Iron deficiency is associated with larger infarcts and with adverse remodeling in STEMI patients and reduces myocardial tolerance to ischemia/reperfusion by inhibiting the eNOS/sGC/PKG pathway in mice

Abstract

Abstract Background Iron deficiency (ID) interferes with the cardioprotective pathway endothelial nitric oxide synthase/soluble guanylate cyclase/protein kinase G (eNOS/sGC/PKG), but its role in acute myocardial infarction remains unclear. Methods Patients (n=125) with a first anterior STEMI treated with PCI underwent magnetic resonance imaging in the acute phase and at 6 months. We assessed whether ID (ferritin level <100 μg/L or <300 μg/L if transferrin saturation was <20%) was associated with infarct size acutely or with adverse left ventricular (LV) remodeling (LV end-diastolic volume increase at 6 months >20%, n=105). C57BL6/N mice were fed with standard diet or iron-deficient diet for 4 weeks before undergoing 45-min coronary occlusion/24-h reperfusion. Results Patients with ID (43.2%) had larger infarcts (22.8±10.2 vs 16.8±9.8% of LV mass, P=0.002) and more frequent microvascular obstruction (70.0 vs 43.3%, P=0.004) in the initial exam than the rest. They also developed adverse LV remodeling more often (38.6 vs 14.8%, P=0.005), even after adjusting by infarct size and final TIMI flow grade (OR 3.1, 95% CI 1.1–8.6, P=0.027). In mice, ID diet reduced myocardial iron content, serum ferritin and hemoglobin levels without reaching anemic values and without inducing echocardiographic alterations. ID diet reduced myocardial eNOS protein content, its dimeric form, and nitrites/nitrates and cGMP levels. eNOS decrease was associated with reduced HSP90 levels and increased eNOS ubiquitination in correlation with oxidative and nitrosative stress. Weekly iv administration of iron sucrose effectively reverted the ID-diet effects. Infarct size was larger in the ID group than in controls (58.8±3.0 vs. 40.3±3.6%, P=0.03) but was not increased in ID-diet animals treated with iron sucrose (36.3±4.0%) or receiving the sGC activator ataciguat before ischemia (31.0±2.5%). Conclusions ID is associated with larger infarcts and with more frequent adverse LV remodeling in patients with STEMI and reduces myocardial tolerance to ischemia/reperfusion in mice by attenuating eNOS/sGC/PKG pathway activity. Iron sucrose treatment and sGC activation reverted these deleterious effects of ID in mice. Iron supplementation might be beneficial in STEMI patients with ID. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): CIBER-CV. Instituto de Salud Carlos III (PI16/00232), co-financed by the ERDF