Investigations on potential digenic HAMP (hepcidin) and HFE haemochromatosis gene mutations in the development of iron overload in Irish patients with dilated cardiomyopathy

Iron overload cardiomyopathy (IOC) has been recently described as a dilated cardiomyopathy, characterized by left ventricular (LV) remodelling with chamber dilatation and reduced LV ejection fraction (LVEF). However, primary haemochromatosis, a genetically determined condition leading to iron overload, is classically categorized as an infiltrative cause of cardiomyopathy. Moreover, secondary haemochromatosis may lead to severe diastolic LV dysfunction in the early stages of the disease, before LVEF is affected. In this study, we describe the forms, pathophysiology, and genotypic expressions of HFE and hepcidin (HAMP) gene mutations focusing on the possibility of digenic occurrence that could lead to potential development of iron overload cardiomyopathy among Irish patients and their direct family members. The prevalence of iron overload cardiomyopathy (IOC) in Irish population is increasing. The spectrum of symptoms of IOC varied. Early in the disease process, patients may be asymptomatic, whereas severely overloaded patients can have terminal heart failure complaints that are refractory to treatment. It has been shown that early recognition and intervention may alter outcomes. In this study the combination of cardiac biomarkers (troponin I and creatine kinase), iron studies (serum ferritin, serum hepcidin, and transferin saturation) level determinations and genotyping of the HFE (C282Y/H63D) and hepcidin HAMP (C70R) gene mutations were carried out and allele frequencies were correlated within the Irish population. The first finding of this study was a trend towards significant elevation of iron studies: serum ferritin level, percent transferin saturation and decreasing serum hepcidin observed in dilated cardiomyopathy patients and direct family members identified with HFE C282Y/H63D and HAMP C70R heterozygotes who were asymptomatic. This was not associated with age and suggests that there is a threshold level of iron studies above which symptoms occur. This discordance between the symptomatic and asymptomatic HFE C282Y/H63D and HAMP C70R heterozygous formed the basis of subsequent analyses. The second finding of this study was a trend towards significant elevation of the selected cardiac biochemical markers from the median level of serum troponin-I and creatine kinase observed in patients and direct family members with HFE C282Y/H63D and HAMP C70R heterozygous who were again asymptomatic. This was not associated with age and cardiac complaints or history and suggests that there is a threshold level of cardiac biochemical marker activities that triggers the condition and as predisposing factors to a potential development of iron overload cardiomyopathy. The genotypic expressions of HFE and HAMP were identified and showed that among the Irish patients diagnosed with dilated cardiomyopathy and their family members, a significant trend of digenic occurrence of both mutations. The heterozygous C282Y/H63D and C70R revealed in this study that it is a predisposing factors developed at certain age of life.