Markers of systemic iron status show sex-specific differences in peripheral artery disease: a cross-sectional analysis of HEIST-DiC and NHANES participants

Abstract

AbstractBackgroundIron has been proposed as a risk factor for atherosclerosis but the data are controversial. We previously showed that non-transferrin-bound iron (a fraction of iron appearing in iron overload) contributes to atherosclerosis. Here, we investigated whether iron within physiological limits influenced atherosclerosis by studying its association with vascular dysfunction and peripheral arterial disease (PAD). Further, we evaluated if this relationship was influenced by comorbidities.MethodsWe studied the association between iron biomarkers in blood and markers for vascular adhesion and PAD in 368 individuals registered in the Heidelberg Study on Diabetes and Complications (HEIST-DiC). Our observations were validated by analyzing the association between iron biomarkers and PAD in the National Health and Nutrition Examination Survey (NHANES 1999-2004) data.ResultsIn both HEIST-DiC and NHANES cohorts, plasma ferritin levels are positively associated with PAD in females and not in males. We further identified negative associations between TIBC and plasma iron levels with PAD among females. These relationships were independent of the presence of other comorbidities including hypertension, insulin resistance, prediabetes, and diabetes.ConclusionWe demonstrate a sex-specific alteration of markers of systemic iron availability in individuals with clinically apparent PAD implying that mechanisms of disease development may differ between males and females. Elevated ferritin levels and hypoferremia in females are indicative of an underlying inflammation that may affect the pathogenesis of PAD. The observed lack of a positive association of PAD with serum iron levels suggest that “physiological” iron concentrations are safe for vascular health.