Distinguishing heart failure with reduced ejection fraction from heart failure with preserved ejection fraction: A phenomics approach

Bart J. van Essen, Ganash N. Tharshana, Wouter Ouwerkerk, Poh Suan Daniel Yeo, David Sim, Fazlur Jaufeerally, Hean Yee Ong, Lieng Hsi Ling, Dinna Kar Nee Soon, Shao Guang Sheldon Lee, Gerard Leong, Seet Yoong Loh, Ru San Tan, Chrishan J. Ramachandra, Derek J. Hausenloy, Oi Wai Liew, Jenny Chong, Adriaan A. Voors, Carolyn S.P. Lam, A. Mark RichardsJasper Tromp*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Aim: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. 

Methods and results: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age- and sex-matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi-block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross-referenced with small-molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60–71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)-8 and IL-6 were possible targets related to lower EF and worsening renal function. 

Conclusion: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF.

Original languageEnglish
Number of pages10
JournalEuropean Journal of Heart Failure
Publication statusAccepted/In press - 4-Feb-2024


  • Biomarkers
  • Heart failure


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