Iron Deficiency Increases Risk for Incident Coronary Heart Disease in Middle Age, Suggests New Study

Iron deficiency can't be causally linked to CHD yet, but evidence is accumulating for the association, according to authors of a new European study.

Approximately 10% of new coronary heart disease cases occurring within a decade of middle age could be avoided by preventing iron deficiency, suggests a study published this week in ESC Heart Failure, a journal of the European Society of Cardiology (ESC).

The results are based on an observational study of more than 12 000 individuals from 3 European population-based cohorts that was designed to better understand the association of absolute (AID) and functional iron deficiency (FID) with cardiovascular disease (CVD) and mortality in the general population.

As context for the research, the authors, led by Dr Benedikt Schrage of the University Heart and Vasculature Centre Hamburg, Germany, cite previous studies that have found iron deficiency linked to worse outcomes, including hospitalization and death, among patients with CVD such as heart failure. Evidence from those led to initiation of a large randomized controlled trial to examine the effects of intravenous iron supplementation in patients with HF (FAIR-HF trial). The study found that iron improved symptoms, functional capacity, and quality of life in the study population. The FAIR-HF 2 trial is investigating the impact of the intervention on risk of death in patients with HF.

Schrage and colleagues’ interest lies in the potential association between iron deficiency and CV outcomes in the population at large.

The investigators drew study data from 12 164 individuals registered in 3 population-based cohorts that are part of a European-wide bio-genetic consortium. All participants had ferritin and transferrin saturation (TSAT) measures available at baseline.

Participants were classified as iron deficient or not according to two definitions: 1) absolute iron deficiency (AID), which includes only ferritin (stored iron) and was defined as: ferritin < 100 μg/L; severe AID, ferritin < 30 μg/L) and 2) functional iron deficiency (FID), which includes both ferritin and transferrin (circulating iron) and was defined as ferritin <100 μg/L or ferritin 100–299 μg/L and TSAT < 20%.

“Absolute iron deficiency is the traditional way of assessing iron status, but it misses circulating iron,” explained Schrage in an ESC statement. “The functional definition is more accurate as it includes both measures and picks up those with sufficient stores but not enough in circulation for the body to work properly.”

All 12 164 individuals were included in the study analysis. Median age was 59 years; 45.2% were men. Approximately one-quarter (24.4%) were daily smokers. Diabetes prevalence was 4.5%, hypertension 45.5%, and average body mass index was 26.1.

Participants were followed up for incident coronary heart disease and stroke, death due to cardiovascular disease, and all-cause death. The researchers analyzed the association between iron deficiency and incident CHD, stroke, CV mortality, and all-cause mortality after adjustments for age, sex, smoking, cholesterol, blood pressure, diabetes, body mass index, and inflammation. Participants with a history of CHD or stroke at baseline were excluded from the analyses of incident disease.


At baseline, AID was identified in 60% of participants and FID in 64%. During a median follow-up of 13.3 years there were 2,212 (18.2%) deaths. Of these, a total of 573 (4.7%) deaths were from a CV cause. Incident coronary heart disease and stroke were diagnosed in 1,033 (8.5%) and 766 (6.3%) participants, respectively.

After adjustment for multiple confounders, AID was not associated with all-cause mortality [hazard ratio (HR) 1.08, 95% CI 0.98–1.19, P = 0.12] or with CV mortality (HR 1.22, 95% CI 1.00–1.48, P = 0.05). AID was associated with incident CHD (HR 1.20, 95% CI 1.04–1.39, P = 0.01), but not with incident stroke (HR 1.11, 95% CI 0.94–1.31, P = 0.22).

FID was significantly associated with all-cause mortality (HR 1.12, 95% CI 1.01–1.24, P = 0.03), with CV mortality (HR 1.26, 95% CI 1.03–1.54, P = 0.03), with incident CHD (HR 1.24, 95% CI 1.07–1.43, P < 0.01), but not with incident stroke (HR 1.15, 95% CI 0.97–1.36, P = 0.12).

Compared with absence of FID, FID was associated with an increased risk of 24% for CHD, 26% for CV mortality, and 12% for all-cause mortality. AID was associated with a 20% increased risk of CHD vs no AID but was there was no association found with mortality. There also were no associations found between iron status and incident stroke.

Investigators then calculated the population attributable fraction (PAF), which estimates the proportion of events in 10 years that would have been avoided if all individuals had the risk of those without iron deficiency at baseline. The models were adjusted for age, sex, smoking, cholesterol, blood pressure, diabetes, BMI, and inflammation. Within a 10-year period, 5.4% of all deaths, 11.7% of cardiovascular deaths, and 10.7% of new coronary heart disease diagnoses were attributable to functional iron deficiency.

“The study showed that iron deficiency was highly prevalent in this middle-aged population, with nearly two-thirds having functional iron deficiency,” said Dr. Schrage. “These individuals were more likely to develop heart disease and were also more likely to die during the next 13 years.”

Dr. Schrage noted that future studies should examine these associations in younger and non-European cohorts. He said: “If the relationships are confirmed, the next step would be a randomized trial investigating the effect of treating iron deficiency in the general population.”

Reference: Schrage B, Rübsamen N, Ojeda FM, et al. Association of iron deficiency with incident cardiovascular diseases and mortality in the general population. ESC Heart Failure. Published online: October 5, 2021. DOI: