HFE variants modify the distribution and prognostic associations of iron deficiency in heart failure

Introduction Iron deficiency (ID) is prevalent in patients with heart failure (HF) and is associated with worse outcomes. Although ID is often viewed as a nutritional systemic disorder, many factors affect iron status and organ distribution, including common genetic variants in the homeostatic iron regulator gene (HFE). We aimed to assess whether HFE variants modify the association between systemic iron status and prognosis in patients with HF, and to explore their association with cardiomyocyte-specific iron handling. Methods We studied 2313 patients with HF that have known iron status and HFE genotype from the BIOSTAT-CHF cohort. Patients with either C282Y and/or H63D variants (heterozygous or homozygous), leading to a loss of function, were classified as HF patients with HFE variants. ID was defined as transferrin saturation (TSAT) <20%. Cellular iron dynamics were studied in lentiviral HFE knockdown vs. control cardiomyocytes derived from human pluripotent stem cells. Results HFE variants were prevalent in 757 (32.7%) patients, mainly heterozygous carriers of H63D (551 [73%]) or C282Y (131 [17%]). HFE variant carriers had lower hepcidin and serum transferrin receptor levels, higher TSAT levels and less often ID (56% vs. 64%, p<0.001). The adverse effect of lower TSAT levels on prognosis was modified by the presence of HFE variants for all-cause mortality and the composite of HF hospitalization and all-cause mortality (both Pinteraction<0.05), but not for HF hospitalisation (Pinteraction=0.188). In non-carriers, a higher TSAT associated with lower risk of all-cause mortality (HR per TSAT doubling 0.81, 95% CI 0.72–0.92), HF hospitalization (0.75, 0.67–0.85) and the combined endpoint (0.81, 0.74–0.90), whereas TSAT was dissociated from outcomes in HFE carriers (all p>0.05). HFE knockdown in human cardiomyocytes resulted in increased iron storage after iron suppletion and resistance to deferoxamine induced iron chelation. Conclusions HF patients carrying common HFE variants had a slightly lower prevalence of ID. In these patients, the adverse association between low TSAT and outcomes was attenuated, potentially reflecting preserved local iron storage despite low circulating iron levels Cox regression forest plot Ferritin quantification