Lower Plasma Ferritin Associated with Heart Failure in Adults Without Anemia

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Observational data from the ARIC study reveals that lower plasma levels correlate with an increased risk of incident heart failure and diastolic dysfunction.

Lower plasma ferritin levels were associated with a greater risk for incident heart failure (HF) and diastolic dysfunction among a population of older adults without anemia or prevalent HF, according to new research.1

Results from the analysis of community-dwelling adults from the ongoing, longitudinal Atherosclerosis Risk in Communities (ARIC) showed these associations remained robust after adjustment for multiple confounders and were consistent across ages, gender, and estimated glomerular filtration rate (eGFR) categories.

“These results support the hypothesis that lower plasma ferritin levels contribute to the pathogenesis of incident HF and diastolic dysfunction in late life,” wrote the investigative team, led by Leo F. Buckley, PharmD, department of pharmacy services, Brigham and Women’s Hospital.

Iron deficiency among those with chronic HF with and without anemia has been linked to impairment in functional capacity and higher risks for hospitalization and death.2 The prevalence of both iron deficiency and HF increases with increasing age. In later life, evidence has shown a reduction in iron stores is associated with a higher risk for impaired physical and cognitive capacity.

Thus, an improved understanding of the relationship between iron stores and HF could have important clinical implications for older, at-risk adults, given the availability of routine blood tests and multiple therapeutics for iron repletion.1 For this analysis of ARIC, the investigative team estimated the association of plasma ferritin level with overall incident HF and HF phenotypes (HF with reduced ejection fraction [HRrEF] and HF with preserved ejection fraction [HFpEF]) using Cox proportional hazards regression models.

The ARIC study has enrolled 15,792, community-dwelling adults between ages 45 and 65 years from 1987 and 1989 at 4 centers across the United States. For Buckley and colleagues’ analysis, the baseline was defined as ARIC visit 5 (2011 to 2013), with participants having no history of heart failure, did not have anemia, and had available plasma ferritin and covariate measures. Exposures for the study included the plasma levels of ferritin light chain and the complex of ferritin heavy and light chains, measured using modified aptamers and quantified on a relative scale.

Overall, the study cohort consisted of 3,472 individuals with a mean age of 54 years (56% women; 14% Black individuals). Those with lower ferritin levels were more likely to be women and to report White race. Analyses revealed lower plasma ferritin levels were associated with lower hemoglobin levels (P = .001), smaller mean red cell volume (P <.001), lower mean corpuscular hemoglobin (P <.001), and lower mean corpuscular hemoglobin concentration (P =.007).

A total of 293 HF events occurred across a median follow-up of 7.2 years (incidence rate: 12.6 per 1,000 person-years [95% CI, 11.3 to 14.2]), including 131 HFrEF events, 131 HFpEF events, and 31 events with unknown left ventricular ejection fraction. Adjustment for demographics and HF risk factors revealed a 50% lower plasma ferritin level was associated with a higher risk of incident HF overall (HR, 1.20 [95% CI, 1.08 - 1.34]; P = .001) as well as a higher risk of incident HFpEF (HR, 1.28 [95% CI, 1.09 - 1.50]; P = .002).

However, Buckley and colleagues found a lack of a statistically significantly higher risk for incident HFrEF (HR, 1.16 [95% CI, 0.99 - 1.36; P = .070). The association of plasma ferritin levels with incident heart failure events was not modified by age, gender, or eGFR <60 mL/min/1.73 m2.

Models adjusted for demographics and HF risk factors showed lower ferritin levels were associated with higher E/e ratio and higher pulmonary artery systolic pressure. However, there were no identified associations for measures of left ventricular size or measures of systolic function.

Further, Buckley and colleagues noted their data showed no evidence of a nonlinear relationship between plasma ferritin level and HF risk, potentially due to the exclusion of participants with anemia.

"The normalization and transformation of our ferritin levels in addition to the restriction to participants without anemia may have limited the range of ferritin levels represented in our cohort and thus the power to detect a nonlinear association," investigators wrote.


  1. Aboelsaad IAF, Claggett BL, Arthur V, et al. Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study. JACC Heart Fail. Published online December 23, 2023. doi:10.1016/j.jchf.2023.11.009
  2. Masini G, Graham FJ, Pellicori P, et al. Criteria for iron deficiency in patients with heart failure. J Am Coll Cardiol. 2022;79(4):341–351. https://doi. org/10.1016/j.jacc.2021.11.039