Physicians' Academy for Cardiovascular Education

IL-6 levels in the general population associated with new-onset HFpEF

Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population

Literature - Chia YC, Kieneker LM, van Hassel G, et al. - J Am Heart Assoc. 2021;10:e018549. doi: 10.1161/JAHA.120.018549.

Introduction and methods

The cause of HFpEF is poorly understood and effective therapies are lacking [1,2]. Previous studies have suggested that inflammation plays a role in the development of HFpEF [3,4]. A recent study in a large, heterogeneous HF cohort found elevated levels of IL-6 in more than half of patients, especially in those with HFpEF (LVEF>40%), and these levels were also independently associated with mortality and/or HF hospitalization [4].

Elevated IL-6 levels are closely related to the induction of iron deficiency by upregulation of hepcidin and to increased levels of fibroblast growth factor 23 (FGF23) [5-7]. Moreover, iron deficiency, anemia, and elevated levels of FGF23 have been shown to play a role in the pathophysiology of HF [8-10]. Therefore, these factors could potentially play a role in the relationship between IL-6 and HF. This study assessed whether IL-6 is associated with the development of HF, HFrEF, or HFpEF in the general healthy population and whether this putative association could be explained by iron deficiency, anemia, or increased levels of FGF23.

This case-cohort study used data from the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study, a prospective general population-based cohort study of inhabitants of the city Groningen in The Netherlands. Inhabitants (28-75 years) received between 1997 and 1998 a questionnaire on demographics, disease history, smoking habits, and use of medication. A second survey took place between April 24, 2001 and December 3, 2003. This substudy included 961 participants (200 cases with new-onset HF and 671 random controls) free from HF at inclusion. IL-6 levels were measured in fasting blood samples obtained at the second survey. Data on markers of iron metabolism and FGF23 were obtained from samples gathered at the second survey. HF was classified as HFrEF with LVEF ≤40% (n=113) or HFpEF with LVEF >40% (n=87) at the time of diagnosis. The median (IQR) follow-up was 8.2 (7.7-8.8) years.

Main results


This case-cohort study using data from the PREVEND study showed that elevated levels of IL-6 were associated with an increased risk for new-onset HFpEF in community-dwelling participants. The association between IL-6 and HFpEF was independent of iron deficiency, anemia, and FGF23 upregulation.

The authors state that the strong relationship between IL-6 and HFpEF might form a basis to investigate whether IL-6 is a potential therapeutic target in the prevention of HFpEF.


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