The C282Y HFE mutation was associated with multiple elevations in cTnT (P=0.039), and HFE carriers had lower left ventricular mass and function in doxorubicin-treated leukemia survivors.
Observational (n=184)
Are hemochromatosis (HFE) gene mutations associated with increased doxorubicin-induced cardiotoxicity in survivors of childhood high-risk leukemia?
HFE gene mutations, particularly C282Y, are associated with an increased risk of doxorubicin-induced myocardial injury and reduced left ventricular function in childhood leukemia survivors.
p-value: p=0.039
BACKGROUND: Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia. METHODS: Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography. RESULTS: A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years-3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (-0.71 standard error (SE), 0.25; P = .008), mass (-0.84 SE, 0.17; P < .001), and end-systolic (-4.36 SE, 0.26, P < .001) and end-diastolic (-0.68 SE, 0.25; P = .01) posterior wall thickness were found to be abnormal in children with either allele (n = 32). Noncarriers (n = 63) also were found to have below-normal LV mass (-0.45 SE, 0.15; P = .006) and end-systolic posterior wall thickness (-4.06 SE, 0.17; P < .001). Later follow-up demonstrated similar results. CONCLUSIONS: Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were found to be abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity.
Lipshultz et al. (Tue,) conducted a observational in Childhood high-risk acute lymphoblastic leukemia (n=184). Hemochromatosis (HFE) gene mutations (C282Y and H63D) vs. Noncarriers was evaluated on Multiple elevations in cTnT concentrations (p=0.039). The C282Y HFE mutation was associated with multiple elevations in cTnT (P=0.039), and HFE carriers had lower left ventricular mass and function in doxorubicin-treated leukemia survivors.