Iron deficiency and diastolic function in heart failure with preserved ejection fraction

Background. Despite the high prevalence of iron deficiency (ID) in heart failure with preserved ejection fraction (HFpEF), relationship between iron status indicators with the presence of the disease and parameters of diastolic function and myocardial strain have been insufficiently studied.

Aim: To evaluate association of iron status indicators with the disease and parameters of diastolic function and myocardial strain in HFpEF patients.

Material and Methods. According to diastolic stress test (DST) 67 patients with EF > 50% (65.8 ± 5.5 years) were divided into 2 groups: Gr.1 with HFpEF (n = 41), Gr.2 without HFpEF (n = 26). Parameters of diastolic function, left atrial reservoir strain (LASr), global longitudinal strain (GLS), diastolic reserve as per DST, serum iron (Fe), ferritin, iron transferrin saturation coefficient (ITSC) , hemoglobin (Hb), N-terminal pro B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), creatinine, estimated glomerular filtration rate (eGFR) were assessed. Spearman method was used to study the relationships between iron status indicators and parameters of diastolic function, LASr, GLS; the cut-off point for ITSC was found by ROC analysis; factors associated with HFpEF were assessed via regression analysis.

Results. In group 1, FCII (NYHA) was revealed more frequent with trends to greater prevalence in women, obesity, higher values of peak E, NT-proBNP, CRP > 3.0 mg/ml, lower values of E/e΄, LASr, Hb, ITSC. As per DST, differences between groups in all variables related elevation left ventricular filling pressure were registered; supreme load and heart rate were lowest in Gr1. Anemia was detected in 6 (9%) patients: 5 (12.2%) vs 1 (3.8%), respectively, p = 0.238; Iron deficiency in 27(40.3%): 18 (43.9%) vs 9 (34.6%), p = 0.157. Correlations were defined between Fe and ITSC with supreme load with DST and diastolic function parameters, but not with LASr and GLS. New cut-off point for ITSC = 29.2% (AUC = 0.699, p = 0.009; sensitivity = 71%, specificity = 69%) associated with HFpEF risk (OR 5.029 95% CI 1.575–16.055; p = 0.006) was revealed.

Conclusion: Regardless of HFpEF, ID prevailed in patients aged over 60 years old, which determined the necessity of its screening study for the purpose of timely correction. Association between ITSC reduction less than 29.2% and the disease presence was found: risk of having HFpEF concurrently increased by five times. Interactions were registered between Fe and ITSC with supreme load and diastolic function parameters, but not with LASr and GLS. Higher incidence of CRP > 3.0 mg/ml with HFpEF confirmed pro-inflammatory status of the disease.

1. Savarese G., Becher P.M., Lund L.H., Seferovic P., Rosano G.M.C., Coats A.J.S. Global burden of heart failure: A comprehensive and updated review of epidemiology. Cardiovasc. Res. 2023;118:3272–3287. DOI: 10.1093/cvr/cvac013.

2. Eidizadeh A., Schnelle M., Leha A., Edelmann F., Nolte K., Werhahn S.M. et al. Biomarker profiles in heart failure with preserved vs. reduced ejection fraction: results from the DIAST-CHF study. ESC Heart Failure. 2023;10:200–210. DOI: 10.1002/ehf2.14167.

3. Pieske B., Tschöpe C., de Boer R.A., Fraser A.G., Anker S.D., Donal E. et al. How to diagnose heart failure with preserved ejection fraction: the HFAPEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur. Heart J. 2019;40(40):3297–3317. DOI: 10.1093/eurheartj/ehz641.

4. Shirokov N.E., Yaroslavskaya E.I., Krinochkin D.V., Musikhina N.A., Gizatulina T.P., Enina T.N. et al. Principles for diagnosing heart fail ure with preserved ejection fraction. Russian Journal of Cardiology. 2023;28(3S):5448. (In Russ.). DOI: 10.15829/1560-4071-2023-5448.

5. Beale A.L., Warren J.L., Roberts N., Meyer P., Townsend N.P., Kaye D. Iron deficiency in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Open Heart. 2019;6(1):e001012. DOI: 10.1136/openhrt-2019-001012.

6. Kasner M., Aleksandrov A.S., Westermann D., Lassner D., Gross M., von Haehling S. et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. Int. J. Cardiol. 2013;168(5):4652–4657. DOI: 10.1016/j.ijcard.2013.07.185.

7. Gevaert A.B., Mueller S., Winzer E.B., Duvinage A., Van de Heyning C.M., Pieske-Kraigher E.; OptimEx-Clin Study Group. Iron deficiency impacts diastolic function, aerobic exercise capacity, and patient phenotyping in heart failure with preserved ejection fraction: A subanalysis of the optimex-clin study. Front. Physiol. 2022;12:757268. DOI: 10.3389/fphys.2021.757268.

8. Elçioğlu B.C., Onur Baydar O., Kılıç A., Tefik N., Helvacı F., Gürsoy E. et al. Effects of iron deficiency on left ventricular functions in young women regardless of anemia: A speckle tracking echocardiography study. Turk. J. Med. Sci. 2022;52(3):754–761. DOI: 10.55730/1300-0144.5370.15.

9. Polyakov D.S., Fomin I.V., Belenkov Yu.N., Mareev V.Yu., Ageev F.T., Artemyeva E.G. et al. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiologiia. 2021;61(4):4–14. DOI: 10.18087/cardio.2021.4.n1628.

10. DuBrock H.M., AbouEzzeddine O.F., Redfield M.M. High-sensitivity C-reactive protein in heart failure with preserved ejection fraction. PLoS One. 2018;13(8):e0201836. DOI: 10.1371/journal.pone.0201836.

11. Ha Manh T., Do Anh D., Le Viet T. Effect of body mass index on N-terminal pro-brain natriuretic peptide values in patients with heart failure. Egypt Heart J. 2023;75(1):75. DOI: 10.1186/s43044-023-00401-1.

12. Wang T.J., Larson M.G., Levy D., Leip E.P., Benjamin E.J., Wilson P.W. et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am. J. Cardiol. 2002;90(3):254–258. DOI:10.1016/s0002-9149(02)02464-5.

13. Verbrugge F.H., Omote K., Reddy Y.N.V., Sorimachi H., Obokata M., Borlaug B.A. Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality. Eur. Heart J. 2022;43(20):1941–1951. DOI: 10.1093/eurheartj/ehab911.

14. Wang X., Wang X., Gong Y., Chen X., Zhong D., Zhu J. et al. Appraising the Causal Association between systemic iron status and heart failure risk: A Mendelian Randomisation Study. Nutrients. 2022;14(16):3258. DOI: 10.3390/nu14163258.

15. Mikhail A., Brown C., Williams J.A., Mathrani V., Shrivastava R., Evans J. et al. Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol. 2017;18(1):345. DOI: 10.1186/s12882-017-0688-1.

16. Cleland J.G.F. Defining iron deficiency in patients with heart failure. Nat. Rev. Cardiol. 2024;21(1):1–2. DOI: 10.1038/s41569-023-00951-6.

17. Savarese G., von Haehling S., Butler J., Cleland J.G.F., Ponikowski P., Anker S.D. Iron deficiency and cardiovascular disease. Eur. Heart J. 2023;44(1):14-27. DOI: 10.1093/eurheartj/ehac569.

18. Cleland J.G.F., Kalra P.A., Pellicori P., Graham F.J., Foley P.W.X., Squire I.B. et al. IRONMAN Study Group. Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial. Eur. Heart J. 2024:ehae086. DOI: 10.1093/eurheartj/ehae086.

19. Graham F.J., Friday J.M., Pellicori P., Greenlaw N., Cleland J.G. Assessment of haemoglobin and serum markers of iron deficiency in people with cardiovascular disease. Heart. 2023;109(17):1294–1301. DOI: 10.1136/heartjnl-2022-322145.

20. Seo M., Yamada T., Tamaki S., Watanabe T., Morita T., Furukawa Y. et al. Prognostic significance of cardiac 123I-MIBG SPECT imaging in heart failure patients with preserved ejection fraction. JACC Cardiovasc Imaging. 2022;15(4):655–668. DOI: 10.1016/j.jcmg.2021.08.003.