Il sovraccarico di ferro: modulatore della risposta adrenergica

Adrenergic vascular hyper-responsiveness is a hallmark of different cardiometabolic disease, including essential hypertension, diabetes, obesity, metabolic syndrome, heart failure and chronic kidney disease. Previous studies have shown that sympathetic activation and insulin resistance are closely related each other, but the cause-and-effect relationship remains undefined. Iron overload impairs glucose metabolism in hemochromatosis patients by either insulin resistance or decreased insulin secretion. There are no data on the effect of iron overload on the adrenergic overdrive. The study groups consisted of 15 HFE iron-loaded hemochromatosis male patients (8 C282Y/C282Y and 7 C282Y/H63D) without iron-related organ damage, at diagnosis, and 16 age-matched healthy male controls. We measured, during a 30-minute resting period, beat-to-beat blood pressure (Finapres), heart rate (ECG) and postganglionic muscle sympathetic nerve traffic (MSNA) via microneurography into the peroneal nerve. Eleven hemochromatosis patients achieved iron depletion: ten underwent again microneurography, one dropt out for leg neuralgia after the first evaluation. All patients underwent Magnetic Resonance for the assessment of hepatic iron concentration (HIC). Metabolic syndrome (defined according to the ATPIII criteria), essential hypertension, diabetes, obesity, heart and kidney failure, and cirrhosis were considered metabolic confounders and they represented the exclusion criteria. Insulin resistance was estimated by HOMA index. In hemochromatosis patients at diagnosis, median serum ferritin was 717 microg/L (334-1372), HIC 210 micromol/g (150-310) and HOMA index was normal (1.49, 0.83-3.26). MSNA values were significantly higher than in controls (median 65 vs 38 bursts/100 heart beats, p<0.0001). After iron depletion sympathetic activation showed 35% mean reduction and significantly decreased in nine patients studied before and after therapy (median 65 vs 40 bursts/100 heart beats, p=0.0002) reaching the normal range. In one patient sympathetic activation did not change after iron depletion. At diagnosis and after iron depletion MSNA values (bursts/100 heart beats) correlate with transferrin saturation (r=0.61 and p=0.016, r=0.69 and p=0.029,respectively). The present study indicates that iron overloaded male patients with hemochromatosis are characterized by a hyperadrenergic state. Iron overload contributes to adrenergic hyper-responsiveness and could be directly involved in the overactivity of the autonomic nervous system also in the absence of an insulin resistance condition. Iron-dependent generation of reactive oxygen species might be involved in the pathogenesis of the adrenergic overdrive and more generally in cardiovascular damage.