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

  • Multivariable regression analysis with additional corrections for hemoglobin and ferritin levels demonstrated a significant association between IL-6 and developing HF (HR 1.47, 95% CI: 1.19-1.83, P<0.001).
  • IL-6 levels were also significantly associated with new-onset HF after adjustment for FGF23 (HR 1.28, 95% CI: 1.02-1.61, P=0.03).
  • Participants in the upper IL-6 tertile had an increased risk for new-onset HFpEF compared to those in the lowest tertile (5.2 [4.2-7.1] pg/mL vs. ≤1.5 pg/mL; HR 2.41, 95% CI:1.16-5.03)
  • IL-6 was significantly associated with new-onset HFpEF independent of potential confounders (HR 1.75, 95% CI: 1.29-2.37, P<0.001 when adjusted for hemoglobin and ferritin, and HR 1.59, 95% CI: 1.16-2.19, P=0.004 when adjusted for FGF23). There was no association between IL-6 and the development of HFrEF.
  • The association between IL-6 and HFpEF remained when participants with HFmrEF were excluded from the HFpEF group (HR 1.47, 95% CI: 1.04-2.06, P=0.03).


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.


1. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–2467. DOI: 10.1056/NEJMoa0805450.

2. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777–781. DOI: 10.1016/S0140-6736(03)14285-7.

3. Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol. 2010;55:2129–2137. DOI: 10.1016/j.jacc.2009.12.045.

4. Markousis-Mavrogenis G, Tromp J, Ouwerkerk W, et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur J Heart Fail. 2019;21:965–973. DOI: 10.1002/ ejhf.1482.

5. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-1276

6. Wrighting DM and Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108:3204-3209

7. Durlacher-Betzer K, Hassan A, Levi R, et al. Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease. Kidney Int. 2018;94:3151-325

8. Beale AL, Warren JL, Roberts N. et al. Iron deficiency in heart failure with preserved ejection fraction: a systemic review and meta-analysis. Open Heart. 2019;6:e001012.

9. Faul C, Amaral Ap, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393-4408

10. Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2019;119:2545-2552

Find this article online at J Am Heart Assoc.

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