Iron deficiency in heart failure

Background: Iron plays a central role in several vital processes in the human body and is fundamental for organs with high energy demands, like the heart. Iron deficiency (ID) is common in patients with heart failure (HF) and independently associated with a poor prognosis. The overall aim of this doctoral project was to examine potential causes of ID in patients with HF, assess pathological changes in the myocardial iron metabolism, investigate time-dependent changes of ID in HF, and study the role of ID in new-onset HF.

Methods and results: Study I. An interventional, non-randomised, open label study where oral iron absorption was assessed in 30 patients with chronic HF and ID, and 12 age- and sex-matched controls without HF and ID at Södersjukhuset, Sweden. Two hours after intake of an oral dose of iron, patients with HF had higher absolute increase of S-iron than controls (median increase 83.8 [interquartile range 61.5;128.5] µg/dL vs 47.5 [30.7;61.5] µg/dL, p = 0.001).

Study II. An observational cross-sectional study including 69 patients undergoing an elective coronary bypass graft operation (CABG) at the Karolinska University Hospital in Sweden. Tissue samples from myocardial and skeletal muscle were analysed regarding expression of genes involved in the regulation of the intracellular iron metabolism. Expression of the proteins transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) was increased in both myocardial and skeletal muscle biopsies from patients with absolute ID (ferritin <100 µg/L) compared with patients with normal iron levels, irrespective of left ventricular function.

Study III. An observational prospective cohort of patients with new-onset HF. Among 482 patients for whom there were iron data at baseline, 34% had ID. The prevalence of ID after 12 months was 32% among those who did not receive i.v. iron and had complete iron data at both baseline and at 12 months (n=368). After 12 months, 19% had persistent ID, 13% had developed ID, 11% had resolved ID, and 57% never had ID. Anaemia at baseline was the strongest independent predictor of ID one year after diagnosis (odds ratio (OR) 3.91, 95% confidence interval (CI) 1.88-8.13, p < 0.001), followed by HF hospitalisation (OR 2.21, 95% CI 1.24–3.95, p < 0.01), female sex (OR 2.04, 95% CI 1.25-3.32, p < 0.01), HF with preserved ejection fraction (OR 1.96, 95% CI 1.13–3.39, p < 0.05) and diabetes mellitus (OR 1.92, 95% CI 1.06–3.48, p < 0.05). ID was associated with low quality of life at baseline (mean difference in Minnesota Living with HF Questionnaire 7.4 points, 95% CI 3.1-11.7, p < 0.001), but not at follow-up.

Study IV. A population-based cohort study of individuals who underwent blood sampling through occupational health checkups or out-patient care in the county of Stockholm during 1985–1996. Individuals who had at least three values of S-iron or transferrin saturation (TSAT) and no previous HF diagnosis (n = 127037 and 125482, respectively) were analysed. During a median follow-up of 24.9 years (interquartile range 19.4-27.2), 9324 (7.3%) individuals in the S-iron cohort and 9209 (7.3%) in the TSAT cohort were diagnosed with new-onset HF. The individuals within the lowest quartile of S-iron (< 15.0 µmol/L) and TSAT (< 0.25) had the highest risk of new-onset HF. Compared with the third quartile, adjusted for age, sex, haemoglobin and other risk factors for HF, their hazard ratios were 1.29 (95% CI 1.17-1.42) and 1.32 (95% CI 1.20–1.46), respectively.

Conclusions: Iron absorption was increased in patients with chronic HF and ID compared with in controls without HF and ID. Expression of the iron importers TfR1 and DMT1 were increased in biopsies from myocardial and skeletal muscle in patients with absolute ID undergoing elective CABG, irrespective of left ventricular function. About one third of the patients with new-onset HF had ID both at the time of HF diagnosis and after one year, though a quarter of the patients changed their ID status. Patients with anaemia, HF hospitalisation, female sex, HF with preserved ejection fraction or diabetes mellitus at baseline were more likely to have ID after one year. Low S-iron and TSAT were independently associated with incident HF.

List of scientific papers

I. Cabrera CC, Ekström M, Linde C. Persson H, Hage C, Eriksson MJ, Wallén H, Persson B, Tornvall P, Lyngå P. Increased iron absorption in patients with chronic heart failure and iron deficiency. Journal of Cardiac Failure. 2020;26(5);440-443.
https://doi.org/10.1016/j.cardfail.2020.03.004

II. Cabrera CC, Frisk C, Löfström U, Lyngå P, Linde C, Hage C, Persson H, Eriksson M.J, Wallén H, Persson B, Ekström M. Relationship between iron deficiency and expression of genes involved in iron metabolism in human myocardium and skeletal muscle. International Journal of Cardiology. 2023, May 15;379:82-88.
https://doi.org/10.1016/j.ijcard.2023.03.032

III. Cabrera CC, Ekström M, Tornvall P, Löfström U, Frisk C, Linde C, Hage C, Persson H, Eriksson MJ, Wallén H, Persson B, Lyngå P. Iron deficiency in new onset heart failure – association with clinical factors and quality of life. [Accepted]

IV. Cabrera CC, Leander K, Vikström M, Jonsson M, Hammar N, Ekström M, Lyngå P, Tornvall P. Association between low serum iron and transferrin saturation and incident heart failure. [Submitted]