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Pulmonary vasodilators and exercise in Fontan circulation: a systematic review and meta-analysis
  1. Diamantis Kosmidis1,
  2. Alexandra Arvanitaki1,2,
  3. Ioannis T Farmakis3,
  4. Aris Liakos4,
  5. Andreas Giannopoulos5,
  6. Antonios Ziakas1,
  7. George Giannakoulas1
  1. 1 First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
  2. 2 Adult Congenital Heart Disease and Pulmonary Hypertension Service, Royal Brompton Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
  3. 3 Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany
  4. 4 Clinical Research and Evidence-Based Medicine Unit, Aristotle University Thessaloniki, Thessaloniki, Greece
  5. 5 Pediatric Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
  1. Correspondence to Prof George Giannakoulas, Cardiology Department, University General Hospital of Thessaloniki AHEPA, Thessaloniki, 54636, Greece; g.giannakoulas{at}


Objective In Fontan circulation, pulmonary arterial hypertension (PAH)-targeted therapies could improve the patients’ exercise capacity. This study aimed to investigate the effects of PAH agents on different exercise parameters in stable Fontan patients by synthesising evidence of randomised controlled trials (RCTs).

Methods A systematic search of PubMed, Cochrane Central Register of Controlled Trials and Web of Science databases, as well as of, was performed. Primary outcomes were specific cardiopulmonary exercise test parameters: peak oxygen uptake (peak VO2), peak heart rate (peak HR), the minute ventilation/produced carbon dioxide (VE/VCO2) slope and the oxygen uptake, both measured at the anaerobic threshold (VO2@AT).

Results Five RCTs were included in the analysis including 573 Fontan patients (mean age 21.2 years, 60% male). PAH-targeted therapies did not affect peak VO2 (mean difference (MD) 0.72, 95% CI −0.25 to 1.70) or peak HR (MD −0.67, 95% CI −3.81 to 2.47), but resulted in a small, significant improvement in VO2@AT (standardised MD 0.24, 95% CI 0.02 to 0.47). VE/VCO2 slope at the anaerobic threshold was also reduced (MD −1.13, 95% CI −2.25 to −0.01).

Conclusions Although PAH-targeted therapies did not affect exercise parameters at maximal effort, they induced slight improvements in indices of submaximal effort, measured at the anaerobic threshold. Pharmacological improvement of submaximal exercise seems to be a more suitable indicator of Fontan individuals’ exercise capacity. Larger RCTs, recruiting specific subpopulations and focusing also on the anaerobic threshold, are warranted to draw more robust conclusions.

PROSPERO registration number CRD42022306674.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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  • Contributors DK, AA and GG designed the research study. DK and AA performed the research. ITF and AL provided help and advice on the research conduction. DK and ITF analysed the data. DK wrote the manuscript. AA, ITF, AL, AG, AZ and GG critically revised the manuscript and contributed to editorial changes. All authors read and approved the final manuscript. GG is the guarantor and accepts full responsibility for the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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