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Original research
Aetiology, ejection fraction and mortality in chronic heart failure: a mediation analysis
  1. Josef Fritz1,
  2. Katrin Belovari2,
  3. Hanno Ulmer1,
  4. Marc-Michael Zaruba2,
  5. Moritz Messner2,
  6. Maria Ungericht2,
  7. Uwe Siebert3,4,5,
  8. Frank Ruschitzka6,
  9. Axel Bauer2,
  10. Gerhard Poelzl2
  1. 1Institute of Medical Statistics and Informatics, Medical University of Innsbruck, Innsbruck, Austria
  2. 2Department of Internal Medicine III Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria
  3. 3Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria
  4. 4Center for Health Decision Science, Departments of Epidemiology and Health Policy & Management, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  5. 5Program on Cardiovascular Research, Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
  1. Correspondence to Professor Gerhard Poelzl, Department of Internal Medicine III Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Austria; gerhard.poelzl{at}


Objective Clinical decision making in chronic heart failure (CHF) is based primarily on left ventricular ejection fraction (LVEF), and only secondarily on aetiology of the underlying disease. Our aim was to investigate the mediating role of LVEF in the relationship between aetiology and mortality.

Methods Using data of 2056 Austrian patients with CHF (mean age 57.2 years; mean follow-up 8.8 years), effects of aetiology on LVEF and overall mortality were estimated using multivariable-adjusted linear and Cox regression models. In causal mediation analyses, we decomposed the total effect of aetiology on mortality into direct and indirect (mediated through LVEF) effects.

Results For the analysed aetiologies (dilated (DCM, n=1009) and hypertrophic (HCM, n=89) cardiomyopathy; ischaemic (IHD, n=529) and hypertensive (HHD, n=320) heart disease; cardiac amyloidosis (CA, n=109)), the effect of LVEF on mortality was similar (HR5%-points lower LVEF=1.07, 95% CI 1.04 to 1.10; pinteraction=0.718). HCM and CA were associated with significantly higher, and IHD and DCM with significantly lower LVEF compared with other aetiologies. Compared with respective other aetiologies, the corresponding total effect HRs for mortality were 0.77 (95% CI 0.67 to 0.89), 0.47 (95% CI 0.25 to 0.88), 1.40 (95% CI 1.21 to 1.62), 0.79 (95% CI 0.67 to 0.95) and 2.36 (95% CI 1.81 to 3.08) for DCM, HCM, IHD, HHD and CA, respectively. CA had the highest mortality despite a HRindirect effect of 0.74 (95% CI 0.65 to 0.83). For all other aetiologies, <20% of the total mortality effects were mediated through LVEF.

Conclusions The direct effect of aetiology on mortality dominates the indirect effect through LVEF. Therefore, clarification of aetiology is as important as measurement of LVEF.

  • heart failure

Data availability statement

Data are available on reasonable request. Data are available from the corresponding author on reasonable request.

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Data availability statement

Data are available on reasonable request. Data are available from the corresponding author on reasonable request.

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  • Contributors JF: conceptualisation, formal analysis, investigation and writing—original draft; KB: data curation, investigation and writing—review and editing; HU: conceptualisation, investigation and writing—review and editing; M-MZ: writing—review and editing; MM: writing—review and editing; MU: writing—review and editing; US: investigation and writing—review and editing; FR: writing—review and editing; AB: writing—review and editing; GP: guarantor, conceptualisation, data curation, investigation and writing—original draft.

  • Funding All authors, except for US and FR, were core funded by the Medical University Innsbruck and the Tyrol State Hospital—University Hospital, Innsbruck, Austria.

  • 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.