefits, including diagnosis, laboratory tests, drugs, medical materials, treatment, surgery, rehabilitation, hospitalization, nursing, and transportation by healthcare providers, and health screening services.2)

Figure 1

Structure of National Health Insurance and National Health Information DB of Korea.

DB = database.

STRUCTURE OF THE KOREAN NATIONAL HEALTH INSURANCE DATABASE

The Korean NHIS constructed the nationwide claims database called the Korean National Health Insurance Database (NHID),3) which consists of five databases, namely the eligibility database, national health screening database, health care utilization database, long-term care insurance database, and health care provider database (Figure 1).

The eligibility database contains information, including sociodemographic data, use of inpatient and outpatient services, pharmacy dispensing claims, and data of death, compiled by Statistics Korea. The annual reports of Statistics Korea reported a 92% accuracy of cause of death.4)

The national health screening database constitutes detailed lifestyle questionnaires, laboratory results, and anthropometric measurements. Health screening programs comprise general national health screening, health screening program for transitional ages (those aged 40 and 66 years), early childhood health screening program, and cancer screening programs.5) All insured Koreans aged 40 years or older, and their dependents are recommended to undergo biannual general health screening without cost. The participation rate of the general health screening program among eligible participants was 74.8% in 2014.6)

The health care utilization database includes information regarding inpatient and outpatient usage and prescription records, which is the largest component of the NHID. Diagnoses were coded in compliance with the Korean Standard Classification of Diseases (KCD) Version 6, which is based on the International Classification of Diseases 10th Revision (ICD-10). However, diagnoses are currently coded as per KCD7, introduced in 2016.

The long-term care insurance database constitutes information on functional assessment, including physical function, nursing, unique treatments, behavioral symptoms, cognitive function, and rehabilitation needs of the beneficiaries.

The health care provider database includes information regarding health care institutions, health care professionals, and equipment. The database contains de-identified personal information to ensure anonymity. NHI system does not cover medical services conducted for cosmetic purposes. Additionally, information regarding new drugs and procedures that are not covered by the NHI system is not included in the NHID.

KOREAN NATIONAL HEALTH INSURANCE SERVICE - NATIONAL SAMPLE COHORT

Since the size of the NHID is too large, which limits usability and accessibility, the NHIS constructed a representative sample database called NHIS-National Sample Cohort (NHIS-NSC).5), 7) NHIS-NSC constitutes approximately a million participants, 2.2% of the total eligible population, who were randomly sampled from the 2002 NHID, and followed for 11 years, until 2013. NHIS-NSC includes information regarding participants' eligibility, history of medical treatment, healthcare providers, and general health screening information.

HEALTH INSURANCE AND REVIEW ASSESSMENT DATABASE

Since the size of the NHID is too large, which limits usability and accessibility, the NHIS constructed a representative sample database called NHIS-National Sample Cohort (NHIS-NSC).8) Researchers have been provided access to the HIRA data since 2009, which was accelerated by promoting “Opening and Sharing Big Data for Value Creation” in 2013. The HIRA data constitutes six files, namely the general information file; healthcare services file, which include inpatient prescriptions; diagnoses file; outpatient prescriptions file; drug master file; and provider information file.8)

Although HIRA data uses the same claims data as the NHID, there are several differences. HIRA data could be analyzed only for a 5-year period beginning from the current year. Recently, this restriction of HIRA data has been changed to the limitation of data size. If the data size is within the limitation, data would be available from 2007. Moreover, HIRA data does not include health screening data, thereby excluding lifestyle questionnaires, laboratory data, and anthropometric information. Further, the mortality data compiled by Statistics Korea was not linked to HIRA data, thus, mortality data could not be analyzed. However, HIRA data does analyze in-hospital death. The eligibility database of the NHID is also not linked to HIRA, thus, HIRA data excludes detailed information regarding participant eligibility.

STRENGTHS AND LIMITATIONS OF THE NHID

The NHID has several strengths (Table 1). First, since the NHID constitutes data for more than 52 million people, it is one of the largest claims datasets. The NHID also contains data regarding all age groups and the entire region, which reduces the possibility of selection bias. Moreover, the NHID is different from the Medicare and Medicaid program of the United States, which are restricted to either elders or those with low income. Second, the NHID includes health screening information containing detailed lifestyle questionnaires, laboratory results, and anthropometric measurements, which are not included in other claims databases. Taiwan has a similar healthcare insurance system as Korea, and the National Health Research Institute collects registration and claims data of the entire population in Taiwan. Various scientific researchers have utilized these reliable data sources and published many relevant papers in cardiovascular science.9), 10), 11), 12), 13), 14), 15), 16) However, Taiwan does not implement a health screening program, thus, the claims data do not include lifestyle variables, laboratory results, and anthropometric data. Third, the NHID includes customized cohort datasets, such as NHIS-NSC. Fourth, since the NHID has been linked to other datasets, such as mortality data from Statistics Korea, further detailed information is available for analysis. However, regulations and social consensus are needed to solve this issue. Fifth, the resident registration number would make it more reliable to track for survival. Multiple databases are operated by private insurers in the United States, thus, the mortality data is not reliable. The longitudinal data of this database may be useful for studying long-term outcomes. Sixth, NHIS is also implementing a rare intractable disease (RID) program to offer financial support to patients diagnosed with certain rare and intractable diseases.

Table 1

Strengths and limitations of Korean National Health Information Database

The NHID also has several limitations. First, since this dataset was established for recording claims and reimbursements, the dataset may not be optimal for research purposes. There may be a discrepancy between the real disease and the diagnosis claimed by the healthcare providers. Over- or under-diagnosis may pose another limitation. Therefore, validating appropriate operational definitions may be needed before performing the main analysis. Second, since not all eligible subjects undergo regular health screening, the NHID may include data based on only parts of the population. Third, the NHID contains basic laboratory test results, thus, excluding more detailed test results, such as time in therapeutic range in warfarin users, and cardiac enzyme in myocardial infarction patients. Therefore, the NHID may need to include data from other datasets or hospital records. Fourth, the NHID does not include information about healthcare services not covered by the NHI system, such as cosmetic procedures, over-the-counter medicines, and uninsured new drugs or treatment. Fifth, although data are publicly available, the complex data structure containing a large number of variables and complicated administrative process pose a challenge for researchers. Research would require access to the database, a proper statistical approach, and an understanding of operational definitions.

The NHID may be accessed via the Health Insurance Data Service home page (http://nhiss.nhis.or.kr). However, the researchers have to submit a study proposal for acquiring approval from each institutional review board, which is also reviewed by the NHIS review committee. Access to the database is allowed only in designated areas, and remote access is available only for NHIS-NSC. The raw data cannot be retrieved from the NHID server, and only analyzed results can be accessed after acquiring approval. The detailed data of the NHID and substructure are summarized elsewhere.2), 3), 5), 7), 8)

CARDIOVASCULAR RESEARCHERS USING THE NATIONAL HEALTH INFORMATION DATABASE AND HEALTH INSURANCE REVIEW AGENCY DATA

NHID and HIRA data may be used in various research areas. Epidemiological studies, describing the prevalence and incidence of disease, temporal trends, or geographical distribution of disease, would be the first steps to reporting basic statistical reports of Korea. These statistics would be important to compare the disease status with other countries. The burden of disease for future generations may be inferred by the current disease status. Atrial fibrillation (AF) is one of the common research topics using NHID and HIRA data. We have summarized recent papers regarding researches on AF (Figure 2).

Figure 2

Researches on atrial fibrillation using National Health Information database and Health Insurance Review and Assessment.

BPV = blood pressure variability; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; DM = diabetes mellitus; GGT = gamma-glutamyl transferase; MHO = metabolically healthy obese; MI = myocardial infarction; NOAC = non-vitamin K antagonist oral anticoagulant; OSA = obstructive sleep apnea.

Epidemiology of atrial fibrillation

AF is the most common cardiac arrhythmia, and the burden of AF has increased gradually, which now poses a major public healthcare burden.17), 18) The temporal trends in the incidence and prevalence of AF in the entire adult population in Korea from 2008 to 2015 have been reported using the NHID.19) The incidence and prevalence of AF have increased gradually in this period. Moreover, the number of patients with a CHA2DS2-VASc score of more than 2 points increased dramatically due to an increase in the elderly population and the prevalence of comorbidities, such as heart failure and diabetes. Kim et al.20) reported that hospitalization for AF, especially due to major bleeding, has increased over the last ten years in Korea. Therefore, AF has resulted in an increment in hospitalization costs due to AF-related complications. AF increased the risk of stroke, hospitalization, and the risk of mortality after adjusting cardiovascular comorbidities.9), 21) The risk of all-cause mortality in Korean patients with AF was 3.7-fold higher than that of the general population.22) The most common cause of death was cardiovascular disease (38.5%), and cerebral infarction was the leading specific cause, which also supports evidence suggesting the need to pay more attention to stroke prevention.

Prescription pattern of oral anticoagulants in patients with atrial fibrillation

The prescription pattern of certain drugs has been analyzed using the NHID. Past findings include temporal trends of antithrombotic therapy for stroke prevention in Korean patients with non-valvular AF.23) Asians with AF are usually less likely to receive anticoagulation therapy compared to the Western population. The global registry on long-term oral antithrombotic treatment in patients with atrial fibrillation (GLORIA-AF) registry reports that only 55% of the Asian population with AF were prescribed oral anticoagulants (OAC), whereas 90% of the European population with AF received OAC, and the most common OAC was non-vitamin K antagonist oral anticoagulants (NOACs).24) In line with GLORIA-AF registry, a 50.6% OAC prescription rate was reported in Korean patients with non-valvular AF, and CHA2DS2-VASc score ≥2 in 2015.23) OAC underuse was predominant in female patients, and patients with presence of vascular disease and prior intracranial hemorrhage (ICH). The geographical location and income levels were also associated with AF prevalence and OAC prescription rates.25) Yu et al.26) reported the implications of NOAC introduction on the OAC prescription pattern in patients with AF after full reimbursement of NOAC in July 2015. The difference in penetration of NOAC was influenced by the different medical systems in tertiary referral hospitals, nursing, and public health centers, which resulted in social inequalities of stroke prevention despite full reimbursement. Lee et al.27) reported the changes in patients' characteristics treated with warfarin or NOAC, and whether OAC prescription patterns affected the clinical outcomes. Between 2015 and 2017, NOAC prescriptions increased significantly from 59% to 89%, whereas warfarin use decreased from 41% to 11%. Patients with warfarin changed to younger and with lower CHA2DS2-VASc score, which resulted in improved clinical outcomes. However, patients with NOAC showed consistent lower risks of the composite outcome compared with warfarin despite these changes. These primary results based on the NHID provide insights into improving outcomes by increasing the rate of OAC use for stroke prevention according to guideline recommendations and may also guide planning and decision making regarding health policies.

Optimal anticoagulation therapy in patients with AF who have undergone percutaneous coronary intervention (PCI) is gaining attention. Recent RCTs have highlighted the benefit of double antithrombotic therapy based on NOACs over triple antithrombotic therapy based on warfarin.28), 29), 30), 31) In real-world clinical practice, OAC is under prescribed in patients with AF undergoing PCI due to the fear of bleeding. A recent report examining the prescription pattern of antithrombotic therapy in patients with AF undergoing PCI revealed that the number of patients with AF and PCI has increased constantly, but OAC prescription was only 40% in 2015.32) Furthermore, more than 70% of patients received antiplatelet agents only one-year after PCI.33) Considering that most of these patients have a high risk of stroke, optimal antithrombotic therapy may be necessary after PCI.

Validation of stroke risk calculator

The risk and number of comorbidities may be calculated using formulae, such as the Charlson Comorbidity Index and CHA2DS2-VASc score.34), 35) The CHA2DS2-VASc score has been effective in predicting the risk of ischemic stroke in Korean patients with non-valvular AF not receiving OAC.36), 37) Therefore, these results highlight the need to introduce OAC in patients with a CHA2DS2-VASc score of more than 2 points, which was adopted in the Korean Guideline of Atrial Fibrillation Management.38)

Real-world evidence of non-vitamin K antagonist oral anticoagulants in Asians with atrial fibrillation

The prescription of NOACs has increased dramatically in Korea. However, only a small number of Asians with AF have been included in pivotal RCTs, thus, evidence based on Asian patients is not sufficient. Asians with AF have a higher risk of stroke and bleeding, especially ICH, compared to non-Asians.39), 40) Therefore, evidence regarding the use of NOACs in Asians with AF is needed. Based on the recent increase in the use of NOAC in real-world clinical practice in the Korean population, comparative effectiveness and safety analyses among different OACs using observational cohorts from the administrative claims data may be useful in obtaining a comprehensive dataset studying the use of NOACs in a large-scale Asian population. For treatment comparison using observational cohorts, a number of statistical methods, including multiple regression analysis, propensity score matching, and inverse probability of treatment weighting, were used to minimize the difference among treatment groups. Researchers from Taiwan have published several papers comparing the effectiveness and safety of NOACs and warfarin.10), 41) Researchers in Korea have also published several studies comparing the effectiveness and safety of NOACs with warfarin.42), 43), 44), 45), 46) Korean researchers have also analyzed special populations, such as patients with low body-weight and liver disease, which were not included in the pivotal RCTs of NOACs.47), 48) Since the number of Asian patients with AF was smaller than non-Asian patients, only a small number of underweight patients were included in RCTs.47) Most patients with active liver disease were also excluded from the pivotal NOAC trials.49), 50), 51), 52) However, patients with low-body weight or liver disease may be selected from the health screening database of the NHID. Future research using these variables may produce more novel findings, thus, highlighting one of the strengths of Korean NHID. Another important laboratory variable is serum creatinine. We calculated the creatinine clearance (Cockcroft-Gault Equation) using serum creatinine, body weight, age, and gender. Renal dysfunction is a criterion for dose reduction of NOACs, which aids in the classification of prescription into on-label or off-label dosing. A comparison between on-label rivaroxaban (20 mg daily, R20) and off-label rivaroxaban (15 mg daily, R15) in patients with AF and normal or mildly impaired renal function (CrCl ≥50 mL/min), revealed better outcomes for both R20 and R15 compared to warfarin.44) However, R20 was associated with a slightly lower risk of composite clinical outcome than off-label R15. Another study used creatinine clearance to compare the outcomes between edoxaban and warfarin,53) which revealed that a low dose edoxaban (30 mg daily) showed a higher risk of stroke and systemic embolism compared to warfarin at higher levels of CrCl (>95 mL/min). The FDA label also restricts the use of edoxaban in patients with a CrCl >95 mL/min due to concerns regarding an increased risk of stroke compared to warfarin.54) A recent study, which evaluated the net clinical benefit in the high-risk population, reported that AF patients with a previous history of ICH were excluded from pivotal NOAC trials, thus, there is limited data on optimal anticoagulation therapy among high-risk patients. Among a total of 5,712 patients with AF and prior ICH, NOAC was associated with a significantly lower risk of ICH and stroke compared to warfarin.55) Additionally, NOAC showed consistent benefits compared to warfarin in a population constituting OAC-naïve patients with non-valvular AF and a history of stroke.56)

Health screening information

The national health screening database constitutes lifestyle questionnaires (drinking, smoking, and exercise), laboratory results, and anthropometric measurements data. Heavy drinking of alcohol is a well-known risk factor for AF, but the impact of a high frequency or binge drinking on AF remains unclear. Kim et al.57) reported that frequent drinking and amount of alcohol consumption were significant risk factors for new-onset of AF, whereas heavy consumption per drink was not. The risk of AF could be evaluated using the laboratory parameters. Proteinuria and gamma-glutamyl transferase were found to have predictive values on the risk of AF.58), 59)

Variability in the individual laboratory results recorded in the NHID over time may be an interesting topic for research. The health screening database contains serial data of the same patients who undergo biannual health screening examinations. Several variability indices, such as coefficient of variation, standard deviation, variability independent of the mean, and average real variability, could be calculated using serial variables, including body weight, total cholesterol, fasting blood glucose, and serum creatinine.60) High variability of metabolic parameters, such as fasting blood glucose, total cholesterol levels, systolic blood pressure, and body mass index, were independent predictors of mortality and cardiovascular events.60), 61) High variabilities of lipid, renal function, blood pressure, and metabolic parameters were associated with the risk of AF, heart failure, myocardial infarction, stroke, and mortality.62), 63), 64), 65), 66), 67) Mildly abnormal lipid levels were also associated with a higher risk of atherosclerotic cardiovascular disease, whereas lipid variability was not.68)

Rare disease research

Studying a rare disease would be another interesting topic for research using the NHID. The number of patients and the accuracy of diagnosis would be important issues in rare disease research. As prescribed in the previous section, a combination of ICD-10 codes and RID code would increase the accuracy of diagnosis. We have validated the ICD-10 codes with RID code (V127) to define hypertrophic cardiomyopathy (HCM).69) The accuracy, sensitivity, and specificity of the RID code for HCM diagnosis were 92.6%, 91.5%, and 100%, respectively. The prevalence and incidence of HCM in Korea have increased substantially with increasing coexisting modifiable risk factors.70) The risk of AF using the RIF code with special populations, including those with HCM, inflammatory bowel disease, ankylosing spondylitis, and Behcet's disease, has also been reported.69), 71), 72), 73) Considering the population size of the NIHD, research on rare diseases would be feasible, while the NHIS-NSC would not be an appropriate database to study rare diseases.

THE OPERATIONAL DEFINITION OF COVARIATES AND OUTCOMES IN CARDIOVASCULAR RESEARCH

Hypertension

Hypertension is most commonly defined using a combination of three major criteria, including ICD-10 codes I10–I13 or I15 for hypertensive disease usually recorded twice in the outpatient clinic, or once in hospitalization, and a history of prescription of antihypertensive drugs classified as No. 214 in Drug Payment Classification List.74) The detailed information on antihypertensive drugs is summarized in Supplementary Table 1. Research based on the NHIS-National health examinee database reported that systolic blood pressure >140 or diastolic blood pressure >90 mmHg were used as an additional criteria for hypertension.60), 75), 76) These studies, however, did not include those with hypertensive end-organ damage, such as hypertensive renal (I12) or heart disease (I13), and secondary hypertension (I15). Definitions of the common cardiovascular diseases are summarized in Table 2.

Table 2

Operational definitions of the comorbidities (I)

Diabetes and dyslipidemia

The Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association has summarized the operational definition of diabetes based on the Korean NHID.77) They have also evaluated the proportion of patients with diabetes according to different combinations of diagnosis and prescription data. The Taskforce team concluded the following criteria: 1) ICD-10 codes E11–E14 for diabetes as either principal diagnosis or 1st to 4th additional diagnosis at least once a year; and 2) prescription of antidiabetic agents (Table 2). Moreover, fasting glucose levels ≥126 mg/dL was considered as additional diagnostic criteria for diabetes. The prevalence of diabetes based on this definition was 11.4%. Many studies that did not include data from the Health check-up database used a combination of ICD-10 codes and antidiabetic agents only.78) The detailed information on antidiabetic agents is summarized in Supplementary Table 2.

Dyslipidemia was defined using the ICD-10 code E78 combined with prescribing lipid-lowering agents at least once a year.79) In addition to this operational definition, total cholesterol ≥240 mg/dL was another criteria for dyslipidemia.60), 65), 76)

Myocardial infarction, heart failure, and other comorbidities

Myocardial infarction was diagnosed using ICD-10 codes I21, I22, with more than one diagnosis during admission or at outpatient clinics. Hospitalization with primary diagnostic ICD-10-codes I21, I22 showed a positive predictive value of 92%.80) Heart failure was defined using ICD-10-code I50 with more than one diagnosis during admission or at outpatient clinics. The definitions of peripheral arterial disease, transient ischemic attack, and end-stage renal disease were summarized in Table 3.

Table 3

Operational definitions of the comorbidities (II)

Atrial fibrillation

The ICD-10 codes for AF were expressed as ‘I48,’ ‘I48.0–I48.4, I48.9’ or ‘I48, I48.0, I48.1’ in different studies, but these expressions included the same AF patients over different study periods (Table 4).19), 20), 81), 82), 83) The KCD was updated in 2011 and 2016, according to the revision of ICD-10-codes. For the accuracy, either one diagnosis during hospitalization or more than twice at outpatient clinics was requited for the diagnosis.81) This criterion was consistent with a Taiwan nationwide population study.84), 85) A study validating the accuracy, which included reviewing 628 randomly chosen patients with ICD-10 codes I48 and matching ECG records, revealed a positive predictive value of 94.1% for the definition of AF.83) To confine the analysis on non-valvular AF, patients with a diagnosis of mitral stenosis (I05.0, I05.2, I05.9) or presence of mechanical heart valves (Z95.2–Z95.4) were regarded as valvular AF and were excluded from the final anlysis.19) A washout period of more than one year was set to ensure accuracy of AF incidence.81), 82) The prevalence of AF was influenced by the inclusion of a previous history of AF. Yang et al.82) compared different approaches for assessing the prevalence and incidence of AF using the NHID. The formal approach involved examining patients with individual AF diagnosis history and mortality, while the medical use approach involved examining patients who claimed medical expenses annually. The overall prevalence of AF using a formal approach was approximately double that of a medical approach. The formal approach would be more suitable to compare the AF epidemiology among different countries. However, overestimation of patients with AF would pose a limitation for the formal approach. The formal approach may include patients with transient AF, who had not been formally diagnosed and did not visit the hospital for AF for several years. Therefore, the medical use approach would be more suitable to estimate usage of medical services. The prescription pattern of OACs by the medical use approach was 30–50% in Korea, which is consistent with that of Asian AF patients in the GLORIA-AF registry.23), 24) Considering the wide variability in the prevalence and incidence of AF in different analysis approaches, careful interpretation, and attention would be needed for comparison with other datasets.

Table 4

Definitions of the outcomes

Ischemic stroke

Ischemic stroke was defined by the diagnosis of ICD-10 codes I63 and I64 with hospitalization and concomitant brain imaging studies, involving computed tomography or magnetic resonance image,36), 42), 43), 44), 45), 46), 47), 48), 86) or related death (Table 4).37), 53) This definition has been widely adopted in previous studies using the claims database. The combination of primary diagnostic code of the ICD-10 codes I65 and I64, and brain imaging showed positive predictive value and sensitivity of 92.2% and 91.2%, respectively.80) A study examining patients with a prior history of ischemic stroke revealed that a primary diagnosis at index hospitalization is a prerequisite of the operational definition of ischemic stroke.87)

Intracranial hemorrhage

ICH was defined by the ICD-10 codes I60, I61, and I62 with hospitalization or red blood cell (RBC) transfusion.36), 42), 43), 44), 45), 46), 47), 48), 86) However, other studies also included hospitalization and concomitant brain imaging studies or related death in the definition of ICH.53), 87) Similar to ischemic stroke, when the study population included patients with prior history of ICH, a primary diagnosis at index hospitalization was a prerequisite.87)

Major gastrointestinal bleeding

The operational definition of major gastrointestinal (GI) bleeding varied across research groups (Table 4). Major GI bleeding using the diagnostic codes with hospitalization and RBC transfusion.43), 44), 45), 46), 47), 48), 86) The ICD-10-CM codes for the definition of major GI bleeding varied across working groups. Yu et al.53) defined GI bleeding in accordance with diagnostic codes, including K25-28 (subcodes 0–2 and 4–6 only), K92.0, K92.1, K92.2, K62.5, I85.0, and I98.3, from admission diagnosis or related death. Cho et al.87) reported GI bleeding as per the following codes: I85.0, K22.1, K22.8, K25.0, K25.2, K25.4, K25.6, K26.0, K26.2, K26.4, K26.6, K27.0, K27.2, K27.4, K27.6, K28.0, K28.2, K28.4, K28.6, K29.0, K31.8, K55.2, K57.0, 57.1, K57.2, K57.3, K57.4, K57.5, K57.8, K57.9, K62.5, K66.1, K92.0, K92.1, and K92.2.

Major bleeding

Major bleeding was defined as ICH or major GI bleeding.43), 44), 45), 46), 47), 48), 86) Essentially, the definition of major bleeding includes ICH and major GI bleeding; however, other relevant diagnoses include hospitalization for extracranial or unclassified sites. Cho et al.87) defined major bleeding as fatal bleeding, bleeding necessitating hospitalization, or bleeding that occurred in critical sites, such as intracranial, intraspinal, intraocular, retroperitoneal, or intramuscular with compartment syndrome. Yu et al.53) defined major bleeding as ICH, gastrointestinal bleeding, or anemia caused by bleeding. The diagnostic codes of extracranial or unclassified sites include D62 (acute posthemorrhagic anemia), H05.2 (hemorrhage of orbit), H35.6 (retinal hemorrhage), H43.1 (vitreous hemorrhage), J94.2 (hemothorax), M25.0 (hemarthrosis), and R04 (hemorrhage from respiratory passages including epistaxis and hemoptysis) (Table 4).53), 87)

CONCLUSION

The Korean NHID is a nationwide claims database that could be used as a research tool for gathering RWE. The ultimate direction of research using the NHID should aim to improve the welfare of the public, while the findings may help in reducing medical costs and improving public health. Using the results of RWE as a basis for medical practice involves many challenges. Expert advice would be necessary for determining the scientific credibility of the big data analysis until proper technology supplementation is achieved in the future. A step-by-step approach adopted by a team of data scientists, epidemiologists, statisticians, and clinical researchers may be most effective while designing research studies.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Classification codes of anti-hypertensive drugs

Click here to view.

(46K, xls)

Supplementary Table 2

Classification codes of diabetes mellitus drugs

Click here to view.

Funding:Dr. Choi received research grants from BMS/Pfizer, Biosense Webster, Chong Kun Dang, Daiichi-Sankyo, Sanofi-Aventis, and Skylabs.

Conflict of Interest:The author has no financial conflicts of interest.

ACKNOWLEDGMENTS

Thanks to So-Ryoung Lee, MD, Kyung-Do Han, PhD, Hyun-Jung Lee, MD, Chan Soon Park, MD, Jiesuck Park, MD, You-Jung Choi, MD, Soonil Kwon, MD for their assistance.

References

Torp-Pedersen C, Goette A, Nielsen PB, et al. ‘Real-world’ observational studies in arrhythmia research: data sources, methodology, and interpretation. A position document from European Heart Rhythm Association (EHRA), endorsed by Heart Rhythm Society (HRS), Asia-Pacific HRS (APHRS), and Latin America HRS (LAHRS). Europace 2020;22:831–832.

Cheol Seong S, Kim YY, Khang YH, et al. Data resource profile: the National Health Information Database of the National Health Insurance Service in South Korea. Int J Epidemiol 2017;46:799–800.

Won TY, Kang BS, Im TH, Choi HJ. The study of accuracy of death statistics. J Korean Soc Emerg Med 2007;18:256–262.

National Health Insurance Service. National health screening statistical yearbook. Seoul: National Health Insurance Service; 2014.

Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: the National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol 2017;46:e15

Lee SR, Choi EK, Han KD, Cha MJ, Oh S, Lip GY. Temporal trends of antithrombotic therapy for stroke prevention in Korean patients with non-valvular atrial fibrillation in the era of non-vitamin K antagonist oral anticoagulants: a nationwide population-based study. PLoS One 2017;12:e0189495

Kim TH, Yang PS, Uhm JS, et al. CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 [doubled], diabetes mellitus, prior stroke or transient ischemic attack [doubled], vascular disease, age 65–74, female) for stroke in Asian patients with atrial fibrillation: a Korean nationwide sample cohort study. Stroke 2017;48:1524–1530.

U.S. Food and Drug Administration. Prescribing information for Savaysa (edoxaban) [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2015 [cited 2018 Feb 22].Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf .

Park J, Lee SR, Choi EK, et al. Effectiveness and safety of direct oral anticoagulant for secondary prevention in Asians with atrial fibrillation. J Clin Med 2019;8:8.

Lee H, Park JB, Hwang IC, et al. Association of four lipid components with mortality, myocardial infarction, and stroke in statin-naïve young adults: a nationwide cohort study. Eur J Prev Cardiol. 2020

Park J, Kwon S, Choi EK, et al. Validation of diagnostic codes of major clinical outcomes in a National Health Insurance database. Int J Arrhythmia 2019;20:5.

Cho MS, Yun JE, Park JJ, et al. Outcomes after use of standard- and low-dose non-vitamin K oral anticoagulants in asian patients with atrial fibrillation. Stroke. 2018

Published online Jan 07, 2019.

https://doi.org/10.4070/kcj.2018.0431

Beta-Blockers in Heart Failure with Preserved Ejection Fraction: Could Their Use Be Vindicated as an Acceptable Option in the Future Treatment Guideline?

Jae Yeong Cho

, MD, PhD

The beneficial effects of beta-blockers (BBs) in heart failure with reduced ejection fraction (HFrEF) are established, because the efficacy of BB for reduction of mortality in patients with HFrEF has been proven in various randomized trials so far.1), 2), 3), 4), 5) However, it is still debatable to use BB for reduction of mortality and hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). Unfortunately, there is no single most reliable agent to improve the prognosis of HFpEF in the current treatment guideline.6) In addition, the heterogenous pathophysiology of HFpEF has hindered researchers from developing an effective therapeutic strategy in HFpEF.

In this edition of the journal, Kim et al.7) investigated the effect of BB in patients with HFpEF in a large domestic acute heart failure (HF) cohort. The authors made every effort to analyze the Korean Acute Heart Failure registry, one of the largest observational HF studies, using propensity score matching. In their study, however, use of spironolactone was greater in BB group than in no BB group (44.2% vs. 38%, p=0.006) even after adjusting confounding using propensity score matching. In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial,8) HFpEF patients with mineralocorticoid receptor antagonist (MRA) showed no significant difference in overall mortality, but MRA group was superior in patients diagnosed with elevated brain natriuretic peptide level and in those from America. We cannot easily rule out the potential influence of spironolactone, an MRA on the primary outcome of mortality. Nevertheless, A post-hoc analysis using the data from the TOPCAT trial9) showed that BB use in HFpEF was associated with increased composite cardiovascular events, including all-cause death, hospitalization for HF, and major cardiovascular events. This result was attenuated only in patients with previous myocardial infarction. Moreover, in the study of Kim et al.7) there were only 23% of patients with ischemic etiology. Then what would be the true reason of beneficial effect of BB in this study? Taken together, it may be noticeable that the results of BB study in HFpEF patients need careful interpretation considering co-administered medications and concomitant coronary artery disease (CAD).

In addition, left ventricular ejection fraction (LVEF) criteria of HFpEF also play an important role in the assessment of efficacy of BB. In a recent study of Cleland et al.,10) BB was not effective in reducing mortality in HF patients with LVEF ≥50%. However, it was effective in reducing cardiovascular death in HF patients with LVEF 40–49%. Although ischemic etiology was attributed to the 90% of patients with LVEF 40–49%, patients with LVEF ≥50% also had comparable 86% of ischemic etiology in the meta-analysis of Cleland et al.10) This suggests that CAD was not an only attributable factor. There were 5 times more patients with LVEF 40–49% (n=1,773) who could be benefitted from BB than those with LVEF 50% (n=314) in the study of Kim et al.7) In addition to CAD and LVEF, maintaining sinus rhythm seems to be associated with the effect of BB. The mortality reduction in HFpEF patients with EF 40–49% only presented in patients with sinus rhythm.10)

Limited data available from studies so far on the effects of BB in HFpEF patients are not consistent. Possible reasons for these conflicting results would be different definitions of HFpEF, baseline heart rate, the history of previous CAD, and the presence of atrial fibrillation. Could BB use in HFpEF be recommended in the future HF guideline? Further randomized controlled trials are warranted to investigate whether BB use is beneficial and safe in HFpEF patients. The investigation of different types of BB on HF outcomes also needed. In conclusion, caution should be exercised for physicians when interpreting future literatures about BB use in HFpEF because there could be quite a number of confounding factors due to heterogenous nature of the disease entity.

The contents of the report are the author's own views and do not necessarily reflect the views of the Korean Circulation Journal.

van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS (study of effects of nebivolol intervention on outcomes and rehospitalization in seniors with heart failure). J Am Coll Cardiol 2009;53:2150–2158.

Published online Jan 02, 2026.

https://doi.org/10.4070/kcj.2025.0455

2025 Clinical Practice Guidelines for the Management of Fontan Patients in Korea: A Consensus Statement With Graded Recommendations by the Committee for Clinical Practice Guidelines on Fontan Patients

Author's summary

With the growing number of Fontan patients surviving into adulthood in Korea, there is a critical need for evidence-based, Korea-specific guidelines for their long-term management. The 2025 Clinical Practice Guidelines for the Management of Fontan Patients in Korea represent the first national consensus statement developed by the Committee for Clinical Practice Guidelines on Fontan Patients. The recommendations were formulated through systematic review, expert consultation, and integration of international guidelines with Korean cohort data. These guidelines provide graded recommendations and tailored follow-up strategies to enhance clinical decision-making and improve outcomes for Fontan patients within the Korean healthcare system.

Over the past 4 decades, significant advances in pediatric cardiology in Korea have led to marked improvements in the prognosis of patients with complex congenital heart diseases, including single ventricle physiology. The number of patients reaching adulthood has steadily increased. In particular, there is a growing need for clinical practice guidelines that reflect the latest medical trends for the long-term management of Fontan circulation patients. Accordingly, a Korean Fontan cohort was established in 2019, and a guideline development committee was formed in 2023 to publish the first Korean clinical practice guidelines for Fontan patients. Nineteen working committee members discussed and reviewed the methodology and content with expert consultation, incorporating both international guidelines and Korean-specific data. Through multiple rounds of review and discussion between authors and editors, the content was finalized, including evaluations of clinical guidelines from the United States, Europe, and Australia. The guidelines also incorporate survey data from members of the Korean Pediatric Cardiology Society and results from meta-analyses, and propose outpatient follow-up schedules tailored to the Korean clinical context. The finalized guidelines underwent rigorous review by leading national experts to enhance their completeness and applicability.

PREAMBLE

Fontan circulation refers to a unique hemodynamic state in which systemic venous blood flows directly into the pulmonary circulation without passing through a subpulmonary ventricle. Over the past five decades, this palliative surgical approach has been employed in patients with complex congenital heart defects for whom biventricular repair is not feasible. Advancements in surgical techniques, along with the accumulation of medical knowledge and clinical experience, have significantly improved early postoperative outcomes and extended long-term survival following the Fontan operation. Recent reports indicate a 30-year survival rate exceeding 80%.1), 2), 3), 4)

In Korea, the Fontan operation was first introduced in the 1970s and has since undergone rapid development. Recent Korean survival data are comparable to international figures, with a 10-year survival rate of 91.7% and a 30-year survival rate of 74.4%.5), 6) The early postoperative mortality rate following Fontan operation in Korea has been reported at 3.2%, with a late mortality rate of 7.4%.6) Globally, as of 2019, it is estimated that over 50,000 to 70,000 individuals are living with Fontan circulation. In Korea, approximately 1,700 patients had undergone the Fontan operation by the end of 2019.6)

Although improved survival has contributed to a growing Fontan population, patients are progressively developing a wide range of complications over time due to their unique hemodynamic physiology. These include circulatory failure or ventricular dysfunction, arrhythmias, and peripheral organ dysfunction.7) A recent Korean cohort study reported complications similar to those observed internationally, including arrhythmias, Fontan-associated liver disease (FALD), thromboembolism, protein-losing enteropathy (PLE), pulmonary arteriovenous fistulas, infective endocarditis, ventricular dysfunction, and renal failure.6) The pathophysiology and mechanisms underlying many of these complications remain incompletely understood, posing challenges to timely diagnosis, effective treatment, and prevention. Therefore, systematic follow-up and long-term surveillance of patients with Fontan physiology are essential to enable early detection and management of complications, thereby helping to preserve Fontan circulation and prevent functional decline. Although guidelines for long-term follow-up of Fontan patients have been previously suggested,3), 4) they are primarily based on expert opinion rather than robust evidence, and there remains a lack of well-established, evidence-based recommendations—both nationally and internationally—particularly regarding follow-up principles.

This guideline has been developed to provide clinicians and researchers with practical, evidence-informed recommendations tailored to the Korean context. It also aims to offer concrete and applicable guidance to trainees and educators involved in the care of patients who have undergone the Fontan operation.

METHODS

Development of clinical topics and questions

Fifteen key clinical topics and questions were identified through a structured survey and consensus process involving members of the Korean Pediatric Heart Society (KPHS) (Table 1). Of these, 10 topics were developed based on expert review and narrative synthesis by clinicians with substantial experience in the management of patients following the Fontan operation. For these topics, the guideline committee reviewed, appraised, and adapted existing clinical practice guidelines issued by relevant professional societies.3), 4), 8), 9) Each relevant section concludes with a brief “Expert summary” highlighting the evidence base, consensus status, target population, cautions, and key references. The remaining 5 key questions were formulated through comprehensive systematic reviews and meta-analyses of the literature. In addition, to enhance the contextual relevance of the recommendations to clinical practice in Korea, findings from a recent multicenter retrospective cohort study conducted in Korea were thoroughly reviewed and integrated into the guideline development process.

Key clinical topics and questions

Literature search and evidence assessment

For topics developed through a systematic literature review, the working group held discussions to formulate search strategies. English-language literature searches were conducted using three databases: PubMed, Embase, and the Cochrane Library.

Selected articles were subjected to a systematic review by 2 independent experts per clinical question. The methodological quality of the studies included in the evidence synthesis was evaluated based on study design. Risk of bias in randomized controlled trials (RCTs) was assessed using the Cochrane Risk of Bias (RoB) tool, whereas for nonrandomized before-and-after studies, the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) was applied.

Level of evidence and grade of recommendation

Recommendations were formulated based on the level of evidence and were finalized through consensus among members of the guideline development committee. Definitions and classifications for levels of evidence and grades of recommendation are presented in Figure 1.

Definitions and classifications for levels of evidence and grades of recommendation.

For topics developed via expert review and narrative synthesis, recommendations are labeled Expert consensus, and a standardized wording-to-class policy is applied (should be considered = Class IIa; may be considered = Class IIb; evidence not established denotes limited or conflicting data). Registry and multicenter cohort evidence were cited when pertinent to contextualize such recommendations

Internal and external review and approval

All drafts prepared by individual committee members were reviewed and approved through meetings of the Guideline Committee. Subsequently, the drafts were revised based on feedback from a panel of 18 experts affiliated with the KPHS. The finalized guideline document underwent external review by 5 independent reviewers appointed by the KPHS Research Committee. It was also made publicly available on the official KPHS website for a 2-week open review period. Following these internal and external reviews, the final guideline was approved by the Board of Directors of the KPHS.

FONTAN CIRCULATION

| ## Expert summary 1. The Fontan operation is the only surgical approach that enables patients with a single functional ventricle to maintain near-normal oxygen saturation and an adequate cardiac output (CO) necessary for survival.2. Due to the inherent absence of a subpulmonary ventricle, central venous pressure (CVP) becomes elevated and CO is restricted, predisposing patients to a wide range of long-term complications. |

In mammals, including humans, the cardiovascular system consists of two circuits—the pulmonary circulation and the systemic circulation—arranged in series and powered by two ventricular pumps (Figure 2A). In congenital heart disease (CHD) with only a single ventricle, however, both the systemic and pulmonary circulations must be maintained in a parallel rather than in series from birth. This parallel circulation leads to 2 major problems: systemic desaturation and chronic volume overload of the single ventricle. Progressive volume overload impairs ventricular function and promotes pulmonary vascular remodeling, ultimately resulting in heart failure and pulmonary hypertension (HTN), with survival rarely beyond 40 years of age. In the early 1970s, Fontan and Kreutzer introduced a surgical technique that diverts systemic venous return directly to the pulmonary arteries, thereby separating the two circulations and resolving the limitations of parallel circulation (Figure 2B).4), 10), 11), 12), 13)

Scheme of the normal cardiovascular circulation, and the Fontan circulation at different stages.13)

(A) Normal biventricular circulation: The P is connected in series to the S. The compliance of the right ventricle ensures that the right atrial pressure remains lower than the left atrial pressure and delivers the driving force to the blood to overcome pulmonary impedance. (B) Fontan circuit: The CV are directly connected to the PA, resulting in elevated systemic venous pressures. (C) Fontan circuit late (superimposed on early Fontan circuit): Over time, a deleterious cycle develops—pulmonary resistance increases, leading to further systemic venous congestion, reduced CO, and elevated ventricular filling pressure.

Line thickness reflects output, and color reflects oxygen saturation.

Panels (A and B) reproduced from: Gewillig and Brown, “The Fontan circulation after 45 years: update in physiology”, Heart 2016;102:1081-6.13) Copyright © 2016, BMJ Publishing Group Ltd and the British Cardiovascular Society. This is an Open Access article distributed under the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license.

Ao = aorta; CO = cardiac output; CV = caval veins; LA = left atrium; LV = left ventricle; P = pulmonary circulation; PA = pulmonary artery; RV = right ventricle; S = systemic circulation; V = single ventricle.

Over subsequent decades, the Fontan operation has evolved significantly through staged palliation establishment, refinements in surgical techniques, and advances in the understanding of Fontan hemodynamics. Current surgical strategies for patients with functional single ventricle physiology generally follow a staged approach. The first-stage operation is performed in the neonatal or early infant period, and the specific procedure is tailored according to the degree of pulmonary blood flow and the presence of pulmonary or aortic outflow tract obstruction. This may involve either augmentation or restriction of pulmonary blood flow, depending on the physiology. In infancy, a second-stage procedure, most commonly the bidirectional cavopulmonary shunt (BCPS) (Figure 3A and B), is performed to reduce the volume load on the single ventricle by directing superior vena caval blood directly to the pulmonary arteries. Finally, completion of single-ventricle palliation is achieved with the Fontan operation, typically around three years of age (Figure 3C and D) by channeling inferior vena cava (IVC) return to the pulmonary arteries and thereby establishing the total cavopulmonary connection (TCPC).14) The early Fontan procedures were designed to utilize contractile force for pulmonary circulation, either by connecting the right atrium to the pulmonary artery (atriopulmonary [AP] connection),10), 11) or by directing atrial flow through the right ventricle (RV) to exploit ventricular contractility for pulmonary blood flow (atrioventricular [AV] connection).15) However, these early techniques were limited in their indications and were associated with complications such as atrial dilation, atrial arrhythmias, and sinus node dysfunction. To overcome these limitations and to minimize energy loss within the Fontan pathway, the lateral tunnel Fontan, which employs an intra-atrial synthetic conduit to channel systemic venous return to the pulmonary artery, was introduced.16) More recently, the extracardiac conduit Fontan has been developed and is now the most widely used surgical modification.17)

Figure 3

Staged surgical palliation for a single ventricle.14)

(A) Hemi Fontan, (B) bidirectional cavopulmonary shunt, (C) lateral tunnel Fontan, (D) extracardiac conduit Fontan.

Reproduced from: Park and Tweddell, “Hypoplastic left heart syndrome,” in Pediatric Cardiac Surgery, 5th ed., West Sussex, UK: John Wiley & Sons Ltd., 2023, p. 705-18, with permission from John Wiley & Sons Ltd.

In the Fontan circulation, there is no subpulmonary ventricle; pulmonary blood flow depends entirely on CVP. Thus, CO is maintained only when CVP is elevated, producing a paradoxical hemodynamic state in which a physiologically detrimental factor becomes beneficial, the so-called Fontan paradox.18) After Fontan operation, most of the ventricular energy is directed to the systemic circulation, leaving only a limited reserve to drive pulmonary blood flow via systemic venous return. Therefore, minimizing energy loss by avoiding turbulence, shear stress, and flow stagnation at the cavopulmonary connections is of critical importance.19)

To optimize hemodynamics, various surgical modifications have been proposed, including introducing a cavopulmonary offset between the superior and IVC,20) creating a flared anastomosis between the venae cavae and pulmonary arteries to promote bidirectional flow (cavopulmonary flaring),21) and utilizing a bifurcated Y-graft Fontan conduit.22) More recently, computational fluid dynamics modeling has been introduced to simulate patient-specific conduit design in order to optimize Fontan flow within the constraints of an individual patient’s anatomy.19)

To mitigate systemic venous HTN and low CO, fenestration was introduced, creating a right-to-left shunt between the systemic venous return and the pulmonary venous atrium. This decompresses the systemic veins, increases preload, and improves CO. Fenestration reduces pleural effusion and shortens hospitalization in the early postoperative period, but its long-term benefits remain uncertain, and some centers electively close fenestrations percutaneously during follow-up.23)

In patients with Fontan failure, there is no effective pharmacologic therapy, and ultimately, heart transplantation may be required. Heart transplantation, however, is constrained by donor shortages and unique challenges in this population. With recent advances and improved outcomes of mechanical ventricular assist devices (VADs) in end-stage heart failure, their use in Fontan failure is being explored. In this context, the application of mechanical circulatory support can be considered according to the underlying mechanism of Fontan failure. First, when ventricular systolic dysfunction predominates, VADs may be used to augment ventricular contractile function. Second, when systolic function is preserved but CVP or pulmonary arterial pressures are elevated with increased pulmonary vascular resistance, VADs may be applied to support the pulmonary circulation. Finally, when both mechanisms coexist, biventricular support may be required. Available devices, such as the paracorporeal Berlin Heart EXCOR (Berlin Heart, Berlin, Germany) and the implantable HeartMate III (Thoratec, Pleasanton, CA, USA), have been introduced.

Beyond conventional VADs, novel devices are under development to address the fundamental limitation of the Fontan circulation—the absence of a subpulmonary ventricle. Studies have demonstrated the feasibility of inserting axial flow pumps into both the superior and IVC to provide subpulmonary ventricular function.24) Using the same model, an Impeller pump based on the von Kármán viscous pump principle has been positioned at the confluence of the caval veins and pulmonary artery to achieve cavopulmonary support.25) Other approaches have been reported, including the use of the Impella device26) or harnessing a portion of the aortic flow energy to augment cavopulmonary circulation.27) Additionally, attempts have been made to repurpose conventional ventricular assist devices for cavopulmonary support in Fontan patients.28)

FONTAN FAILURE AND VENTRICULAR DYSFUNCTION

| ## Expert summary 1. Evaluation of systolic function and AV valve regurgitation in Fontan patients should be performed using echocardiography or cardiac magnetic resonance imaging (MRI).2. Assessment of diastolic function is challenging; echocardiographic findings are not consistently correlated with symptoms, and early dysfunction may not be detected by catheterization.3. Management of Fontan failure may be guided by the underlying mechanism and may include medical therapy, surgical intervention, or catheter-based procedures. If anatomical defects are present, surgical or interventional correction can be considered first.4. Diuretics may provide symptomatic benefit. Conventional heart failure medications, such as beta-blockers or angiotensin-converting enzyme (ACE) inhibitors, may be considered, although their efficacy in Fontan patients has not been clearly established. |

Circulatory failure and ventricular dysfunction are among the most important late complications. Unlike in the general population, where heart failure is usually attributable to systolic or diastolic dysfunction, Fontan failure is more complex, resulting from the interplay of ventricular dysfunction, structural or valvular abnormalities, arrhythmias, and the passive venous hemodynamics driving pulmonary circulation.

Heart failure in Fontan patients can be categorized into 2 types: conventional ventricular dysfunction caused by impaired systolic function, and Fontan circulatory failure characterized by chronic systemic venous HTN, low CO, and progressive multi-organ involvement—often referred to as the “failing Fontan circulation.” Associated complications include atrial tachyarrhythmias, reduced CO, coagulopathy, thromboembolism, hepatic cirrhosis, hypoalbuminemia, venous insufficiency, ascites, PLE, and plastic bronchitis.

Circulatory failure

In the context of the Fontan circulation, circulatory failure is a broad and nonspecific term that refers to impaired Fontan physiology affecting the patient’s ability to perform daily activities. It describes a state in which patients with a Fontan circulation are unable to maintain normal cardiac function, leading to circulatory compromise and limitations in physical activity.29)

The potential causes of Fontan circulatory failure include ventricular dysfunction, AV valve regurgitation, elevated pulmonary vascular resistance, recurrent arrhythmias, obstruction within the Fontan pathway, lymphatic insufficiency or peripheral organ dysfunction, and volume-loading shunts. This section will focus primarily on ventricular dysfunction and AV valve regurgitation as key mechanisms underlying circulatory failure.

Ventricular dysfunction

Systolic dysfunction

At the time of the Fontan operation, most patients exhibit preserved ventricular systolic function; however, function tends to deteriorate over time.30), 31) In a large cohort study with more than 20 years of follow-up, Fontan failure occurred at a median of 18.1 years, and 46% of patients demonstrated systolic dysfunction. These findings suggest that ventricular dysfunction is more closely associated with Fontan failure than with elevated pulmonary vascular resistance.31)

The mechanisms underlying the progressive decline in systolic function after Fontan palliation are not fully understood. Before Fontan completion, the single ventricle is exposed to chronic volume overload and hypoxemia, which may lead to ventricular dilation and dysfunction. Although ventricular size and hypertrophy often improve immediately after Fontan operation, systolic function gradually declines in some patients over time.4), 32) Patients with hypoplastic left heart syndrome are particularly vulnerable, as the systemic RV faces structural limitations in coping with systemic afterload.33) In this population, myocardial fibrosis has been correlated with reduced mean ejection fraction,34) and both fibrosis and abnormal myofiber architecture may contribute to mechanical dyssynchrony, thereby accelerating systolic dysfunction.35)

In addition, the Fontan circulation is chronically preload-deficient, which may contribute to reduced contractility due to inadequate sarcomere stretch and increased myocardial stiffness.4) Fontan patients inherently operate at a low CO state, making the impact of systolic dysfunction particularly pronounced. Loss of the suction force generated by AV valve descent during systole further reduces pulmonary blood flow, a mechanism especially important in the Fontan circulation. When systolic function declines, this force is diminished.36) Recent studies have examined atrial function as a predictor of exercise capacity and outcomes in Fontan patients, but findings are heterogeneous and comprehensive evaluations remain limited.37), 38) Echocardiographic evaluation of systolic function is limited, particularly in patients with a systemic RV, and is therefore complemented by cardiac MRI. Cardiac MRI provides quantitative indices such as end-diastolic volume, global circumferential strain, and the ventricular–arterial coupling ratio, which have been shown to improve prognostic assessment.39), 40)

In patients with Fontan circulation, the prognostic value of cardiopulmonary exercise testing (CPET) and circulating levels of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) remains inconsistent. A peak oxygen consumption (peak VO2) ≤16.6 mL/kg/min was associated with a 7.5-fold higher mortality risk in one study,41) whereas another found that peak VO2 alone was not prognostic; instead, arrhythmia history, AP connection Fontan, and clinical heart failure were stronger predictors.42) Elevated BNP has been linked to Fontan failure and mortality, but no threshold value reliably diagnoses heart failure or predicts short-term outcomes.43) Nevertheless, CPET and BNP remain useful for longitudinal follow-up, and significant changes in peak VO2 or BNP should raise concern for progression of Fontan failure and prompt consideration of invasive hemodynamic evaluation.

Diastolic dysfunction

Diastolic dysfunction is a highly prevalent and clinically significant problem following the Fontan operation. Studies have reported diastolic dysfunction in approximately 70% of Fontan patients, with rates exceeding 80% in those with a systemic RV.4), 33), 44) The mechanisms are multifactorial, involving postoperative structural and functional changes such as ventricular dyssynchrony, myocardial fibrosis, abnormal ventricular geometry, increased wall stress, and chronic hypoxemia. These alterations, compounded by the unique Fontan hemodynamics, predispose patients to progressive diastolic impairment, a critical determinant of long-term outcomes.4), 45)

Diastolic dysfunction typically begins with abnormalities of early relaxation, reflected by prolonged isovolumic relaxation time. Such abnormalities disrupt the normal relaxation process of the ventricle, leading to impaired wall motion and abnormal intracardiac flow patterns.35), 46) Over time, reduced ventricular compliance further compromises diastolic filling, resulting in clinically significant dysfunction.44), 46) Notably, diastolic impairment in Fontan patients is closely linked to their passive pulmonary blood flow. An elevation of ventricular filling pressures increases atrial pressures, thereby diminishing forward flow across the pulmonary vasculature and ultimately reducing preload. Consequently, CO may decline even in the absence of systolic dysfunction.47)

The early stages of diastolic dysfunction are often difficult to detect clinically. While echocardiographic and tissue Doppler parameters may demonstrate abnormalities, their correlation with clinical outcomes or catheterization data is limited.45), 48) Cardiac catheterization provides precise measurement of diastolic filling pressures but is invasive and performed only at rest, which may fail to identify early diastolic impairment.47) More recently, speckle-tracking echocardiography has shown promise for assessing diastolic function, though its clinical utility in single ventricle patients requires further validation.48)

Atrioventricular valve regurgitation

In Fontan patients, clinically significant AV valve regurgitation, defined as moderate or greater regurgitation or cases requiring valve repair or replacement, has been reported in approximately 7% at 5 years, 12% at 10 years, and 21% at 20 years post-surgery.49) Mechanisms include annular dilation, intrinsic valvular malformations, leaflet tethering or prolapse, and abnormalities of the subvalvular apparatus.50)

AV valve regurgitation initiates a vicious cycle in which regurgitant flow exacerbates ventricular dysfunction and annular dilation, leading to reduced CO and elevated atrial pressures. This can clinically manifest as low CO or congestive symptoms. The regurgitation further compromises ventricular filling and pulmonary blood flow, exacerbating circulatory inefficiency.36) Consequently, the presence of AV valve regurgitation has been associated with more than a twofold increased risk of Fontan failure.49)

Various imaging modalities are available for the diagnosis and management of AV valve regurgitation. While conventional echocardiography is the primary tool, it has limitations in identifying specific structural etiologies. Advances in 3-dimensional echocardiography have improved the assessment of valve morphology and function, and cardiac MRI provides flow visualization and a quantitative assessment of regurgitant volume. However, its use may be limited in patients with metallic stents or implanted devices, in which cases computed tomography (CT) may be considered as an alternative.50)

Management

Management of circulatory failure in patients with Fontan circulation is highly variable and lacks robust, evidence-based recommendations.51) Generally, surgical or catheter-based interventions yield better outcomes than medical therapy, although success is dependent on patient selection and procedural indication. When these options are not feasible, advanced therapies such as inotropic support, mechanical circulatory support, or cardiac transplantation may be required. Consequently, early referral to a heart failure specialist is essential. Catheter-based strategies include fenestration creation, angioplasty with or without stent placement, catheter ablation, and lymphatic interventions such as selective lymphatic embolization, thoracic duct embolization, or decompression. Surgical options encompass Fontan takedown, revision, or conversion; atrial arrhythmia surgery; reimplantation of the innominate vein; biventricular conversion; and AV valve repair or replacement. Medical therapy is primarily supportive and will be discussed in detail in a subsequent section.

Circulatory failure and ventricular dysfunction represent serious complications of the Fontan circulation, with a profound impact on patients’ quality of life. Therefore, long-term management and close surveillance are essential, requiring a comprehensive and multidisciplinary approach that integrates multiple contributing factors.

PHARMACOLOGIC THERAPY FOR HEART FAILURE IN FONTAN PATIENTS

| ## Expert summary 1. Evidence supporting pharmacologic therapy in Fontan patients is limited, and management generally requires an individualized approach tailored to the patient’s clinical status.2. ACE inhibitors have been used to reduce afterload; however, evidence supporting their routine prophylactic use is lacking.3. Beta-blockers may offer sympathetic inhibition and antiarrhythmic benefits, but concerns regarding reduced exercise capacity and decreased CO preclude their routine use in clinically stable patients.4. Mineralocorticoid receptor antagonists (MRAs) are useful for controlling congestion and maintaining electrolyte balance, and are often employed as supportive therapy in conditions such as protein-losing enteropathy. Nevertheless, direct evidence of benefit on ventricular function remains limited.5. Digoxin can provide symptomatic relief by enhancing contractility and controlling heart rate, but it must be used cautiously due to its potential toxicity, and its clinical efficacy in Fontan patients remains uncertain.6. Angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown symptomatic improvement in case reports of Fontan patients, and ongoing clinical trials are evaluating their therapeutic role. |

Despite the high prevalence of circulatory failure in Fontan patients, evidence for pharmacologic therapy remains limited. Conventional heart failure medications, including ACE inhibitors or angiotensin II receptor blocker (ARB), beta-blockers, digoxin, and diuretics, have been used empirically, but their efficacy in Fontan patients has not been established, with only modest and inconsistent benefits reported.52), 53) Emerging studies have evaluated newer agents such as ARNIs and SGLT2 inhibitors in patients with single-ventricle/Fontan physiology. However, available data are limited to small series and observational reports, and these drugs cannot be regarded as standard therapy in failing Fontan; these agents are briefly discussed in this guideline for completeness.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

ACE inhibitors reduce preload and afterload while attenuating adverse ventricular remodeling, thereby lowering mortality in patients with heart failure with reduced ejection fraction (HFrEF).54) In Fontan patients, they have been used to reduce afterload in the single ventricle and to mitigate AV valve regurgitation, but supporting evidence is limited.55), 56), 57)

A 1997 randomized trial of enalapril showed no improvement in exercise capacity, and even reduced cardiac index during exercise in some patients.55) A 2022 prospective interventional study in pediatric Fontan patients with relatively preserved ventricular function also showed no significant benefit from enalapril, with 21% developing hypotension.58) While retrospective studies in single-ventricle patients, including those with Fontan circulation, have reported reductions in end-diastolic pressure, mean pulmonary artery pressure, and atrial pressure, the sample sizes were small and these findings require further validation.56) A 2016 registry analysis noted concerns about overuse for prophylactic purpose without clear evidence.57) In adult Fontan patients, ACE inhibitors are used in the setting of concomitant systemic HTN or ventricular dysfunction, but renal function monitoring is essential. The PREpArE-Fontan registry demonstrated an association between ACE inhibitor use and reduced glomerular filtration rate (creatinine clearance <90 mL/min), underscoring the importance of renal monitoring in this population.59) ARBs are generally considered alternatives to ACE inhibitors and are primarily used in patients with contraindications to ACE inhibition. To date, there is no evidence to support the prophylactic use of ACE inhibitors in Fontan patients. Their use may be selectively considered in individual cases, such as patients with a systemic left ventricle and documented systolic dysfunction.

Beta-blockers

Beta-blockers reduce heart rate and myocardial oxygen demand and are established therapies in adult left ventricular failure.60) In Fontan patients, their use has been explored for sympathetic inhibition, prolongation of diastolic filling, and arrhythmia control, but clinical outcomes have been inconsistent. Some studies reported improvements in ventricular function and exercise capacity,61) whereas others showed reduced CO or increased NT-proBNP.62) No significant clinical benefit has been demonstrated in pediatric single-ventricle cohorts.63)

Because Fontan circulation often depends on relatively high heart rates to maintain CO, routine use in asymptomatic patients is not supported. They may be considered cautiously in patients with impaired ventricular function, but high doses should be avoided, and contraindications include sinus node dysfunction and AV block. As adjunctive therapy for arrhythmia control, their efficacy is limited. Adverse effects include bradycardia, hypotension, fatigue, growth retardation, and worsening bronchospasm in patients with asthma. In patients with hepatic dysfunction, dose adjustment and monitoring are required. Tapering is recommended upon discontinuation to avoid rebound tachycardia and HTN.64)

Angiotensin receptor-neprilysin inhibitor

Sacubitril/valsartan is the only available ARNI and has become a standard therapy for HFrEF after the PARADIGM-HF trial,65) with Food and Drug Administration (FDA) approval for pediatric use in patients ≥1 year of age. However, all prior studies have been restricted to biventricular physiology, and evidence in Fontan patients is lacking.

Its combined effects of afterload reduction and natriuretic peptide pathway activation may theoretically benefit Fontan physiology by alleviating congestion and attenuating adverse remodeling. Although randomized trials are absent, observational studies and case reports suggest potential benefit, including improvement in PLE, reductions in edema and fewer hospitalization.66) Studies in systemic RVs have demonstrated improved ventricular function, exercise capacity, and New York Heart Association (NYHA) class,67), 68), 69) while others showed no clear benefit.70), 71) Findings remain limited and require cautious interpretation.

Because the Fontan circulation is preload-dependent and requires adequate mean arterial pressure, ARNI should be initiated at low doses with careful titration and diuretic adjustments. No major adverse events have been reported, but close monitoring is required. Large multicenter trials, including ENTRUST-ACHD HF, are ongoing.72)

Mineralocorticoid receptor antagonist

MRAs, such as spironolactone and eplerenone, inhibit aldosterone, reduce sodium and water retention, and preserve potassium. In adult HFrEF, they have been shown to attenuate myocardial fibrosis and remodeling and to improve survival.54), 73) In Fontan patients, activation of the renin-angiotensin-aldosterone system (RAAS) provides a rationale for their use. Clinically, MRAs are employed as adjunctive diuretics to enhance natriuresis, prevent hypokalemia, and maintain potassium balance. Potential benefits have also been proposed for hepatic and intestinal congestion and for PLE. However, improvement in ventricular function or exercise capacity has not been demonstrated. In a 4-week trial, spironolactone showed no clinical benefit.74) Possible long-term antifibrotic effects remain unproven. MRAs are therefore considered supportive therapy for congestion relief, diuretic augmentation, and electrolyte balance rather than agents to improve ventricular performance.

Digoxin

Digoxin enhances myocardial contractility and suppresses AV nodal conduction. In Fontan patients, it has been used for the augmentation of CO and tachyarrhythmia control. In adult heart failure, it does not reduce mortality but lowers hospitalization. Although randomized data are lacking, digoxin may be helpful in cases of ventricular dysfunction by increasing contractility and prolonging diastolic filling.54) It is also effective for ventricular rate control in atrial fibrillation or flutter. In Fontan patients, impaired renal perfusion due to low CO may increase serum digoxin levels, requiring dose adjustment. Concomitant loop diuretics increase the risk of hypokalemia and digoxin toxicity; use with potassium-sparing diuretics is recommended. In patients with sinus node dysfunction, digoxin should be used with caution due to the risk of bradycardia, and close monitoring is advised.

Sodium-glucose cotransporter 2 inhibitor

SGLT2 inhibitors, such as dapagliflozin and empagliflozin, were initially developed as antidiabetic agents but have been shown to reduce mortality and heart failure hospitalization in adults.75), 76) Their mechanisms are multifactorial and may include improved myocardial metabolism, osmotic diuresis, renal protection, attenuation of sympathetic activation, antifibrotic effects, and anti-inflammatory actions.77) Based on these properties, SGLT2 inhibitors have been explored in Fontan patients, with potential benefits including relief of fluid retention and improvement of myocardial energetics.78) Observational studies since 2020 have reported trends toward reduced congestion, improved exercise capacity, and amelioration of protein-losing enteropathy, with associated decreases in BNP/NT-proBNP and, in some cases, increased glomerular filtration rate (GFR) and serum albumin.78), 79), 80), 81), 82) Although these findings are encouraging, sample sizes have been small and results heterogeneous.

SGLT2 inhibitors are generally well tolerated in Fontan patients. Their osmotic diuretic effect produces gradual fluid removal without significant blood pressure reduction, which may be advantageous in patients prone to hypotension.79) They can be used in patients with an estimated GFR ≥30 mL/min, with careful attention to fluid intake and adjustment of concomitant diuretic therapy. Adverse events are uncommon but include urinary tract infections and, rarely, euglycemic ketoacidosis.

Prospective trials of dapagliflozin in Fontan patients are ongoing and are expected to provide more definitive evidence (NCT06762964,NCT05741658)

Other agents

Isosorbide dinitrate

In a prospective study, short-term use of isosorbide dinitrate did not change peak exercise capacity but showed trends toward increased oxygen consumption at anaerobic threshold, lower peripheral venous pressure during exercise, and reduced hepatic stiffness. These findings were limited by the small sample size and lack of statistical significance.83)

Probenecid

Probenecid activates the TRPV2 channel, increasing calcium influx as a non-cyclic adenosine monophosphate-dependent inotrope. This may enhance contractility and diastolic function without increasing arrhythmic risk.84), 85) Positive effects have been shown in preclinical studies and adult heart failure cohorts,86), 87), 88) and clinical trials are ongoing.89) In a double-blind crossover study of 8 Fontan patients, probenecid did not change ejection fraction (EF) but improved systolic longitudinal and diastolic strain, with trends toward increased peak VO2 and longer exercise duration.85) Its oral formulation, tolerability, and potential to counter progressive ventricular dysfunction make it a promising candidate for Fontan patients.

Overall, given the heterogeneity of Fontan physiology, pharmacologic management should be individualized according to patient-specific physiology until more definitive data become available. Evidence regarding the use of heart failure medications in patients with Fontan circulation is summarized in Tables 2 and 3.55), 56), 58), 61), 62), 66), 78), 79), 82), 83), 85), 90)

Heart failure medications: mechanisms of action, effects in Fontan patients, and safety considerations

Clinical studies of heart failure medications in patients with Fontan circulation

ARRHYTHMIAS

| ## Expert summary 1. In patients with Fontan circulation, arrhythmias may occur due to surgical scarring, atrial enlargement, and sinus node dysfunction, and their incidence and clinical risk increase over time.2. The most common arrhythmia is intra-atrial reentrant tachycardia (IART), a major cause of heart failure exacerbation and sudden cardiac death. Early diagnosis with electrocardiogram (ECG), Holter monitoring, echocardiography, and electrophysiologic studies is essential.3. Given the elevated risk of intracardiac thrombosis, anticoagulation is indicated in patients with arrhythmias.4. The goal of treatment is to maintain sinus rhythm and ensure hemodynamic stability. Direct cardioversion is indicated for hemodynamically unstable atrial tachycardia (AT); long-term options include antiarrhythmic drugs, atrial pacing, catheter ablation, Fontan conversion, and Maze operation.5. Ventricular arrhythmias should be managed according to standard resuscitation guidelines, with implantable cardioverter defibrillator (ICD) implantation considered when indicated.6. In patients with clinically significant sinus node dysfunction or AV block, permanent pacemaker implantation is recommended. |

Prevalence

While long-term complications remain common after the Fontan procedure,91) arrhythmias are particularly important, presenting in diverse forms including atrial and ventricular tachyarrhythmias.1) Reported prevalence of arrhythmias in Fontan patients ranges from 13% to 54%,9), 92) with a Korean registry showing an incidence of approximately 12.5%.5) In a multicenter European cohort of adult Fontan patients aged ≥35 years, 66% had documented arrhythmias, and a prior history of atrial tachyarrhythmias was identified as a major predictor of death or transplantation.91)

Within 10 years after Fontan surgery, AT develops in about 20% of patients, most commonly as IART.7), 93), 94), 95) With aging, the prevalence of atrial fibrillation increases,92), 96), 97), 98) and rapid-conduction atrial tachyarrhythmias can cause sudden cardiac death.99), 100) Ventricular tachycardia (VT) is less common but may be fatal.101), 102), 103) Approximately 3–12% of Fontan patient deaths are reported as sudden and unexplained, with ventricular arrhythmias suspected in many cases.92), 93), 104), 105)

Arrhythmia prevalence also differs by surgical type, being lower after TCPC than after the classic Fontan, and lower after extracardiac conduit Fontan than after lateral tunnel Fontan (Table 4).4), 30), 93), 99), 104), 106), 107), 108), 109) Incidence increases with age.110) In one study of adult Fontan patients, 44% experienced bradyarrhythmias, 28% supraventricular tachycardia (SVT), and 12% ventricular arrhythmias, with some requiring pacemaker implantation or catheter ablation.103) The clinical impact of arrhythmias varies by patient, underscoring the importance of comprehensive evaluation that integrates electrophysiologic testing with anatomic and hemodynamic assessment, and the need for individualized management strategies.9), 111)

Incidence of supraventricular arrhythmias by Fontan type

Mechanisms and predisposing factors for arrhythmias

In Fontan patients, arrhythmias arise from the complex interplay of structural, electrophysiologic, hemodynamic, and autonomic abnormalities. In the classic Fontan procedure, extensive right atrial incisions create large atrial scars, and elevated right atrial pressure with volume overload promotes atrial enlargement, predisposing to IART.109), 110), 112), 113) While modifications such as the lateral tunnel and extracardiac conduit lessen these changes, they do not eliminate arrhythmia risk. Postoperative conduction heterogeneity further facilitates the formation of reentrant circuits, increasing the likelihood of AT and fibrillation.94), 114) Ventricular arrhythmias can occur due to scarring from ventricular incisions or progressive fibrosis of the systemic ventricle.34), 115)

Sinus node dysfunction, which may result from direct surgical injury to the node or its artery, has been reported in up to 50% of classic Fontan patients within 10–15 years.116), 117), 118) Furthermore, elevated atrial pressure and venous congestion can induce an arrhythmic substrate in the atrium.113), 119) Increased pulmonary vascular resistance and diastolic dysfunction reduce ventricular filling and CO, leading to myocardial ischemia and further arrhythmogenic risk.120) Fontan patients also frequently exhibit heightened sympathetic tone with impaired parasympathetic activity, which destabilizes the cardiac conduction system and predisposes to bradyarrhythmia and SVT.121), 122) Finally, congenital anomalies such as left isomerism or congenitally corrected transposition of the great arteries inherently increase arrhythmia susceptibility.9), 111) Postsurgical structural and hemodynamic alterations may also contribute to sinus node dysfunction, loss of AV synchrony, or AV block. The loss of organized atrial rhythm can impair pulmonary venous return, reducing ventricular preload and CO, and is associated with increased risk of plastic bronchitis and protein-losing enteropathy.123), 124)

Diagnosis

Early detection of arrhythmias through routine surveillance is crucial, regardless of symptoms. Evaluation should be tailored to patient’s anatomic features, surgical history, and hemodynamics. A careful history and physical examination should characterize arrhythmia-related symptoms and guide test selection. A 12-lead ECG should be performed at least annually to screen for arrhythmias.9) For intermittent events, Holter monitors, event monitors, or wearable ECG devices may be used. Even asymptomatic patients can benefit from periodic monitoring to detect silent arrhythmias. In high-risk patients with recurrent palpitations or unexplained syncope, an implantable loop recorder may be considered. Electrophysiology study is used to define the arrhythmia mechanism, guide therapy, and, in high-risk patients with unexplained syncope or suspected significant arrhythmia, stratify risk of sudden death; therapeutic catheter ablation can be performed when appropriate. Echocardiography and cardiovascular magnetic resonance (CMR) provide complementary anatomic, functional, and hemodynamic data. Echocardiography assesses ventricular and valvular function and, in tachyarrhythmias, screens for intracardiac thrombus. CMR, on the other hand, quantifies ventricular volumes, evaluates the Fontan pathway and thrombus, and detects myocardial fibrosis; therefore, periodic assessment is necessary. When a new arrhythmia is identified, cardiac catheterization may be considered to assess hemodynamics and evaluate ventricular function and Fontan circulatory failure.9), 111)

Treatment

Atrial arrhythmias

Management of atrial arrhythmias is dependent on the patient’s hemodynamic status. Rapid ventricular conduction can precipitate decompensation, making termination of tachycardia crucial.9), 111) Given the high thromboembolic risk in Fontan patients, which further increases with atrial flutter or fibrillation persisting for more than 48 hours, evaluation for intracardiac thrombus and initiation of anticoagulation are recommended upon the diagnosis of a new atrial tachyarrhythmia, regardless of its duration.112)

Hemodynamically unstable AT requires immediate synchronized direct current cardioversion, irrespective of anticoagulation status. In Fontan physiology, both the loss of AV synchrony and rapid ventricular rates can cause hemodynamic compromise, making timely cardioversion essential. Pad placement may need adjustment based on atrial anatomy, for example, using an anteroposterior position in cases of marked atrial enlargement or dextroposition. In patients with a pacemaker or ICD, atrial overdrive pacing may also be considered. Due to high risk of sinus node dysfunction, clinicians must be alert to the possibility of post-cardioversion sinus arrest.

In hemodynamically stable patients with SVT or focal AT, vagal maneuvers, intravenous adenosine, or a nondihydropyridine calcium channel blocker (CCB) may be used to terminate the arrhythmia. In the context of Fontan circulation, rhythm control is the preferred strategy. If pharmacologic cardioversion is unsuccessful or not feasible, synchronized electrical cardioversion may be performed in a monitored setting with immediate defibrillation and resuscitation capabilities.

Optimal long-term care is best achieved through coordination between congenital cardiologists and electrophysiology specialists. Options include antiarrhythmic drugs, atrial pacing, and catheter ablation. Because AV synchrony is critical in single ventricle physiology, the goal extends beyond simple rate control to maintenance of sinus rhythm or an atrially paced rhythm.125) If arrhythmias are refractory, invasive hemodynamic assessment is appropriate, as noninvasive tests may miss contributory lesions or pressure abnormalities.9) Antiarrhythmic therapy can be used as first-line treatment, though success is modest, and caution is required in patients with sinus node dysfunction due to the risk of drug-induced bradycardia. Class I agents are generally avoided because of their proarrhythmic potential.111) Class III agents such as sotalol and amiodarone are preferred. Amiodarone is particularly useful in the presence of ventricular dysfunction, but close monitoring for thyroid and pulmonary toxicity is required.126), 127) If rhythm control is not achievable, rate control with a beta-blocker or a non-dihydropyridine CCB may be used, but only when sinus node function is preserved.4) Furthermore, warfarin is indicated for the prevention of thromboembolism in atrial tachyarrhythmias. Direct oral anticoagulants (DOACs) may be used as an alternative when warfarin is not feasible.111) Fontan patients are prone to thrombosis even without atrial tachyarrhythmias, and silent recurrent pulmonary emboli can raise pulmonary vascular resistance and worsen hemodynamics. Therefore, sustained anticoagulation is appropriate when atrial tachyarrhythmias are present.

Catheter ablation can be considered for recurrent AT. Reported acute success ranges from 54% to 94%,4) with recurrence approaching 50%.94), 114) The complex anatomy, multiple reentrant circuits, and access challenges argue for performing these procedures at high-volume centers with specialized congenital and electrophysiology expertise.9), 111)

Finally, sinus node dysfunction may lead to bradycardia or junctional rhythm. Atrial overdrive pacing can terminate tachycardia. Chronic atrial pacing can prevent bradycardia-triggered tachyarrhythmias and can facilitate antiarrhythmic drug therapy.111) In patients with a AP Fontan and severe refractory atrial arrhythmias, conversion to TCPC with concomitant surgical ablation, such as a Maze procedure, can reduce arrhythmia burden and improve hemodynamics.128)

Ventricular arrhythmias

Hemodynamically unstable VT or ventricular fibrillation should be treated immediately according to resuscitation guidelines, whereas in hemodynamically stable patients, standard arrhythmia protocols are followed with attention to Fontan physiology. Sustained VT requires prompt termination with electrical or pharmacologic cardioversion, and defibrillation pad placement should be adjusted to the anatomic configuration. Amiodarone or procainamide may be used, and continuous blood pressure monitoring is required to detect hypotension. When ischemia is suspected as the mechanism, lidocaine may be effective.9), 111)

For long-term management, catheter ablation can be attempted for sustained monomorphic VT, although its relationship to sudden death in Fontan patients remains uncertain. Even after successful ablation, recurrence is common; therefore, ablation is usually used as an adjunct to ICD therapy.129), 130) Detailed mapping, including anatomic and electroanatomic assessment, is essential, and critical conduction pathways such as the His bundle, must be protected.9), 111)

An ICD may be considered for survivors of cardiac arrest or for sustained VT without a reversible cause.131) Lead placement must be tailored to the patient’s anatomy and hemodynamics, as transvenous access is often not feasible. Consequently, epicardial leads or a subcutaneous ICD may be more appropriate.132) Concomitant antiarrhythmic drug therapy can be used to reduce recurrent shocks.

Bradyarrhythmias

In Korean Fontan cohorts, pacemakers were implanted in approximately four to 6% of patients during long term follow up.5), 6) One study reported a 4.4% implantation rate over a mean of 7.5 years, most commonly for sinus node dysfunction.6) Compared with the extracardiac conduit procedure, the lateral tunnel procedure has been associated with a higher incidence of sinus node dysfunction and a higher pacemaker implantation rate.133)

Pacemaker indications include symptomatic sinus node dysfunction, loss of AV synchrony, exercise intolerance due to chronotropic incompetence, complete AV block, and bradycardia with hemodynamic instability.123) A paced QRS duration greater than 153 milliseconds has been associated with increased risk of death, transplantation, or Fontan failure.123) Apical pacing has been reported to better preserve synchrony.134) For hemodynamic optimization, a dual-chamber DDD strategy is preferred, as it maintains AV synchrony, with programmed prolongation of the AV interval and rate adaptation during exercise.134), 135) Device selection should match the patient’s anatomy and arrhythmia substrate, with an emphasis on preserving AV synchrony and minimizing ventricular dyssynchrony. Dual-chamber systems with atrial anti-tachycardia pacing capability are reasonable options, especially in patients with recurrent atrial tachyarrhythmias. The choice of device should be individualized to the patient’s anatomy and electrophysiology.9), 111), 136), 137) The lead strategy depends on the Fontan anatomy and is often epicardial.138) In selected patients, a hybrid approach using a transvenous atrial lead combined with an epicardial ventricular lead may be considered.

In summary, the prevalence of arrhythmias in Fontan patients increases over time and, when accompanied by heart failure, adversely affects quality of life and survival. Early detection through regular electrocardiography and rhythm monitoring, along with individualized management, is essential. Lifestyle measures that may reduce arrhythmic risk include avoiding excessive cardiac workload, maintaining hydration, limiting caffeine and alcohol, and engaging in appropriate cardiopulmonary exercise.3)

PROTEIN-LOSING ENTEROPATHY

| ## Expert summary 1. PLE is a serious complication of Fontan circulation, resulting from chronic venous and lymphatic dysfunction.2. Clinical manifestations of PLE include edema, ascites, growth retardation, decreased bone mineral density, coagulopathy, and lymphopenia, and the condition is associated with increased mortality in patients with Fontan circulation.3. Treatment strategies include symptomatic management, hemodynamic optimization, lymphatic interventions, and, in severe cases, heart transplantation. |

PLE is a rare but serious late complication in patients with a Fontan circulation, characterized by the excessive loss of serum proteins into the gastrointestinal tract. It is believed to result from a complex pathophysiology involving sustained elevation of CVP, lymphatic congestion, intestinal mucosal inflammation, and structural lymphatic abnormalities. PLE has been reported in approximately 5–12% of Fontan survivors and is often chronic and progressively worsening, necessitating early diagnosis and proactive multidisciplinary management.139)

Clinical manifestations

The severity and clinical course of PLE vary widely, ranging from mild to chronic, recurrent, and irreversible forms. Major clinical manifestations include weight gain, peripheral edema, ascites, pleural effusion, and pericardial effusion; all primarily resulting from reduced intravascular oncotic pressure.

Patients often experience chronic or intermittent diarrhea, abdominal distension, and pain due to intestinal protein loss and impaired nutrient absorption. Persistent PLE leads to chronic protein depletion, which can result in long-term complications and a high risk of severe malnutrition. Chronic generalized edema compromises tissue integrity, impairs wound healing. When combined with coagulation abnormalities, it increases the risk of both thrombosis and bleeding. Hypoalbuminemia may lead to hypocalcemia and reduced bone mineral density, while decreased immunoglobulin levels and lymphopenia contribute to an increased susceptibility to infection and sepsis.140), 141)

Pathophysiology

Several key mechanisms have been proposed to contribute to the development of PLE in patients with Fontan circulation.4) A primary factor is chronically elevated CVP, resulting from the absence of a sub-pulmonary ventricle, which renders pulmonary blood flow dependent on passive venous return prolonged elevation of this pressure impairs lymphatic drainage, leading to congestion and stasis. Over time, increased pressure within the intestinal lymphatic vessels may exceed their structural capacity, resulting in lymph leakage into the intestinal lumen.142)

In addition, structural and functional abnormalities of the lymphatic system are frequently observed in Fontan patients. Lymphatic vessels may be dilated, malformed, or abnormally connected, facilitating leakage of lymph into the intestinal lumen or airways. In some cases, direct lymphatic-enteric fistulas are present, allowing continuous loss of protein-rich lymph into the bowel, leading to systemic hypoproteinemia.142)

Low CO and mesenteric ischemia also contribute to PLE. Due to the inherent limitations of Fontan physiology, CO is often reduced, leading to diminished mesenteric perfusion. Reduced oxygen and nutrient delivery to the intestinal mucosa causes mucosal dysfunction and increased endothelial permeability, promoting plasma protein leakage across the gut wall in conjunction with lymphatic mechanisms.143)

Inflammation and immune activation of the intestinal mucosa are additional contributing factors. Mesenteric hypoperfusion and stasis promote mucosal hypoxia and localized inflammation. Proinflammatory cytokines released during this process disrupt tight junctions within the intestinal epithelium, further increasing permeability. In some patients, viral infections or gut dysbiosis may exacerbate this inflammation, accelerating protein loss.144)

Lastly, deficiency of heparan sulfate proteoglycans (HSPGs) has been implicated. HSPGs are key components of the intestinal epithelial membrane, involved in electrostatic binding and reabsorption of proteins. In patients with Fontan-associated PLE, decreased expression of HSPGs may render the mucosa more permeable to protein leakage.

PLE should be suspected in patients with Fontan circulation who present with edema and hypoalbuminemia. A stepwise diagnostic approach is recommended to exclude other causes of protein loss and to identify any potentially correctable cardiac lesions. The diagnosis is confirmed by demonstrating increased stool alpha-1-antitrypsin levels or an elevated alpha-1 antitrypsin clearance (≥24 mL/24 hours, or ≥56 mL/24 hours in patients with diarrhea).

To assess lymphatic abnormalities, T2-weighted magnetic resonance lymphangiography may also be performed.142)

The management of PLE in patients with Fontan circulation is multifaceted and can be broadly categorized into three main approaches: dietary and supportive medical therapy, pathophysiology-targeted pharmacologic treatment, and interventional procedures (Table 5).140), 145), 146), 147), 148), 149), 150), 151), 152), 153), 154), 155), 156), 157), 158), 159), 160)

Table 5

Therapeutic approaches for protein-losing enteropathy

Supportive therapy serves as the cornerstone of both initial and long-term management. Depending on the severity of protein loss, a high-protein diet may be beneficial in replenishing serum protein levels. Nutritional strategies incorporating medium-chain triglycerides (MCTs) are also commonly employed, as MCTs are absorbed directly into the bloodstream without entering the lymphatic system, thereby reducing lymphatic congestion. Diuretics are often administered to relieve peripheral edema and lower CVP. In addition, other supportive measures may include intravenous albumin replacement to correct hypoalbuminemia, immunoglobulin supplementation to restore humoral immunity, use of loperamide to manage diarrhea, and correction of electrolyte imbalances when present.

Pharmacologic treatments targeting the underlying pathophysiology of PLE have shown variable success. Commonly used agents include spironolactone, corticosteroids such as budesonide, heparin, and the somatostatin analogue octreotide. Midodrine, an alpha-adrenergic agonist, has also been utilized to improve vascular tone and reduce intestinal protein loss. In refractory cases, dopamine infusion has been trialed to enhance mesenteric perfusion. Pulmonary vasodilators like sildenafil may help optimize pulmonary blood flow and reduce CVP. More recently, ARNIs have emerged as a potential therapeutic option, with observational studies and case reports suggesting possible benefits in selected patients.

Interventional approaches are aimed at optimizing Fontan circulation and addressing anatomical or functional contributors to elevated venous pressure or lymphatic leakage. These may include stent placement in areas of vascular stenosis, or the creation or enlargement of a Fontan fenestration to decompress the systemic venous system. In some patients, management of arrhythmias or structural heart lesions may be necessary through valve repair or replacement, surgical or catheter-based Fontan revision, or venous rerouting procedures. A more recent development is percutaneous lymphatic embolization, which allows for targeted occlusion of abnormal gastrointestinal lymphatic vessels contributing to protein leakage. For patients who remain refractory to medical and interventional therapies, heart transplantation remains the final therapeutic option.

Prognosis

The prognosis of PLE varies depending on the patient’s clinical condition. Historically, the 5-year survival rate was reported to be approximately 50%. However, more recent data suggest improved outcomes, with survival approaching 88% in certain cohorts. Despite this progress, prognosis remains heterogeneous and is influenced by several important factors.

Notably, patients with a Fontan pathway pressure ≥15 mmHg, impaired ventricular function, or NYHA functional class III or higher are at significantly increased risk of mortality. In a recent multicenter study conducted in Korea, the 5- and 10-year survival rates among patients diagnosed with PLE following Fontan surgery were reported to be 76.6% and 66.9%, respectively.6)

FONTAN-ASSOCIATED LIVER DISEASE

| ## Expert summary 1. FALD is a chronic hepatic complication that develops after Fontan surgery. It can progress to hepatic fibrosis and cirrhosis and significantly increases the risk of hepatocellular carcinoma (HCC).2. Currently, there are no clearly established diagnostic criteria or standardized treatment guidelines for FALD. However, both American and European guidelines recommend routine hepatic imaging and laboratory monitoring after Fontan surgery (Class IIa, Level of Evidence C).3. Management of FALD primarily focuses on optimizing Fontan hemodynamics. In advanced cases, heart transplantation or combined heart-liver transplantation may be considered, requiring a multidisciplinary approach. |

FALD is a chronic hepatic condition that develops after Fontan surgery and represents a major long-term complication in this population. It is typically asymptomatic in the early stages but can progress to hepatomegaly, fatigue, and weight loss. In advanced cases, complications such as ascites, esophageal variceal bleeding, jaundice, and hepatic encephalopathy may occur.

Hepatic fibrosis after Fontan surgery was first reported in 1981.161) While the exact prevalence of FALD remains uncertain, long-term follow-up studies have shown a high incidence among Fontan patients. Studies from both Japan and Korea have reported that the prevalence of hepatic complications reaches approximately 40% at 10 to 15 years post-Fontan. In particular, a single-center study in Korea found that 41% of patients exhibited hepatic complications at a mean follow-up of 11.5 years, with cirrhotic changes observed on CT imaging in 25.9% of cases.162), 163) Additionally, data from the Quebec Congenital Heart Disease Database reported a cumulative incidence of 11.95% at 10 years and 52.24% at 35 years post-Fontan, indicating that FALD is a progressive condition over time.164)

HCC is a serious long-term complication in patients with FALD.165), 166) Cirrhosis is a major risk factor for HCC in this population, with reported incidence rates ranging from 0.18% to 1.3%.162), 167), 168) A recent study based on a national Fontan registry in Korea reported that, after an average of 16.9 years post-surgery, cirrhosis was diagnosed in 37.4% of patients and HCC in 1.5%.6)

The pathophysiology of FALD is multifactorial, with the unique hemodynamic alterations inherent to the Fontan circulation playing a central role. Chronic elevation of CVP and reduced CO in Fontan patients result in sustained hepatic venous congestion, which increases intravascular shear stress within the liver. This mechanical stress induces reactive fibrogenesis. Unlike typical cirrhosis, FALD is characterized by “inverted cirrhosis,” where fibrosis begins in the pericentral (zone 3) region of the hepatic lobule.166) These changes progress through stages of centrilobular hepatocyte atrophy, sinusoidal fibrosis, and bridging fibrosis, ultimately leading to cirrhosis.169) In addition to venous congestion, reduced CO and chronic hypoxia contribute to hepatic injury in the Fontan circulation. Hepatocytes in zone 3, which are particularly vulnerable to hypoxic injury, may suffer long-term oxygen deprivation, leading to the development of portal HTN. Consequently, complications such as esophageal varices, splenomegaly, and ascites may arise, with increased risk of gastrointestinal bleeding and hepatic encephalopathy in severe cases. Furthermore, neurohormonal activation is believed to contribute to the progression of FALD. Patients with Fontan circulation often exhibit overactivation of the RAAS, and angiotensin II, in particular, has been shown to stimulate the production of collagen I, thereby accelerating hepatic fibrosis.170), 171)

The development of HCC is a critical consideration in FALD. As cirrhosis progresses, the chronic inflammatory and fibrotic milieu leads to cumulative DNA damage in hepatocytes, increasing the risk of malignant transformation. Chronic hypoxia and hepatic congestion in the Fontan circulation are known to activate hypoxia-inducible factors, which promote oncogene expression and tumorigenesis.172), 173) Notably, HCC can occur even in the absence of cirrhosis in Fontan patients, suggesting that alterations in the hepatic microenvironment may directly contribute to carcinogenesis.167)

Currently, there are no clearly defined diagnostic criteria or standardized treatment guidelines for FALD. Available data are limited and inconsistent, primarily derived from cross-sectional and observational studies, resulting in a low level of evidence. Nonetheless, current recommendations include the following: The 2018 American Heart Association (AHA) guidelines advise routine hepatic imaging and laboratory testing following Fontan surgery, with a Class IIa recommendation (moderate strength) and Level of Evidence C-LD (limited data).8) Similarly, the 2020 European Society of Cardiology (ESC) guidelines provide a Class IIa recommendation (should be considered) with Level of Evidence C (based on small or non-randomized studies).9)

Laboratory testing

Liver function tests—including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), international normalized ratio (INR), albumin, bilirubin, and platelet count—can serve as indirect markers of hepatic fibrosis progression in FALD. However, these parameters alone lack sufficient reliability for staging disease severity (Table 6). While commonly used laboratory-based scoring systems for liver disease have not been fully validated in FALD, several studies have explored the potential applicability of indices such as the AST to Platelet Ratio Index (APRI), Fibrosis-4 Index (Fib-4), Model for End-Stage Liver Disease excluding INR (MELD-XI), Enhanced Liver Fibrosis (ELF) score, and the Fons index (Table 7).163), 174), 175), 176), 177) Alpha-fetoprotein (AFP) testing is used for HCC screening in this population; however, AFP alone has limited diagnostic utility. In cases where cirrhosis is present or hepatic nodules are detected, serial monitoring with both AFP levels and imaging studies is recommended.

Table 6

Laboratory parameters in FALD and their clinical implications

Table 7

Non-invasive hepatic fibrosis assessment

Hemodynamic factors

To assess risk factors for FALD, hemodynamic parameters of the Fontan circulation are analyzed using cardiac catheterization. Measurements typically include Fontan pressure, CVP, pulmonary vascular resistance index (PVRI), cardiac index (CI), left ventricular end-diastolic pressure (LVEDP), pulmonary artery pressure (PAP), and pulmonary capillary wedge pressure. Numerous studies have reported a significant association between elevated Fontan pressure and CVP with the severity of hepatic fibrosis.176), 178), 179), 180)

Imaging studies

Non-invasive imaging modalities for evaluating FALD include abdominal ultrasound, CT, MRI, and liver elastography. Ultrasound is cost-effective and widely accessible but has limited sensitivity for detecting hepatic fibrosis.181), 182) CT and MRI are useful for identifying hepatic nodules and surveillance of HCC; however, studies assessing their utility in fibrosis evaluation are limited. Liver elastography, while sometimes challenged by differentiating hepatic congestion from fibrosis, provides quantitative assessment of liver stiffness, is non-invasive, and cost-effective, making it a valuable tool for fibrosis evaluation.177), 180), 183), 184) Liver elastography techniques can be categorized into ultrasound-based methods and magnetic resonance elastography (MRE).185), 186) Ultrasound elastography is further divided into strain elastography and shear wave elastography (SWE), depending on the type of tissue deformation applied. Strain elastography has limited application and research in hepatic fibrosis assessment. SWE includes transient elastography, which uses external mechanical vibration to generate shear waves, and acoustic radiation force impulse-based techniques, which comprise point-SWE and 2-dimensional-SWE (Table 8). Additionally, some Fontan patients may undergo endoscopy where esophageal varices can be detected, serving as an adjunctive tool for assessing hepatic congestion and portal HTN.187), 188)

Table 8

Principles and characteristics of non-invasive elastography techniques

Liver biopsy

Liver biopsy remains the most accurate method for diagnosing hepatic fibrosis. In FALD patients, standard histopathologic scoring systems used for chronic liver disease—such as the Congestive Hepatic Fibrosis Score, Meta-analysis of Histological Data in Viral Hepatitis, Ishak scoring system, and collagen deposition analysis—can be applied (Table 9). However, liver biopsy is an invasive procedure with a risk of bleeding, which may limit its clinical use. Furthermore, due to the heterogeneous distribution of liver lesions in FALD, performing 2 biopsies is recommended for a more accurate assessment.166), 180), 189)

Table 9

Liver fibrosis scoring systems

Management and treatment

Surveillance and follow-up for Fontan-associated liver disease

The optimal surveillance strategies and follow-up intervals for FALD have not yet been clearly established. Current recommendations from cardiology societies in the United States, Australia, and New Zealand are summarized in Table 10.3), 4) Since some degree of hepatic fibrosis is reported in most patients after 10 years post-Fontan surgery, initiating surveillance at this time point is considered important.190), 191)

Table 10

Recommendations for liver surveillance in Fontan patients

Although evidence for HCC surveillance in Fontan patients is limited, the 2018 guidelines from the American Association for the Study of Liver Diseases recommend liver ultrasound and AFP testing every 6 months for Fontan patients with hepatic fibrosis or cirrhosis.192) The Australian and New Zealand guidelines also note that imaging findings in Fontan patients may be atypical. They recommend further evaluation with quad-phase CT or liver MRI for nodules ≥1 cm or those showing interval growth. Small, non-suspicious nodules may be followed with short-term ultrasound monitoring.3) Given the complexity of FALD, a multidisciplinary team approach is essential for effective surveillance. This team should include specialists in CHD, heart failure, interventional cardiology, cardiothoracic surgery, radiology, and hepatology.

Treatment strategies

To date, no established pharmacologic therapy exists that can directly prevent or treat FALD. The primary therapeutic goal is to optimize Fontan hemodynamics in order to mitigate the progression of liver injury. Fenestration may be considered as a therapeutic intervention, as it can reduce CVP and increase CO, thereby alleviating hepatic congestion. Additionally, pharmacologic agents that lower pulmonary vascular resistance—such as phosphodiesterase-5 inhibitors (e.g., udenafil, sildenafil) and endothelin receptor antagonists (e.g., bosentan)—may be employed. The recent FUEL trial demonstrated that while udenafil (87.5 mg twice daily) did not significantly improve peak VO2 in Fontan patients, it did lead to meaningful improvements in exercise capacity at the ventilatory anaerobic threshold, ventilatory efficiency (VE/VCO2), and workload.193) These findings suggest that udenafil may play a role in attenuating long-term hepatic deterioration in Fontan patients, although further studies are needed to assess its long-term efficacy.

Lifestyle modification also plays a critical role in FALD management. Aerobic exercise and low-carbohydrate, low-fat diet are recommended to prevent obesity and metabolic syndrome. The use of potentially hepatotoxic medications—such as nonsteroidal anti-inflammatory drugs and high-dose acetaminophen—should be minimized, and alcohol consumption should be strictly avoided. Vaccination against hepatitis A and B is also essential to reduce the risk of viral hepatitis in this vulnerable population.

Transplantation

There are currently no internationally established guidelines for determining whether Fontan patients should undergo isolated heart transplantation or combined heart-liver transplantation. However, in cases where decompensated cirrhosis or HCC is present, combined transplantation is more likely to be necessary.190) Recent data have shown high mortality rates among Fontan patients awaiting liver transplantation after heart transplantation alone. This trend is also supported by data from the Organ Procurement and Transplantation Network.194) Therefore, when planning transplantation strategies in Fontan patients, it is essential to consider the degree of hepatic fibrosis, overall clinical status, and immunologic factors. Treatment decisions should be made through a multidisciplinary discussion to determine the most appropriate therapeutic approach. In particular, patients with advanced hepatic fibrosis are at significant risk of rapid liver function deterioration after isolated heart transplantation. Thus, the potential need for combined heart-liver transplantation must be carefully assessed in advance. In the future, noninvasive tools for liver fibrosis assessment (e.g., MRI, liver elastography) and hepatic venous pressure measurements are expected to play a critical role in refining indications for combined transplantation in this patient population.

Future directions

Most patients develop hepatic fibrosis following Fontan surgery, which significantly increases the risk of cirrhosis and HCC. The diagnosis and management of FALD remain major clinical challenges. To establish standardized guidelines for the care of FALD patients, ongoing prospective studies in Fontan populations are essential. In particular, further research is needed to identify reliable and validated noninvasive surveillance methods for early detection and monitoring of FALD.

THROMBOEMBOLIC EVENTS IN FONTAN PATIENTS

| ## Expert summary 1. Fontan patients are at increased risk of thromboembolic events, with the highest incidence occurring within the first year after surgery.2. Although often asymptomatic, events such as pulmonary embolism and cerebral infarction can result in serious complications, highlighting the need for proactive thromboprophylaxis.3. While no definitive guidelines exist, both aspirin and warfarin have been shown to be effective in preventing thromboembolism. In high-risk patients—including those with a history of thrombosis or arrhythmia—warfarin with regular INR monitoring is recommended.4. Recent meta-analyses emphasize the importance of thromboprophylaxis, and emerging evidence suggests that DOACs may be a viable alternative to aspirin or warfarin in reducing thromboembolic risk. However, further studies are warranted. |

Incidence

Determining the exact incidence of thromboembolism in Fontan patients remains challenging, as many thromboembolic events are “silent,” presenting without any overt symptoms or clinical signs. A meta-analysis involving approximately 1,200 Fontan patients reported a thromboembolism incidence rate of 11.8%.1) Various studies have reported incidence rates ranging from 4% to 20%, which may be attributed to differences in study populations and, importantly, the use of diverse diagnostic modalities such as transthoracic echo (TTE), transesophageal echo (TEE), and MRI.195) In one study, stroke—a major complication—was observed in approximately 5% of Fontan patients.196) In another, asymptomatic thromboembolic events were detected by TTE or TEE in up to 33% of patients.197), 198) Although the first year following Fontan surgery is considered the period of highest risk for thromboembolic complications, the risk persists beyond the initial postoperative period. Furthermore, as long-term survival in Fontan patients continues to improve, the cumulative incidence of thromboembolism is also expected to rise over time.

Etiology and pathophysiology

Following Fontan surgery, a combination of abnormal hemodynamics, venous congestion, and dysregulation of the coagulation and fibrinolytic systems contributes to an increased risk of thromboembolism.3) Among these factors, the absence of a sub-pulmonary ventricular pump—resulting in sluggish pulmonary blood flow—is considered the most critical determinant. Alterations in anticoagulant proteins and coagulation factors have also been identified as key contributors. In a study by Odegard et al.,199) significant coagulation abnormalities were observed even in the early stages of single-ventricle palliation, prior to Fontan completion. Specifically, levels of protein C, factors II, V, VII, IX, X, plasminogen, fibrinogen, and antithrombin III were significantly reduced compared to normal ranges before bidirectional cavopulmonary anastomosis. These findings may be associated with chronic hepatic dysfunction caused by elevated CVP after the Fontan procedure, leading to impaired synthesis of coagulation factors.199), 200) In addition, atrial tachyarrhythmias, which are common in Fontan patients, can further increase thromboembolic risk by promoting intra-atrial blood stasis and mechanical dyssynchrony within the heart.201)

Differences according to the type of Fontan procedure

The risk of thrombus formation is higher in the classical Fontan procedure due to greater blood flow stagnation and a higher incidence of atrial tachyarrhythmias, thereby increasing the likelihood of intracardiac thrombus formation.202), 203)

In a study by McCrindle et al.204) involving 111 patients, thromboembolic events were identified in 28% of cases, with no significant difference in the incidence of thromboembolism between the extracardiac conduit Fontan and the lateral tunnel Fontan. Another retrospective study that followed 207 patients who underwent the extracardiac conduit Fontan procedure over a 20-year period reported that 98% of patients did not experience thromboembolic events.205) Although studies examining the relationship between the presence of fenestration and the occurrence of thromboembolism or stroke are limited, existing data suggest no significant differences.196), 204)

Prevention

Studies have reported that patients who received thromboprophylaxis had a significantly lower incidence of thromboembolic events compared to those who did not.203), 206), 207), 208) Recent meta-analysis showed that the incidence of thrombus formation was lower in patients who received prophylactic treatment with either aspirin or warfarin, compared to those who received no prophylaxis (odds ratio, 0.425; p<0.01). Thrombus formation occurred in 8.6% of the aspirin group and 9% of the warfarin group, whereas the incidence was 18.6% in the non-prophylaxis group.206) Meanwhile, a study from Germany supported an individualized approach to thromboprophylaxis by finding that the overall low incidence of thrombus formation was maintained even in select groups who received no long-term anticoagulation, particularly those with a complete autologous venous pathway. Based on these findings, the authors advocated for an individualized approach to thromboprophylaxis rather than a uniform strategy for all Fontan patients. They emphasized the importance of tailoring therapy according to each patient’s underlying clinical conditions, such as the presence of atrial arrhythmias, protein-losing enteropathy, or a persistent pulmonary artery stump.209) Nevertheless, conflicting evidence exists.207)

The difference in thromboembolic risk between warfarin and aspirin remains unclear. While some studies have suggested that warfarin may be superior to aspirin immediately after the Fontan procedure,203) the majority of studies have not demonstrated a statistically significant difference in efficacy.204), 206), 207) For instance, a study by Jacobs et al.210) involving 72 patients receiving aspirin alone showed no thromboembolic events during a mean follow-up period of 40 months. When using warfarin, the target INR may vary depending on the patient’s clinical status, and there is currently no consensus on the optimal therapeutic range. However, RCTs involving Fontan patients have typically targeted an INR range of 2.0–3.0.204), 211) Maintaining this target requires regular blood monitoring, and INR variability as well as the complexity of treatment may negatively impact patient adherence. While existing studies have not consistently demonstrated a statistically significant superiority of either warfarin or aspirin, some reports have indicated that subtherapeutic INR levels in warfarin users may lead to a higher risk of thromboembolism compared to patients on aspirin.204), 211)

Meanwhile, studies have increasingly investigated the use of novel DOACs, such as rivaroxaban, particularly in adult Fontan patients.211), 212) Among pediatric patients with CHD, including those who have undergone the Fontan procedure, the SAXOPHONE trial, a representative RCT, evaluated the safety and efficacy of apixaban compared to standard thromboprophylaxis.213) Another RCT, the UNIVERSE study, focused on children aged 2–8 years post-Fontan procedure, and reported that while the rivaroxaban group did not show statistically significant differences compared to the aspirin group, it demonstrated similar safety profiles and a lower incidence of thrombus formation. Based on these findings, rivaroxaban received FDA approval in December 2021 for use in pediatric patients following the Fontan procedure.214) A meta-analysis published in 2023 reported that aspirin, warfarin, and DOACs were all effective in preventing thromboembolic events in patients with Fontan circulation.215) According to the thromboembolic prevention efficacy scores presented in the study, DOACs were evaluated as the most effective agents. However, it was also noted that the number of studies and patients involving DOACs remains limited, posing challenges to generalizing their efficacy and safety.215)

Summary for thromboprophylaxis

The 2018 AHA/American College of Cardiology and 2020 ESC guidelines for the management of adults with CHD recommend the use of anticoagulants in patients with Fontan circulation who have risk factors for thromboembolism—such as a history of thromboembolic events or arrhythmias—provided there are no contraindications.9) Although the importance of thromboprophylaxis in this population is widely recognized, the level of evidence supporting these recommendations remains low. While the optimal thromboprophylactic strategy and choice of agent in Fontan patients have yet to be clearly established, there is general consensus on the need for thromboprophylactic therapy, including either antiplatelet agents or anticoagulants.4)

EXERCISE PRESCRIPTION IN FONTAN PATIENTS

| ## Expert summary 1. Serial cardiopulmonary exercise testing is a valuable tool for assessing exercise capacity and monitoring clinical status in Fontan patients.2. Exercise training may improve exercise capacity and is associated with better long-term outcomes in this population.3. Aerobic exercise of at least moderate intensity, combined with resistance training targeting the lower limb muscles, is recommended. |

With improved long-term survival in patients with Fontan physiology, increasing attention has been paid to daily functioning and exercise capacity as key determinants of quality of life. Exercise capacity in Fontan patients is known to be reduced to approximately 60–65% of that observed in healthy individuals. This reduction is primarily due to decreased preload and limited CO resulting from the absence of a subpulmonary pump.3), 216) Additional contributing factors include chronotropic incompetence, cyanosis, restrictive pulmonary dysfunction, reduced skeletal muscle mass, impaired respiratory muscle function, and physical inactivity.4)

To address these limitations, various exercise rehabilitation programs have been studied in both pediatric and adult patients with Fontan circulation.

Cardiopulmonary exercise testing

CPET is a valuable tool for objectively assessing maximal exercise capacity in patients with Fontan physiology. While a single assessment provides important information regarding current functional status, serial testing allows for the evaluation of changes over time and may help predict future clinical outcomes. Key parameters include peak VO2, which reflects aerobic capacity, and the VE/VCO2 ratio, which reflects ventilatory efficiency and anaerobic threshold. Reductions in these values have been associated with increased risks of hospitalization and adverse cardiovascular events.4) CPET can also help elucidate the causes of exercise intolerance—such as restricted pulmonary function, reduced CO, or ventilation–perfusion mismatch—and guide further interventions, including fenestration closure to improve oxygenation or atrial pacing to enhance chronotropic response. Although there is no clear consensus on the optimal timing of initial CPET in asymptomatic or mildly symptomatic patients, it is generally recommended to begin testing every three years starting between ages 12 and 16.3), 8) Reference values for CPET variables in children and adolescents can be found in the study by Butts et al.217)

Effects of exercise

Aerobic exercise can improve pulmonary blood flow within the Fontan circulation, thereby enhancing respiratory efficiency. In addition, resistance training targeting skeletal muscles—particularly the lower limbs—may improve peripheral muscle function, increase venous return, and ultimately enhance CO and overall exercise capacity.4), 8) Scheffers et al.218) reviewed 16 studies involving 264 pediatric and adult patients with Fontan physiology and found that 9 of these studies demonstrated a significant increase in peak VO2 following exercise training. Similarly, Herrmann and Selamet Tierney200) reviewed 9 training programs conducted in patients under 20 years of age and reported that 5 studies showed a significant improvement in peak VO2.

Beyond physiological benefits, exercise training has been shown to contribute to improvements in body image through weight reduction and to enhance psychological well-being, thereby improving quality of life.3) In pediatric patients, who are undergoing emotional and social development, physical activity also provides valuable opportunities for peer interaction, which may promote emotional stability and improve social functioning.220)

Exercise training programs

Established guidelines

To date, many studies have demonstrated that both aerobic and resistance exercise can improve physical activity levels and exercise capacity in patients with Fontan physiology, ultimately contributing to better long-term outcomes.221), 222) Based on such evidence, the 2018 AHA guidelines for adults with CHD recommend regular, individualized exercise programs for adult patients who have undergone the Fontan procedure.8) In 2019, position statements on exercise in Fontan patients highlighted the significance of resistance training, especially for strengthening lower limb muscles. This recommendation was supported by findings from Cordina et al.,223) who reported that lower limb resistance training in adults with Fontan physiology led to increased peripheral muscle mass, enhanced venous return, and improved CO. Additionally, Laohachai et al.224) demonstrated that inspiratory muscle training improved ventilatory efficiency (VE/VCO2 ratio) and resting CO. The 2020 ESC guidelines for adults with CHD also recommend moderate-intensity aerobic exercise in Fontan patients, not only to enhance muscular strength but also to improve quality of life.9)

General recommendations for exercise training

To maximize improvements in exercise capacity in patients with Fontan circulation, it is recommended that exercise programs include components that target the cardiovascular pump, respiratory muscles, and skeletal muscles, with appropriate adjustments in intensity and duration.219) Both aerobic and resistance training should be incorporated, aiming for at least 30 minutes of physical activity per day.3) In general, 60 minutes of moderate-to-vigorous physical activity daily is encouraged. Even for patients who do not participate in structured exercise programs, regular engagement in diverse physical activities is strongly recommended, and activity should not be restricted as long as the patient is able to rest as needed.143) Regarding competitive sports, participation in low-to-moderate intensity dynamic exercise or low-intensity static exercise may be considered for patients without exercise-related symptoms, who have preserved ventricular function and normal oxygen saturation.143) Prior to engaging in competitive sports, a comprehensive evaluation—including clinical assessment, electrocardiography, imaging-based evaluation of ventricular function, and cardiopulmonary exercise testing—is essential to assess individual exercise capacity.144) In pediatric patients, parental understanding of the benefits of physical activity and active support for their child’s participation is crucial.7) To improve adherence in children, the use of game-based or play-oriented exercise is also encouraged.

Safety considerations in exercise training

When appropriately tailored to the patient’s condition, exercise-based rehabilitation programs can be safely implemented not only in adults but also in pediatric patients with Fontan physiology. Previous studies have not reported serious exercise-related adverse events in this population.225) However, patients, families, and caregivers should be educated to monitor exercise intensity and recognize warning signs during physical activity.226) In patients with implanted devices or those receiving anticoagulation therapy, exercise modalities should be carefully selected to minimize the risk of trauma or bleeding. Activities with low impact and reduced risk of physical contact are recommended in such cases.3), 226)

Proposed exercise training protocols for Fontan patients

In 2020, Tran et al.227) published exercise recommendations for adolescents and adults with CHD, emphasizing the importance of prescribing individualized exercise rehabilitation programs based on each patient’s clinical status. Prior to initiating rehabilitation, a thorough evaluation by a specialist is required to assess risk based on factors such as ventricular function, aortic and vascular anatomy, outflow tract obstruction, pulmonary HTN, valvular function, and arrhythmic burden. Based on the assessed risk level, personalized aerobic and resistance training programs should be designed with specific intensity, frequency, and duration, and carried out under the supervision of qualified exercise professionals. Both medical and exercise specialists should continuously monitor the patient’s progress, as well as any signs or symptoms of adverse responses—such as dizziness, syncope, headache, or severe dyspnea. Using existing rehabilitation frameworks for patients with CHD as a reference, a detailed exercise training protocol for Fontan patients can be proposed based on risk stratification (Table 11).3), 227)

Table 11

Risk stratification based on cardiac abnormalities and recommended exercise intensity

PREGNANCY AND DELIVERY IN PATIENTS WITH FONTAN CIRCULATION

| ## Expert summary 1. With advances in post-Fontan survival, more women are reaching reproductive age, making pregnancy management increasingly important.2. Pregnancy in patients with Fontan circulation is classified as high risk because adaptation to the pregnancy-related rise in CO and hemodynamic load is limited, increasing the risk of heart failure, arrhythmias, thromboembolism, and hemorrhagic maternal and obstetric complications.3. Fetal outcomes are less favorable, with lower live birth rates and higher risks of preterm birth, low birth weight, and fetal growth restriction.4. Preconception evaluation should include oxygen saturation, ventricular function, and hepatic function, with thorough counseling on maternal and fetal risks; in selected cases, pregnancy avoidance or termination may need to be considered.5. For patients planning pregnancy or with a confirmed pregnancy, risk mitigation requires multidisciplinary care, adjustment of anticoagulation and other medications, and scheduled maternal and fetal surveillance. |

Improved survival of Fontan patients has increased the number of women reaching reproductive age, which raises the importance of pregnancy management. Pregnancy induces increases in CO and reductions in systemic vascular resistance, which heighten the risk of heart failure, arrhythmias, thrombosis, and hepatic decompensation.228), 229), 230), 231)

Pregnancy risk in Fontan patients

Pregnancy in women with Fontan circulation is classified as modified World Health Organization class III, and it is classified as class IV when any Fontan related complication is present.232) Pregnancy is generally contraindicated when oxygen saturation is less than 85%, when ventricular function is reduced, when AV valve regurgitation is moderate or greater, when arrhythmias are refractory, or when PLE is present. Preconception counseling and careful monitoring are required, and continuation of pregnancy may need to be reconsidered in selected high-risk situations.232)

Maternal complications and outcomes

Adaptation to the physiologic load of pregnancy is limited in Fontan circulation, and the expansion of blood volume and hormonal changes can aggravate arrhythmias.229), 233), 234), 235) While certain adult Fontan patients are able to tolerate pregnancy and respond to therapy when complications such as heart failure or arrhythmia arise, overall prognosis is largely determined by the individual clinical condition.230), 233), 236) Major pregnancy-related complications are summarized in Table 12.230), 232), 233), 236), 237), 238), 239), 240), 241), 242), 243), 244), 245) Although no maternal deaths have been reported in published series, these cohorts include relatively stable patients,230), 233) and because life-threatening events remain possible, pregnancy should still be regarded as high risk.236) About 9% of mothers with Fontan physiology required intensive care in a large survey, a 6-fold higher rate than in the general obstetric population.237) Postpartum hemorrhage occurred in about 13% to 14%, more than four times higher than in controls, and bleeding risk may increase during the puerperium when anticoagulation is used.237), 246) Hypertensive disorders of pregnancy, including preeclampsia, were reported in about 14%, approximately twice the rate in the general population.237) Premature rupture of membranes and placental abruption were also reported more frequently.236) Cesarean delivery occurred in about two-thirds of cases, most commonly for preterm delivery, failure to progress, or breech presentation.233)

Hormonal changes during pregnancy increase the risk of atrial and ventricular arrhythmias.238) In Fontan pregnancies, arrhythmias have been reported in about ten percent, usually after the first trimester, and often respond to medical therapy. Flecainide or amiodarone and electrical cardioversion were used for acute events.233) Sotalol is considered relatively safe but may prolong the QT interval, and amiodarone and propafenone are used with caution due to fetal safety concerns.

The incidence of heart failure is about 3% to 4%, with a higher risk in the second and third trimesters and in the postpartum period.247), 248) After delivery, uterine contraction can produce an autotransfusion effect and relief of caval compression increases preload, which may precipitate decompensation. Unrecognized diastolic dysfunction and pregnancy related reductions in myocardial strain may contribute.233), 249) When heart failure occurs, precipitating factors such as arrhythmia, thrombosis, hypertensive disorders, and anemia should be identified and treated.

The long-term impact of pregnancy on Fontan circulation remains uncertain. Some studies suggest transient worsening, whereas women who complete pregnancy without major events do not show markedly reduced long term survival. Data on repeated pregnancies and late outcomes are limited, so ongoing surveillance of cardiac and hepatic function is advised.

Perinatal outcomes

Fetal outcomes in pregnancies of women with Fontan circulation are less favorable, with higher risks of early pregnancy loss, preterm birth, fetal growth restriction, and perinatal mortality (Table 13).230), 233), 234), 236), 239), 241), 242), 243), 244), 250) These risks reflect multiple factors, including chronic limitation of maternal CO, placentally mediated HTN and hypoxemia, and maternal medication exposure (e.g., beta blockers). Close fetal surveillance and growth monitoring are warranted, and early delivery should be considered when indicated.

Table 13

Fetal and neonatal outcomes in pregnancies of women with Fontan circulation

Neonatal outcomes are also compromised. Admission to a neonatal intensive care unit occurs in approximately 25–50%, most commonly for neonatal respiratory distress, feeding difficulty, or hemodynamic instability.239), 252) Reported neonatal mortality is 5–18.8%, largely related to complications of extreme prematurity.234) In addition, the risk of CHD in offspring is approximately 3–10%, higher than the 1% risk in the general population. Most cases appear multifactorial rather than following a single gene inheritance pattern.234)

Management of pregnancy and delivery

Pregnancy in women with Fontan circulation is high risk and requires coordinated care from the preconception period through the postpartum phase. A multidisciplinary team that includes adult congenital cardiology, maternal fetal medicine, cardiac anesthesia, and neonatology is essential.

Preconception counseling and risk assessment

All women with Fontan circulation should receive counseling before conception.8), 238), 241) Stability is determined by a comprehensive review of cardiac status, complications such as arrhythmia, protein-losing enteropathy, or cirrhosis, and resting oxygen saturation.234) Severe hypoxemia with oxygen saturation less than 85%, systemic ventricular dysfunction with EF less than 50%, moderate or greater AV valve regurgitation, and PLE are considered contraindications to pregnancy.232), 253) Preconception testing may include echocardiography, cardiopulmonary exercise testing, NT-proBNP, and hepatic assessment, and arrhythmia or thrombosis should be treated before conception. Patients should be counseled about pregnancy-related risks and advised to avoid unplanned pregnancy. Estrogen-containing contraception increases thrombotic risk and should be avoided.8)

Antenatal management

Once pregnancy is confirmed, referral to a high-risk center is advised, and a follow-up plan is established by a congenital cardiologist, a high-risk obstetrician, and an anesthesiologist. Cardiac evaluation is performed in the first, second, and third trimesters and after delivery, with increased frequency as needed. At each visit, assess symptoms such as reduced exercise tolerance, dyspnea, or worsening edema, measure oxygen saturation, and obtain an ECG. Echocardiography is used when indicated to follow ventricular and valvular function and to screen for thrombus in the Fontan pathway. Liver function and coagulation are monitored periodically. For the fetus, serial growth assessment is performed to detect fetal growth restriction or placental insufficiency. 234), 239), 245), 247)

Medication and special considerations

Medication adjustments are summarized in Table 14.231), 255), 258), 259) ACE inhibitors, ARBs, and spironolactone are contraindicated during pregnancy.254) Beta blockers may impair fetal growth and should be used at the lowest effective dose. Diuretics can reduce placental perfusion and are used cautiously at the minimum necessary dose. Anticoagulation is a central issue. In high-risk patients with prior thromboembolism, atrial arrhythmias, or a right to left shunt, anticoagulation during pregnancy is generally required. When pregnancy is confirmed, warfarin is typically switched to low molecular weight heparin and continued until 36 weeks.230) Decisions about antiplatelet or anticoagulant therapy should be individualized.232)

Delivery planning and peripartum care

Delivery between 37 and 39 weeks is preferred when feasible, individualized by fetal growth and obstetric factors.236) Mode of delivery is based on maternal cardiac status and obstetric indications. Vaginal delivery is generally favored to minimize cardiovascular stress, but in Fontan physiology venous return may be reduced during the second stage of labor because of increased intrathoracic pressure.255) Early neuraxial analgesia may be initiated to blunt pain related sympathetic activation, and assisted vaginal delivery with vacuum or forceps may be used when indicated.256), 257) Vaginal delivery is generally targeted for women with CHD, and cesarean delivery is reserved for obstetric indications or maternal cardiac instability. In Fontan pregnancies, however, some centers may elect a planned cesarean delivery given the clinical unpredictability. In a UK series, 58% underwent cesarean delivery with a high rate of emergency procedures, suggesting the need for readiness to escalate care.239) Delivery should be conducted in a CHD center with multidisciplinary support and preparedness for urgent intervention.234), 239), 252), 255), 256)

Postpartum care

The immediate postpartum period through the first 48 hours is a high-risk period in women with Fontan circulation because an abrupt rise in preload can precipitate acute heart failure.233), 249) During this time, care in an intensive or high acuity setting is advised with close monitoring of vital signs, strict fluid balance, and diuretics as needed to prevent or treat decompensation.247) The first 72 hours postpartum also carry increased risks of thromboembolism and postpartum hemorrhage. Oxytocin should be used carefully to prevent uterine atony and bleeding while thromboprophylaxis is being resumed, which creates a management dilemma.236) Once bleeding is controlled, low molecular weight heparin should be restarted within 12 to 24 hours to prevent thrombosis, and anticoagulation is continued for six weeks postpartum. Most patients are transitioned to warfarin after delivery, but to accommodate the possibility of delayed postpartum bleeding many centers maintain low molecular weight heparin for several weeks before switching to an oral agent. Medications requiring caution during pregnancy and lactation are summarized in Table 14.231), 255), 258), 259)

RECOMMENDATIONS FOR SCREENING AND FOLLOW-UP IN PATIENTS WITH FONTAN CIRCULATION

| ## Expert summary Because Fontan palliation for a functional single ventricle is associated with multiorgan complications that evolve over time, planned surveillance is required to enable early detection. |

Since the first Fontan operation in 1968, mortality among patients with a functional single ventricle has decreased substantially. However, the absence of a subpulmonary ventricle is associated with rising risks over time of protein-losing enteropathy, hepatic dysfunction, renal impairment, and reduced exercise capacity, underscoring the need for meticulous follow-up.9) To detect these complications early and to improve long-term outcomes and quality of life, patients with Fontan circulation require lifelong, regular surveillance and management.4), 8), 260)

Interval of routine clinical assessment

In clinically stable patients with Fontan circulation, it is reasonable to provide periodic, structured assessments of the cardiovascular system and peripheral organs. U.S. and European adult CHD guidelines and the Australian Fontan guideline generally advise at least annual clinical review unless more frequent evaluation is warranted.3), 4), 8), 9)

When the patient is not stable, the frequency and content of testing should be individualized at the clinician’s discretion.

Cardiovascular surveillance

In clinically stable patients, schedule outpatient visits every 6 to 12 months to assess for progression of cyanosis, new murmurs, increased jugular venous distention, ascites, peripheral edema, or unexpected weight change. Examples of tests and suggested intervals are summarized in Table 15. The type and frequency of investigations vary by age and should be adjusted across the transition from childhood to adolescence and adulthood as organ complications emerge or the pace of functional decline changes. For condition-specific evaluations, see the relevant sections of this document.

Table 15

Cardiovascular surveillance items and suggested testing intervals

Electrocardiography and Holter monitoring

A 12-lead ECG is a simple and useful tool to detect and follow sinus node dysfunction, conduction disease, and other arrhythmias, and is particularly important in AP connection Fontan patients or those anatomically at higher risk of sinus or conduction abnormalities. Holter monitoring is helpful when assessment of chronotropic competence is needed and can be added when an intermittent arrhythmia is suspected.

Electrophysiology study

New or worsening atrial tachyarrhythmias should be addressed promptly with appropriate thromboprophylaxis, and consultation with an electrophysiologist experienced in CHD is advised.

Exercise testing

Exercise testing is useful in Fontan patients because exercise-related symptoms are heterogeneous, underreporting is common, and subjective assessment often diverges from objective performance.261) Serial CPET is therefore a valuable tool for routine follow-up.

Transthoracic and transesophageal echocardiography

Echocardiography is the basic imaging modality, but in adults and in patients with complex systemic ventricular morphology, accurate quantification of ventricular size and function is challenging. Transesophageal echocardiography requires general anesthesia or procedural sedation and should be reserved for specific indications, such as preoperative imaging for surgical planning, intraprocedural guidance during transcatheter interventions, evaluation for intracardiac thrombus, or assessment of suspected residual intracardiac shunts at prior device or surgical sites.

Cardiac magnetic resonance imaging

Compared with echocardiography, cardiac MRI provides superior quantification of size and function, including a systemic RV, and allows detailed visualization of Fontan hemodynamics. In addition, MRI can be used to surveil the Fontan pathway (conduit or extracardiac tunnel configuration, anastomotic sites, and pulmonary arterial connections) and to screen for extracardiac complications relevant to long-term Fontan circulation. Its value and need as a routine surveillance tool in adults are increasingly emphasized.

Cardiac computed tomography and cardiac catheterization

Because CT and catheterization involve radiation exposure, decisions should consider cumulative prior and anticipated exposure. CT offers less comprehensive hemodynamic information than MRI and is therefore limited as a routine surveillance tool, but it is appropriate when echocardiography or MRI is nondiagnostic or contraindicated. Cardiac catheterization may be undertaken for hemodynamic assessment or for diagnosis and treatment of important residual lesions. It should also be considered in the setting of otherwise unexplained edema, decline in exercise capacity, new arrhythmia, cyanosis, or hemoptysis. Catheterization can define ventricular and valvular function, pulmonary vascular resistance, Fontan pathway obstruction or stenosis, and abnormal vascular connections, and it may be combined with interventions such as fenestration closure, pulmonary artery balloon angioplasty or stenting, collateral vessel embolization, aortic arch interventions, fenestration creation, or stenting of the Fontan pathway.

Peripheral organ and system specific evaluations

The frequency of surveillance for peripheral organ function should be adjusted for age. When baseline screening reveals abnormalities, additional diagnostic testing should be considered based on the clinical context and clinician judgment. For organ specific details, see the relevant sections (Table 16).

Table 16

Organ system surveillance and suggested intervals

Hepatic surveillance

(1) Laboratory testing

Baseline laboratory testing include platelet count, electrolytes, glucose, albumin, total protein, liver enzymes (AST, ALT, alkaline phosphatase), total bilirubin, gamma-glutamyl transferase, and coagulation tests. For patients more than ten years after Fontan or when baseline results are abnormal, an extended panel is recommended with the addition of serum AFP, total cholesterol, and a lipid profile. In the presence of cirrhosis or portal HTN, perform HCC surveillance every six months with AFP with or without liver ultrasound.262)

(2) Imaging

Use liver ultrasound as the initial study. When progressive fibrosis is suspected clinically, or after ten years post Fontan, consider liver elastography every one to two years, and consider CT or MRI when indicated.

(3) Liver biopsy

When periodic assessments show abnormalities that require definitive diagnosis, liver biopsy can be performed.9), 192), 263) Indications include: 1) High risk patients with cirrhosis or portal HTN, according to institutional practice or clinical judgment; 2) Suspicion of HCC, such as persistent elevation of alpha fetoprotein with concordant abnormalities on imaging; 3) Concern for disease progression on noninvasive testing, such as a downward trend in platelet count, increasing liver stiffness, or new abnormalities on imaging.

Hematologic surveillance and thrombosis monitoring

A complete blood count and prothrombin time with activated partial thromboplastin time are obtained at age appropriate intervals, typically every one to three years. In patients receiving anticoagulation, the testing frequency is adjusted according to clinical status and changes in therapy. When thrombosis is suspected, D-dimer is measured, and imaging with echocardiography, CT angiography, or magnetic resonance angiography is considered. If necessary, estrogen-containing contraceptives should be used with caution, and thromboembolic risk should be assessed and monitored.

Renal, nutrition, and endocrine assessment

(1) Renal surveillance

In clinically stable patients, obtain blood urea nitrogen, creatinine, electrolytes, and urinalysis at least annually. Since creatinine-based estimated GFR is less reliable in children, a cystatin C-based estimate may be used.264) Renal assessment is performed more frequently when clinical status worsens, after combined acute illness, after procedures or surgery, or when medications such as diuretics are initiated or adjusted. A persistent decline in renal function or a clinically meaningful fall in glomerular filtration rate should prompt nephrology referral.265)

(2) Nutrition, bone health, and growth

Children and adolescents after Fontan may have abnormalities of body composition, bone structure, and growth factors. Skeletal abnormalities are frequent, unlike in healthy children.266), 267) Low vitamin D levels are often observed and are associated with greater losses in lean mass.267), 268) Serum calcium and vitamin D are measured at age-appropriate intervals, and supplementation is provided when indicated. Bone mineral density is assessed when appropriate, and parathyroid hormone is measured when secondary hyperparathyroidism is suspected.

(3) Dietetic assessment

Periodic evaluation by a dietitian is used to confirm adequate nutritional intake.

(4) Puberty and development

During growth, sexual maturity is documented with Tanner staging and developmental milestones are recorded.

Neurodevelopmental and psychological assessment

(1) Neurocognitive evaluation

Compared with the general population, children and adolescents after Fontan more often exhibit cognitive deficits, anxiety, and problems with attention and self-regulation,269), 270) These issues affect school performance, transition to adult care, employment, and adherence. Periodic screening for developmental delay, learning disorders, and cognitive impairment is reasonable, with coordinated support among patients, families, schools, and clinicians.

(2) Psychological evaluation

From childhood into adulthood, patients are at increased risk for psychosocial difficulties. 270), 271) In North American cohorts, adults after Fontan have higher rates of mood disorders, anxiety disorders, and post-traumatic stress disorder.272), 273) Clinicians should screen for psychosocial maladaptation, pursue preventive approaches beginning in childhood, and refer to mental health professionals when indicated.

Pulmonary and exercise assessment

(1) Cardiopulmonary exercise testing

Assessment at intervals of one to 2 years is considered. Serial evaluation may facilitate early detection of Fontan circulatory failure.274)

(2) Pulmonary function test

Perform annually or when indicated. Restrictive physiology, reduced gas transfer, and respiratory muscle weakness have been reported in Fontan patients.275) Pulmonary function test documents and monitors respiratory impairment.

Infection prevention

(1) Immunizations

Beyond routine vaccinations, immunization against influenza, pneumococcus, and meningococcus is advised. Although Fontan physiology alone does not confer high risk for meningococcal disease, patients with heterotaxy and functional asplenia have increased risk for invasive infection and should be vaccinated carefully. Because FALD is common, confirm completion of hepatitis A and hepatitis B vaccination.

(2) Endocarditis prophylaxis

Antibiotic prophylaxis is used during the first 6 months after Fontan surgery, in patients with cyanosis, with prosthetic valves, with residual defects after device closure, or with a prior history of endocarditis. In other circumstances, management follows established endocarditis guidelines.276), 277), 278)

KEY QUESTIONS

Is thromboprophylaxis beneficial in patients with Fontan circulation?

Patients with Fontan circulation commonly present with conditions such as venous congestion, blood flow stasis, atrial arrhythmias, and elevated CVP, all of which contribute to an increased risk of thromboembolism. Accordingly, several professional societies, including the AHA, recommend thromboprophylaxis for all patients with Fontan circulation.3), 4), 9), 232) While the choice of antithrombotic therapy should be guided by individual risk factors and bleeding risk, a 2019 AHA scientific statement reported no significant difference in preventive efficacy between warfarin and aspirin. However, it also noted that warfarin presents challenges, including the need for close INR monitoring and a higher risk of bleeding. Furthermore, the use of non-vitamin K antagonist oral anticoagulants is not recommended in children due to insufficient evidence, reflecting a cautious stance.4) In the present guideline, we conducted a systematic review and meta-analysis incorporating the characteristics of East Asian populations to determine the optimal thromboprophylaxis strategy for Korean patients with Fontan circulation. Subgroup analysis by ethnicity (East Asian vs. non-East Asian populations) suggested that the efficacy of aspirin and warfarin in preventing thromboembolism may differ across ethnic groups. In East Asian patients, warfarin appeared to be effective at lower doses, and thrombotic risk remained relatively low even at lower INR levels (Supplementary Data 1).

Is pulmonary vasodilator therapy beneficial in patients with Fontan circulation?

Conflicting conclusions have been reported in two meta-analyses published prior to 2020 that investigated the efficacy of pulmonary vasodilator therapy in patients with Fontan circulation.279), 280) Current guidelines from the AHA and the ESC offer cautious recommendations regarding the use of pulmonary vasodilators in this population.8), 9)

The 2018 AHA Guideline for the Management of Adults with Congenital Heart Disease provides a Class IIa (moderate recommendation) and Level of Evidence B-R (moderate-quality evidence from randomized trials) for the use of pulmonary vasodilators in adult patients after the Fontan procedure, suggesting that such agents may improve exercise capacity.8) This recommendation is primarily supported by 2 key studies. The 2014 TEMPO trial—a randomized, placebo-controlled, double-blind study—demonstrated that bosentan significantly improved peak VO2.281) Similarly, a 2011 study by Goldberg et al.282) reported that sildenafil treatment led to improvements in anaerobic threshold (VO2 at AT) and VE/VCO2 slope. However, other studies, such as that of Schuuring et al.283) in 2013, failed to show significant clinical benefit, which has limited the strength of recommendation to below Level A.

Since the 2018 AHA guidelines, no substantial new RCT data have emerged to strengthen the evidence base. Accordingly, the 2020 ESC Guidelines for the Management of Adult Congenital Heart Disease provide similar recommendations.9) In this document, the selective use of endothelin receptor antagonists and phosphodiesterase-5 inhibitors may be considered in Fontan patients with elevated pulmonary artery pressure and pulmonary vascular resistance (Class IIb recommendation: usefulness/efficacy is less well established by evidence or expert opinion; Level of Evidence C: based on expert consensus, small studies, retrospective data, or registries). They also emphasize that current evidence is insufficient to support the routine use of these agents in all patients with Fontan circulation.

To address the key questions of this guideline, a systematic review and meta-analysis were conducted to evaluate the efficacy of pulmonary vasodilator therapy in patients with Fontan circulation, including both adult and pediatric populations. To assess the impact on exercise capacity, outcome measures included peak VO2, anaerobic threshold (VO2 at AT), VE/VCO2 slope, 36-Item Short-Form Health Survey, 6-minute walk distance (6MWD), and NYHA functional class. Hemodynamic outcomes included PVRI, mean PAP, Qp, and transpulmonary pressure gradient. In pooled analyses of data from RCTs, significant improvements were observed in VO2 at AT and Ve/VCO2 in the treatment group, suggesting a beneficial effect of pulmonary vasodilators on exercise capacity. These findings are further supported by the recently published FUEL trial.193) No significant differences in treatment effect were noted between different classes of pulmonary vasodilators.

Due to the limited number of RCTs available for outcomes such as 6MWD, NYHA functional class, and hemodynamic parameters, a pre–post treatment comparison was performed instead. Given these methodological limitations, the results should be interpreted with caution (Supplementary Data 1).

Is exercise rehabilitation beneficial in patients with Fontan circulation?

With the increasing long-term survival of patients after the Fontan procedure, physical activity and exercise capacity—key components of quality of life—have received growing attention, and structured exercise rehabilitation programs have been implemented to address these aspects.4) To date, various studies have evaluated the effects of different exercise rehabilitation programs in both pediatric and adult Fontan populations. Based on this body of evidence, the 2018 AHA guidelines recommended the implementation of individualized, regular exercise training for adults with Fontan circulation (Class IIa, Level of Evidence B-R).8) Subsequently, the 2019 guidelines for pediatric and adult Fontan patients emphasized the benefits of resistance training—particularly lower limb strengthening—and inspiratory muscle training, while rating the evidence for aerobic exercise as less robust.4) However, more recent studies have reported that aerobic exercise can lead to meaningful improvements in exercise capacity.221), 284) The 2020 ESC guidelines for adult CHD further supported this, recommending moderate aerobic exercise for its benefits on muscle strength and quality of life.9)

These findings suggest that exercise rehabilitation programs can enhance exercise capacity and potentially improve long-term outcomes in patients with Fontan circulation.285) However, the heterogeneity in study populations, exercise modalities, and reported outcomes has limited the ability to recommend specific training protocols. To address these uncertainties, this guideline includes a comprehensive meta-analysis evaluating the effectiveness of exercise rehabilitation and explores which exercise modalities and age groups may derive the most benefit. The studies were stratified into three age groups—pediatric, adult, and mixed pediatric/adult cohorts—and into three types of exercise interventions: aerobic training, resistance training, and inspiratory muscle training. The primary outcome for assessing the effect of exercise rehabilitation was the change in peak VO2 as measured by CPET.

In this meta-analysis, data from 5 RCTs demonstrated a statistically significant improvement in peak VO2 among patients who underwent exercise training compared to controls. Furthermore, in 20 pre–post intervention studies, peak VO2 significantly increased following exercise rehabilitation relative to baseline values. Subgroup analyses revealed that studies involving pediatric patients, as well as those including both pediatric and adult populations, showed significant improvements in peak VO2 after training. In terms of exercise modality, aerobic training was associated with a statistically significant increase in peak VO2, suggesting its particular benefit in this population (Supplementary Data 1).

Is persistent fenestration after the Fontan procedure beneficial for long-term outcomes?

Two recently published meta-analyses have evaluated the impact of fenestration performed concomitantly with the Fontan procedure on long-term outcomes.279), 286) Neither study demonstrated a clear advantage in long-term prognosis for patients who underwent fenestration compared to those who did not. Patients with fenestration were noted to have longer cardiopulmonary bypass times. Key clinical outcomes, including mortality and Fontan circulatory failure, did not differ significantly between the two groups in both analyses. Consequently, neither the AHA8) nor the ESC9) guidelines for adult CHD provide specific recommendations regarding the use of fenestration at the time of Fontan surgery.

A propensity score-matched study conducted in a Korean national cohort of Fontan patients similarly found no significant differences in critical outcomes such as mortality and Fontan circulatory failure between patients with and without fenestration. However, hemodynamic parameters including oxygen saturation, CVP, and left atrial pressure were more favorable in patients without fenestration.287)

Given the inconclusive evidence regarding the impact of fenestration on long-term outcomes in Fontan patients, this guideline focuses specifically on the question of the effects of fenestration persisting beyond 6 months. To address this key question, a systematic literature review and meta-analysis were performed. Primary outcomes analyzed included mortality, Fontan circulatory failure, Fontan takedown, and heart transplantation. Exercise capacity was assessed using peak VO2 and NYHA functional class, while hemodynamic effects were evaluated based on oxygen saturation and BNP levels. Important complications relevant to long-term prognosis—including protein-losing enteropathy, plastic bronchitis, stroke and systemic thrombosis, and arrhythmias—were also compared between groups.

The analysis revealed no significant advantage in patients with persistent fenestration compared to those without. Mortality was significantly higher in patients with fenestration remaining beyond 6 months. Among exercise capacity measures, peak VO2 and NYHA functional class showed no benefit with fenestration, and oxygen saturation was significantly better in patients without fenestration. Plastic bronchitis was more frequently observed in patients with persistent fenestration.

Interpretation of these findings requires caution due to several limitations: 1) fenestration is often selectively performed in patients with poorer preoperative status; 2) persistent fenestration may reflect underlying worse cardiac condition; 3) variability in post-fenestration observation periods across studies; and 4) the absence of studies with follow-up exceeding 15 years. In light of these limitations, further well-designed randomized controlled trials are needed to provide more definitive evidence (Supplementary Data 1).

What is the most appropriate method for early diagnosis of liver fibrosis in Fontan patients?

Evidences were synthesized through systematic review and meta-analysis. Subgroup analyses based on histopathological fibrosis staging were conducted to evaluate the association between hepatic fibrosis severity and hemodynamic or hematologic parameters in patients with Fontan circulation. The correlation between histologic fibrosis severity and non-invasive imaging findings was also assessed through a comprehensive review of the literature.

Correlation analyses between post-Fontan duration and histopathologic severity of liver disease demonstrated a trend toward progressive fibrosis over time. Notably, moderate or greater degrees of fibrosis were commonly observed after 10 years post-procedure. Based on these findings, a comprehensive hepatic assessment and annual surveillance should be initiated approximately 10 years after the Fontan procedure.

To evaluate FALD, various hemodynamic parameters—including Fontan pressure, CVP, PVRI, CI, and LVEDP—were assessed for their association with the severity of hepatic fibrosis. Meta-analysis results showed that elevated Fontan pressure was significantly associated with advanced fibrosis. From a hematologic perspective, increasing fibrosis severity was consistently associated with a decrease in platelet count. While individual serum markers have limitations in predicting fibrosis severity, composite indices such as APRI, Fib-4, MELD-XI, ELF score, and the Fons index have been developed and studied for their clinical utility. Meta-analysis demonstrated that higher APRI and Fib-4 scores correlated with greater fibrosis severity, highlighting the importance of serial assessment using these indices. However, the overall quality of evidence is limited by the absence of randomized controlled trials and the predominance of cross-sectional or observational studies in the literature.

Regarding imaging-based diagnosis, abdominal ultrasonography has limited sensitivity in detecting early fibrosis or accurately staging its severity. The evidence supporting the utility of CT and MRI for fibrosis assessment remains limited. In contrast, liver elastography allows for quantitative evaluation of liver stiffness and is widely recognized as a standard non-invasive tool for fibrosis assessment. Literature review supports that MRE and SWE show a consistent and strong correlation with fibrosis severity, suggesting that serial liver stiffness measurements may serve as a valuable tool for the long-term management of FALD (Supplementary Data 1).

SUPPLEMENTARY MATERIAL

Supplementary Data 1

Results of evidence synthesis

Click here to view.

(4M, doc)

Funding:This research was supported and funded by SNUH Lee Kun-hee Child Cancer & Rare Disease Project, Republic of Korea (grant number: 23C-030-0100).

Conflict of Interest:The authors have no financial conflicts of interest.

Endorsement:This guideline has been officially approved by the Korean Society of Pediatric Cardiology.

Data Sharing Statement:The data required to reproduce these findings cannot be shared that this article does not report original clinical trial data.

Author Contributions:

Conceptualization:Kim SJ.
Data curation:Cho MJ, Jeong SI, Oh KJ, Choi HJ.
Formal analysis:Cho MJ, Seol JH, Choi HJ, Choi M.
Investigation:Seol JH, Oh KJ, Kim JA, Na JY.
Methodology:Choi M.
Project administration:Kim SJ.
Supervision:Kim SJ, Jung SY, Song JY.
Visualization:Oh KJ.
Writing - original draft:Cho MJ, Jeong SI, Park CS, Baek JS, Yoon JK, Lee SY, Jang SI, Kwak S, Na JY.
Writing - review & editing:Cho MJ, Jeong SI, Kim SJ, Seol JH, Oh KJ, Choi HJ.

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Figures

Tables

ORCID IDs

Funding Information

Seoul National University Bundang Hospital23C-030-0100

Published online Jul 07, 2023.

https://doi.org/10.4070/kcj.2023.0115

Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Advanced and Acute Heart Failure

With evolving evidence from many trials, the diagnostic and therapeutic approach to heart failure (HF) has changed rapidly in recent years. The contemporary management of acute HF focuses on the rapid stabilization of hemodynamic status and optimization of medical therapy before discharge. Early recognition, assessment of the hemodynamic profile, and sophisticated management are important for patients with advanced HF. Therefore, the rapidly evolving evidence leads to updates of existing guidelines. Here, the Korean Society of Heart Failure provides updated guidelines focused on acute and advanced HF, adapting the latest evidence especially based on Korean data.

The Korean Society of Heart Failure (KSHF) Guidelines provide evidence-based recommendations based on Korean and international data to guide adequate diagnosis and management of heart failure (HF). Since introduction of 2017 edition of the guidelines, management of advanced HF has considerably improved, especially with advances in mechanical circulatory support and devices. The current guidelines addressed these improvements. In addition, we have included recently updated evidence-based recommendations regarding acute HF in these guidelines. In summary, Part IV of the KSHF Guidelines covers the appropriate diagnosis and optimized management of advanced and acute HF.

Globally, heart failure (HF) is a major cause of morbidity and mortality.1), 2) Patients presenting with acute HF are especially at a high risk of adverse outcomes, which necessitates prompt and accurate diagnosis and timely management. Moreover, progressive HF leads to an advanced stage of HF, which is characterized by a devastating clinical course and poor prognosis. Therefore, advanced HF requires timely assessment and management with specialized therapy. In Korea, the introduction of left ventricular assist device (LVAD) improved the management strategy of advanced HF. The Korean Society of Heart Failure (KSHF) had introduced guidelines for the management of acute and chronic HF.3), 4) Subsequently, rapid advances improved clinical outcomes remarkably for acute and advanced HF, which indicated the need for updated guidelines. Herein, we have appended latest evidence to the updated guidelines with a focus on acute and advanced HF.

ADVANCED HEART FAILURE

| Timely referral of patients with advanced HF to an appropriate center is recommended to assess risk stratification and provide appropriate therapy for advanced HF. (Class I, Level of Evidence C) |

Definition

Some patients with HF do not respond to medical therapy and progress to the advanced stage. In advanced HF, symptoms or signs of HF are not improved and worsen even with guideline-directed medical therapy (GDMT); specialized therapy such as mechanical circulatory assist (MCS) devices, heart transplantation, or palliative care are often required.5), 6), 7) Patients with advanced HF have persistent severe symptoms that limits activities of daily living, impairs the quality of life, and requires frequent administration of intravenous agents for symptom relief. The inclusion criteria for defining the stage of advanced HF is listed in Table 1.7) Left ventricular ejection fraction (LVEF) is not the only mandatory defining factor of HF; in addition, symptom burden and anticipated prognosis of HF are more crucial factors to define this stage. Therefore, HF with preserved LVEF can be classified as advanced HF.

European Society of Cardiology criteria defining stage of advanced HF

Classification

Conventionally, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles are used to classify patients with advanced HF who require mechanical support such as left ventricular assistive devices and total artificial hearts. The INTERMACS classification ranges from 1–7 profiles; the lower profiles indicate a more urgent requirement for additional circulatory adjuvant treatment (Table 2).8) Patients with severe HF symptoms and/or signs despite GDMT should be referred to a medical center to receive prompt and specialized treatment for HF. Furthermore, medical staff of the primary or secondary hospitals that treat patients with HF should suspect advanced HF and assess whether the findings correspond to the patients’ symptoms (Table 3).

Interagency for Mechanically Assisted Circulatory Support profiles

Clinical criteria of referral for advanced HF

CARDIOGENIC SHOCK

| 1. For patients with cardiogenic shock, the Society for Cardiovascular Angiography and Interventions classification may be used to assess individual risk and predict prognosis. (Class IIb, Level of Evidence C)2. Supplemental oxygen is recommended for patients with cardiogenic shock and hypoxemia. (Class I, Level of Evidence C)3. Mechanical ventilation should be considered for patients with cardiogenic shock and persistent respiratory failure despite supplemental oxygen or non-invasive ventilation. (Class IIa, Level of Evidence C)4. Adequate support with vasoactive agents may be considered for patients with cardiogenic shock to maintain end-organ perfusion. (Class IIb, Level of Evidence C) |

Cardiogenic shock is a severe impairment of cardiac performance that results in inadequate end-organ perfusion and causes life-threatening consequences such as multi-organ failure or mortality. Decline of cardiac function can occur suddenly due to myocardial infarction and myocarditis or gradually due to exacerbation of chronic HF. Identifying tissue hypoxia and alteration of cellular metabolism as indicated by evidence of hypoperfusion on physical examination (including oliguria, altered consciousness, and low pulse pressure) and biochemical studies (including renal dysfunction, metabolic acidosis, and elevated serum lactate) is vital. The Society for Cardiovascular Angiography and Interventions classifies cardiogenic shock into five stages according to the types and intensity of treatment; it is effective in mortality risk stratification (Figure 1).9), 10) Treatment for cardiogenic shock should be promptly initiated to restore hemodynamic stability and prevent organ failure; however, early identification and treatment of the causative disease are equally important (Figure 2).6)

Treatment algorithm for cardiogenic shock.

ACS = acute coronary syndrome; MCS = mechanical circulatory support; PCI = percutaneous coronary intervention; RRT = renal replacement therapy.

TEMPORARY CIRCULATORY SUPPORT DEVICES

| 1. Routine use of intraaortic balloon pump (IABP) is not recommended for cardiogenic shock. (Class III, Level of Evidence B)2. Use of IABP can be considered for cardiogenic shock resulting from acute mitral regurgitation or ventricular septal defect. (Class IIa, Level of Evidence C)3. Use of extracorporeal membrane oxygenation (ECMO) should be considered for cardiogenic shock refractory to medical therapy. (Class IIa, Level of Evidence C)4. Extracorporeal cardiopulmonary resuscitation using ECMO is not recommended for patients with unwitnessed, out-of-hospital cardiac arrest, and signs of irreversible neurologic impairment. (Class III, Level of Evidence C)5. Evaluation of cardiac function recovery to determine adequacy for weaning from ECMO should be assessed by echocardiography, hemodynamic (e.g., central venous pressure, mean arterial blood pressure [BP]), and biochemical parameters (e.g., lactate). (Class IIa, Level of Evidence C) |

The use of temporary MCS devices should be considered for patients with acute HF who are refractory to fluid and vasoactive/inotropic therapy. The application of specific type of devices should be individualized based on the mechanical characteristics and amount of hemodynamic support required (Figure 3). Current United States and European practice guidelines do not recommend the routine use of intra-aortic balloon pumps; however, these may be helpful for acute MR or VSD, which result from mechanical complication of acute myocardial infarction.5), 6) In Korea, the Impella device (Abiomed, Danvers, MA, USA) is unavailable; hence, ECMO is widely used as a bridge to recovery or bridge to LVAD/heart transplantation (HT).

Temporary circulatory support for drug-refractory cardiogenic shock.

ECMO = extracorporeal membrane oxygenation; IABP = intra-aortic balloon counterpulsation; MI = myocardial infarction; MR = mitral regurgitation; VSD = ventricular septal defect.

Although clear criteria are yet to be established, weaning from ECMO can be considered in those exhibiting stable hemodynamics with minimal support level of ECMO (<1–1.5 L/min) and vasoactive agents (Figure 4).11) Moreover, the use of echocardiographic parameters may help guide weaning decisions.12), 13)

Figure 4

Weaning of percutaneous ECMO.

CVP = central venous pressure; ECMO = extracorporeal membrane oxygenation; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; MAP = mean arterial pressure; MCS = mechanical circulatory support; SFA = superficial femoral artery; SvO2 = mixed venous oxygen saturation; S’ = tissue Doppler tricuspid lateral peak systolic velocity; PAOD = peripheral arterial occlusive disease; RV = right ventricular; VTI = velocity time integral.

*Low level of vasopressor/inotropes refers to norepinephrine ≤0.03 μg/min/kg and dobutamine ≤5 μg/min/kg.

LEFT VENTRICULAR ASSIST DEVICE

A LVAD improve survival and the quality of life for patients with advanced HF. The LVAD can be used in following clinical situations: as a bridge to transplantation, bridge to candidacy to determine adequacy of transplantation, and destination therapy. It can be used in patients with refractory cardiogenic shock who are dependent on temporary MCS as well. The LVAD can be implanted in patients with INTERMACS profiles 2–4 and 5, especially those with a potential risk of sudden cardiac death or irreversible organ failure (Figure 5). The outcomes after durable, centrifugal-flow LVAD implantation as a bridge to transplantation is comparable with HT.14) In Korea, hemorrhagic stroke is a leading cause of mortality and bleeding is most common complication during the first year after LVAD implantation.15)

Figure 5

Treatment strategy according to the INTERMACS profile.

ECMO = extracorporeal membrane oxygenation; INTERMACS = Interagency Registry for Mechanically Assisted Circulatory Support; LVAD = left ventricular assist device; NYHA = New York Heart Association; MCS = mechanical circulatory support.

HEART TRANSPLANTATION

| 1. HT is recommended to improve survival and quality of life for selected patients with advanced HF. (Class I, Level of Evidence C)2. Cardiopulmonary exercise test is recommended in patients with advanced HF to guide HT listing. (Class I, Level of Evidence B)3. Annual evaluation of right heart catheterization is recommended to evaluate hemodynamic status in patients listed for HT. (Class I, Level of Evidence C) |

HT is gold standard therapy for patients with advanced HF; it helps improve survival, exercise capacity, and the quality of life.16) In Korea, nearly 200 heart transplants are performed annually and this number has been gradually increasing since 2000.1), 17) However, donor shortage is a major limitation of HT18); hence, appropriate recipient selection is important to maximize post-transplant outcome (Table 4). In Korea, the one-year survival after transplantation was reported to reach 90%19) and the International Society for Heart and Lung Transplantation reported a median survival of 12.5 years.20) Cardiopulmonary exercise test helps guide listing for evaluating the candidacy for HT.16), 21) HT can be considered if peak oxygen consumption is <14 mL/kg/min for non-beta-blocker (BB) users and <12 mL/kg/min for BB users, achieved during maximal exercise workload represented by a respiratory exchange ratio >1.05.16) Annual right heart catheterizations should be performed to evaluate hemodynamic status in patients who have been listed for HT.16)

Common indications and contraindications of heart transplantation

PALLIATIVE AND END-OF-LIFE CARE

| 1. Patients with advanced HF refractory to medical therapy and not indicated for HT or LVAD can benefit from palliative and end-of-life care. (Class IIa, Level of Evidence C)2. Morphine, antiemetics, diuretics, and oxygen therapy may be considered for palliative care in patients with severe pain and congestive symptoms; GDMT, which lower BP without immediate effect, prescribed for long-term benefit may be continued at a reduced dose or discontinued. (Class IIb, Level of Evidence C)3. Physician Orders for Life Sustaining Treatment may be prepared after multidisciplinary discussion and review. (Class IIa, Level of Evidence C) |

Palliative and end-of-life care can be considered for patients with advanced HF who are not indicated for LVAD implantation or HT, those who are unable to maintain independent daily activities, and those with deteriorating symptoms despite appropriate therapy. Palliative care mainly focuses on providing symptomatic relief to maintain the quality of life and offers psychological support through a multidisciplinary approach that includes the patient, physician, nurse, and other specialists.22), 23)

Morphine can reduce breathing difficulty, pain, and anxiety; however, patients should be informed of the following side effects: constipation, nausea, and altered mental status.24), 25) Supplemental oxygen and diuretics can help reduce dyspnea or congestive symptoms. BP lowering HF medications with a well-proven efficacy in improving long-term survival can be reduced or withdrawn based on the patient’s condition, thereby reducing risk of falls. A special care plan needs to be established for some patients including desired place for death and deactivation of implanted devices such as pacemakers or implantable cardioverter defibrillators (ICDs); it should consider the legal policies in the country.

ACUTE HEART FAILURE

Definition and aggravating factors

Acute HF, characterized by the rapid onset and deterioration of the symptoms or signs of HF, requires prompt medical attention and often leads to emergency room visits or unexpected hospitalization. If acute HF is suspected, diagnostic tests should be performed immediately and adequate therapy initiated simultaneously. In Korea, among patients with acute HF, approximately 52% were newly-diagnosed with HF and 48% had acute decompensation of pre-existing chronic HF.26) The aggravating factors of HF, albeit not as a cause that leads to worsening events, are diverse (Table 5).

Common aggravating factors of acute HF

Patients presenting with acute HF are at a high risk of in-hospital mortality, which is substantially lowered once they are stabilized and discharged. The Korean Acute Heart Failure (KorAHF) Registry study reported an in-hospital mortality rate of 4.8%.26) The rates of mortality and re-hospitalization of Korean HF population are presented in Table 6.

The rates of mortality and re-hospitalization of acute heart failure in Korea

Acute HF should be immediately diagnosed during the hospital visit. The diagnosis should aim to assess the hemodynamic profile and investigate reversible causes and aggravating factors, which require prompt treatment (Figure 6). In addition, natriuretic peptides (NPs) measurement and echocardiography should be performed to confirm the diagnosis. NPs measurement can help rule out HF in patients who have symptoms or signs suggestive of HF; although elevated NP levels support a diagnosis of HF, they are not essentially diagnostic because other non-cardiac medical conditions can cause elevated NP levels as well.27), 28) Chest radiography and lung ultrasound may help assess acute HF, especially when NP levels cannot be measured. In patients with acute HF, measurement of serum creatinine, blood urea nitrogen, and electrolytes levels is useful for therapeutic management. Elevated liver enzymes suggest poor prognosis.29), 30) Hypothyroidism or hyperthyroidism may precipitate HF; hence, thyroid-stimulating hormone levels should be measured. Lactate and hydrogen ion concentration, obtained via arterial blood gas analysis, may help assess hemodynamic condition and predict prognosis. Troponin elevation can be observed in the absence of definite myocardial ischemia or stenotic coronary artery disease in patients with acute HF and provide clinical evidence of acute coronary syndrome as a possible etiology of acute HF.31)

Figure 6

Diagnostic approach to suspected acute HF.

BNP = brain natriuretic peptide; CAG = coronary angiography; CT = computed tomography; HF = heart failure; NT-pro-BNP = N-terminal pro-B-type natriuretic peptide; US = ultrasound.

*Blood tests include troponin, serum creatinine, electrolytes, blood urea nitrogen, thyroid stimulating hormone, liver function test, d-dimer, procalcitonin, arterial blood gas analysis, lactate.

†Coronary angiography can be performed if acute coronary syndrome is suspected, and chest CT if pulmonary embolism is suspected.

According to clinical status, acute HF can be classified into four subgroups that may overlap with each other (Table 7). Each subgroup is distinguished based on the status of congestion and tissue perfusion, thereby necessitating appropriate management for each group (Figure 7).

Subtypes of acute HF

Figure 7

Therapeutic algorithm of acute HF.

HF = heart failure; MCS = mechanical circulatory support; RRT = renal replacement therapy; SBP = systolic blood pressure.

MONITORING ACUTE HEART FAILURE

| 1. Vital signs and oxygen saturation should be continuously monitored in patients with acute HF. (Class I, Level of Evidence C)2. Volume status and fluid balance should be assessed by symptoms (orthopnea) and signs (jugular venous distention, peripheral edema, and body weight gain). (Class I, Level of Evidence C)3. Renal function and serum electrolytes should be assessed frequently when initiating treatment with intravenous diuretics or renin-angiotensin-aldosterone system blockers. (Class I, Level of Evidence C)4. Hemodynamic assessment using pulmonary artery catheter can be considered for refractory symptoms despite standard therapy with uncertainty of volume or perfusion status, low systolic BP, worsening renal function, and need for inotropes or MCS or HT. (Class IIa, Level of Evidence C)5. Measurement of brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and/or cardiac troponin levels is recommended to predict prognosis and assess HF severity. (Class I, Level of Evidence A) |

More than 90% of patients presenting with acute HF have dyspnea; it is an important surrogate to evaluate treatment efficacy. Orthopnea predicts elevated pulmonary capillary wedge pressure (PCWP) with approximately 90% sensitivity.32) Along with symptom improvement, measurement of body weight, jugular venous pressure (JVP), pulmonary rales on auscultation, and assessment of peripheral edema provide important evidence for treatment effect.33) Daily measurement of body weight with a standardized scale at a certain time is recommended. Since JVP reflects right atrial pressure, PCWP can be indirectly assessed by JVP measurement, which is an efficient method to evaluate volume status.32), 33), 34), 35) Pulmonary congestion can be evaluated via auscultation and chest radiography. Loop diuretics and renin-angiotensin-aldosterone system blockers can reduce glomerular filtration rate and result in electrolyte imbalance; hence, assessment of renal function and serum electrolyte levels are important. Routine use of pulmonary artery catheter is not recommended for patients with acute HF36), 37); however, it may help guide management of patients with HF with uncertain hemodynamic and/or volume status, refractoriness of initial therapy, persistent hypotension, progressively worsening renal function, and those considering MCS or HT. The CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III HF Patients) trial reported that individualized adjustment of diuretics doses through pulmonary artery pressure monitoring may reduce the risk of HF-related hospitalization by 28% in patients with New York Heart Association functional class III symptom.38), 39) The subsequent GUIDE-HF (haemodynamic-GUIDEd management of Heart Failure) study did not report significant benefits of pulmonary artery pressure monitoring in HF with mild symptoms; hence, further studies are needed to clarify the merits of pulmonary artery pressure monitoring.40)

DIURETICS

| 1. Intravenous loop diuretics should be used to improve symptoms for all patients admitted for acute HF with symptoms or signs of volume overload. (Class I, Level of Evidence C)2. The recommended initial doses of intravenous loop diuretics are 20–40 mg of furosemide for non-users of diuretics and an equivalent dose or more for those already on diuretics for acute exacerbation of pre-existing HF. (Class I, Level of Evidence B)3. Measurement of urine sodium and urine output can be helpful to assess diuretic response. (Class IIa, Level of Evidence C)4. Combination therapy of loop diuretics and thiazides can be considered for those with inadequate response to loop diuretics. (Class IIa, Level of Evidence C) |

Diuretics prevent the renal absorption of salt and water and consequently, promote their excretion, thereby relieving fluid accumulation and congestion. Diuretics should be administered in the early course of management of acute HF in all patients presenting with symptoms or signs of congestion and volume overload, regardless of LVEF. Although the level of evidence for mortality was low because of the lack of randomized controlled trials, most HF trials were conducted on the basis of sufficient diuretic usage. Diuretic therapy is targeted at achieving and maintaining euvolemic status at the lowest dose. Reduced dose or treatment withdrawal should be considered after achievement of euvolemic or hypovolemic status because excessive diuretics can cause hypotension and renal dysfunction.41)

Loop diuretics are first-line agents because of their rapid action and strong diuretic effect, especially via the intravenous route, which is beneficial in the early presentation of acute HF. These diuretics can be initiated at a low dose and gradually increased if the diuretic effect is insufficient, while monitoring the response. An initial dose of 20–40 mg of furosemide or 10–20 mg of torsemide may be intravenously administered for patients with de novo acute HF. Furosemide can be administered as a twice or three times daily bolus injection or as a continuous infusion. If the patient is on oral diuretics before exacerbation, intravenous administration of an equivalent or twice the dose of the total daily oral dose can be administered.

Diuretic responses are targeted at a weight loss of 0.75–1.0 kg/day with sufficient urine output. The response should be assessed by estimating the spot urine sodium excretion (>50–79 mEq/L at after 2 or 6 hours) and hourly urine output (>100–150 mL during first 6 hours) after initiation of diuretic therapy.41), 42), 43) In case of insufficient response, the diuretic dose can be doubled until it reaches the maximal dose. If diuretic response remains unsatisfactory (hourly urine volume <100 mL) despite the doubled dose, a combination therapy of other diuretic classes including acetazolamide and thiazides may be considered.44), 45), 46) Diuretic doses should gradually be reduced upon achieving euvolemia, while maintaining the lowest dose of diuretics that can prevent congestion. Concomitant therapy with angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 inhibitors should be monitored for excessive diuresis as these agents also have diuretic properties.47), 48)

VASODILATORS AND OTHER DRUGS

| 1. Intravenous nitroglycerin or nitroprusside may be considered in patients with acute HF and systolic BP >110 mmHg to help improve symptoms and congestion. (Class IIb, Level of Evidence B)2. Prophylactic anticoagulation therapy is recommended to prevent deep vein thrombosis and pulmonary thromboembolism in patients not on anticoagulants and where it is not contraindicated. (Class I, Level of Evidence A)3. Routine use of opiates is not recommended to control symptoms except in selected patients with severe pain or anxiety. (Class III, Level of Evidence C) |

Intravenous vasodilators

Intravenous vasodilators, nitrates or nitroprusside, induce arterial and venous dilation, reduce preload and afterload, and subsequently, lead to increased stroke volume, decreased congestion, and symptom relief. Although evidence supporting the use of these agents is lacking, certain patients with acute HF may be considered suitable for receiving intravenous vasodilators especially those with acute pulmonary edema and increased afterload manifested as high BP, coronary ischemia, or significant MR.49), 50) However, vasodilators may increase the risk of hypotension, tachyphylaxis; therefore, adequate hemodynamic monitoring is essential. The criterion for systolic BP of 110 mmHg to initiate vasodilator therapy lacks robust evidence and is primarily based on expert opinion derived from large-scale randomized trials.

Venous thromboprophylaxis

Anticoagulation therapy is recommended for patients hospitalized for worsening HF and other medical problems in pre-existing HF to decrease the risk of deep vein thrombosis and pulmonary embolism for those who do not have contraindications to and are not already on anticoagulant therapy. Unfractionated heparin, low-molecular-weight heparins, warfarin, or approved direct oral anticoagulants can be used.

Opiates

Opiates reduce dyspnea and anxiety and can be used as sedatives in patients with non-invasive positive pressure ventilation. However, routine use of opiates for acute HF is not recommended because some retrospective studies have reported that morphine increased the risk of mechanical ventilation, prolonged the length of hospital stay, increased admissions to intensive care units, and increased mortality.51), 52)

Digoxin can be considered in patients with atrial fibrillation intolerable to BBs and a higher heart rate (>110 beats/min) despite BB use. However, since the metabolism of digoxin can be influenced by multiple factors including other drugs or renal function, serum level of digoxin should be measured.

INOTROPES AND VASOPRESSORS

| 1. Inotropes may be considered to maintain systemic perfusion in patients with hypotension and evidence of end-organ hypoperfusion despite standard therapy and adequate fluid resuscitation. (Class IIb, Level of Evidence C)2. Routine administration of inotropes is not recommended unless symptomatic hypotension and evidence of systemic hypoperfusion are observed. (Class III, Level of Evidence C)3. Vasopressors may be used to maintain hemodynamics and end-organ perfusion for patients with cardiogenic shock. (Class IIb, Level of Evidence B) |

In some patients, acute HF can be accompanied by a decrease in end-organ perfusion due to low cardiac output and systemic BP. In such patients, inotropes and/or vasopressors may be necessary to maintain adequate hemodynamics and restore systemic perfusion. Each agent has different properties or mechanism of action; hence, they should be used accordingly (Table 8).53) Inotropes/vasopressors should be initiated at low doses and gradually increased, and the hemodynamic response should be monitored to maintain adequate blood pressure (mean BP 65–70 mmHg). Results from the KorAHF registry study suggested that use of inotropes/vasopressors in patients with systolic BP >90 mmHg was associated with poor prognosis.54) Since these agents may increase the risk of arrhythmia and myocardial ischemia, they should be used in minimal doses and for a short-term, if possible, until end-organ perfusion improvement.55)

Hemodynamic properties of common inotropes and vasopressors

Inotropes

Dobutamine mainly acts on β1 receptors to increase myocardial contractility and consequently, cardiac output. However, dobutamine increases the risk of arrhythmia and myocardial ischemia.56), 57) Dobutamine acts on β2 receptor of peripheral vessels causes vasodilation and subsequent reduction of BP, which require hemodynamic monitoring. Milrinone, a type-3-phosphodiesterase inhibitor, increases myocardial contractility and reduces pulmonary vascular resistance. Since milrinone does not act on β1 receptors, it can be used with BBs. However, milrinone decreases systemic BP and should be cautiously used especially in patients with shock.

Vasopressors

Norepinephrine, epinephrine, and dopamine are commonly used vasopressors, which increase both myocardial contractility and systemic vascular resistance. Vasopressors are often combined with inotropes for patients with cardiogenic shock and hypotension. Evidence supporting the superiority of one specific agent over another is lacking. In the SOAP (Sepsis Occurrence in Acutely Ill Patients) II trial, dopamine use significantly increased the risk of arrhythmia in patients with shock and norepinephrine was reportedly favorable in terms of mortality for a subgroup of patients with cardiogenic shock.58) Another study reported that norepinephrine was favorable over epinephrine regarding heart rate and lactic acidosis, without differences in hemodynamic profiles in patients with myocardial infarction-induced cardiogenic shock.59) Therefore, based on available evidence, norepinephrine may be prioritized over various vasopressors for cardiogenic shock necessitating vasoactive agents.

PRE- AND POST-DISCHARGE MANAGEMENT

| 1. Patients admitted for HF should be evaluated for the achievement of adequate decongestion before discharge. (Class I, Level of Evidence C)2. GDMT should be initiated and preferably optimized before discharge. (Class I, Level of Evidence C)3. Early follow-up evaluation within 1–2 weeks after discharge is recommended to assess volume status and drug tolerance. (Class I, Level of Evidence C) |

The early period of post-hospitalization discharge for worsening HF refers a vulnerable period that demonstrates a high risk of mortality and readmission.60) Therefore, it is necessary to ensure that the precipitating factors are appropriately corrected and symptoms and/or signs of HF are improved before discharge. Approximately 30% of patients discharged from HF hospitalization have residual congestion and a higher risk of first-year mortality compared with those without congestion.61) Therefore, appropriate decongestion before discharge through diuretic therapy is mandatory.

Furthermore, optimization of medical therapy, evaluation for clinical need of device therapy (e.g. ICD), and appropriate patient education for diet and physical exercise are important.62) Patients admitted for acute HF should be initiated on evidence-based medical therapy prior to discharge unless it is contraindicated.63) In Korea, the at-discharge prescription rates of renin-angiotensin system blockers, BBs, and MRAs were 68.8%, 52.2%, and 46.6%, respectively,26) which is suboptimal. Medical therapy with these agents at discharge is reported to improve clinical outcomes; hence, physicians should check whether these medications are prescribed.63), 64) Furthermore, in-hospital initiation of ARNI can reduce NT-pro-BNP levels and reduce the risk of HF-related adverse clinical outcomes.65) Therefore, early initiation of ARNI should be considered.

The diagnosis and management of acute and advanced HF is rapidly advancing recently. Early diagnosis and optimization of therapy is cornerstone for acute HF, and adequate assessment and management in accordance with the patient’s profile is crucial in patients with advanced HF. This Part 4 of the HF guidelines adapted latest evidence and provided optimal approach focused on the patients with acute or advanced HF.

Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data Sharing Statement:The data generated in this study is available from the corresponding author(s) upon reasonable request.

Conceptualization:Cho JH, Kang SM.
Funding acquisition:Cho JH, Yoo BS, Kang SM.
Supervision:Cho JH, Kang SM.
Writing - original draft:Hyun J.
Writing - review & editing:Cho JY, Youn JC, Kim D, Cho DH, Park SM, Jung MH, Cho JH, Park SM, Choi JO, Chung WJ, Yoo BS, Kang SM.

This article has been published jointly, with consent, in both Korean Circulation Journal and International Journal of Heart Failure.

Also, the final version of this guideline was endorsed by Korean Society of Cardiology, Korean Society of Lipid and Atherosclerosis, Korean Association of Clinical Cardiology, Korean Society of Hypertension, Korean Society of Heart Failure, Korean Society of Echocardiography, Korean Society of Interventional Cardiology, Korean Heart Rhythm Society, and Korean Society of CardioMetabolic Syndrome.

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