Hypoferremia reduces long-term risk of major adverse cardiovascular events after STEMI by averting the myocardial reactive iron storm

Background and aims Iron deficiency (ID) is common in patients with acute STEMI. ID has previously been associated with either adverse or favourable effects, depending on the definition of ID, sampling timepoint, outcome measures and follow-up duration. This study systematically addresses the impact of ID on long-term outcomes and explores the underlying mechanisms. Methods Patients with acute STEMI (n=167) were followed for 4.5 years for major adverse cardiovascular events (MACE), including new HF diagnosis, recurrent MI or cardiac death. Iron markers were sampled at presentation and later timepoints. Myocardial injury was assessed by CMR at 2 days and 6 months. Mechanisms underlying clinical findings were evaluated in a mouse model of MI. Results ID, by any definition, was common in acute STEMI patients at presentation. Hypoferremia (Tsat<20% or iron<13uM) but not hypoferritinemia (ferritin<100ug/L) predicted lower risk of MACE. Hypoferremia predicted lower troponin, acute myocardial T1, LVESV and LVEDV at 2 days, but lower myocardial salvage at 6 months. Iron status sampled from 6 hours after presentation was no longer associated with MACE. In mice, MI rapidly triggered a myocardial reactive iron storm, early LV remodelling, and eventually HF. These effects were averted by iron restriction. Conclusions This study reveals that hypoferremia in acute STEMI exerts both favourable and adverse effects, that nonetheless translate into better long-term clinical outcomes. This research reconciles previous seemingly conflicting reports. It also highlights a potential stepwise approach of acute iron chelation to reduce myocardial injury, followed days later by iron supplementation to promote myocardial salvage.