Sex determines myocardial iron load and its hemodynamic correlates in advanced heart failure

Background

Serum iron deficiency affects up to 50% of patients with chronic heart failure (HF) and worsens outcomes independently of anemia. While systemic iron deficiency is well characterized, myocardial iron load (MIrL) in the failing heart remains insufficiently explored. Available data suggest reduced myocardial iron content in advanced HF, but marked inter-individual variability has been reported.

Purpose

To assess MIrL in advanced HF and determine its associations with demographic, biochemical, echocardiographic, and hemodynamic parameters, with particular attention to sex differences.

Methods

Fifty-eight consecutive patients (13 women, 45 men; mean age 50.6 ± 12.3 years) undergoing heart transplantation for advanced HF were included. HF etiology was idiopathic cardiomyopathy (n=36), ischemic (n=18), or other (n=4). All patients were in NYHA class III–IV despite optimal medical therapy (LVEF 22.9 ± 12.6%; NT-proBNP 5277 ± 4975 pg/mL; PVR 2.47 ± 1.5 WU).

Control myocardial samples were obtained from 31 non-failing hearts (NFH, 11 women, 20 men). MIrL was quantified using instrumental neutron activation analysis.

Results

Compared with NFH reference values, 79% of HF patients had normal myocardial iron load (MIrN), 16% were myocardial iron deficient (MIrD), and 5% showed myocardial iron excess (MIrE).

In the overall HF cohort, MIrL was not associated with age, HF etiology, LVEF, NT-proBNP, or pulmonary vascular resistance. However, sex significantly influenced MIrL: men had higher myocardial iron content than women (p=0.012), a difference not observed in NFH controls (Fig.1).

Sex-stratified analyses revealed distinct patterns: Men: MIrL correlated positively with iron-handling proteins (TfR2: r=0.56; FTL: r=0.45; FTMT: r=0.33) and inversely with LV end-diastolic diameter (r= –0.43); Women: MIrL correlated positively with RV diameter (r=0.68) and inversely with TAPSE (r= –0.64), mean pulmonary artery pressure (r= –0.65), and pulmonary wedge pressure (r= –0.76) (Fig. 2).

Conclusions

In advanced HF, MIrL is highly heterogeneous and does not correlate with conventional markers of HF severity. Sex emerges as the primary determinant of myocardial iron content. Notably, MIrL exhibits sex-specific associations: in men, it is predominantly linked to intracellular iron-regulatory pathways and LV remodeling, whereas in women, it is associated with RV structure and pulmonary hemodynamics. These findings suggest sex-dependent differences in myocardial iron handling and distinct pathophysiological interactions between iron metabolism and ventricular remodeling, indicating that sex-specific approaches to targeting iron metabolism may be warranted.