ETD

• coronary syndromes
• heart failure
• iron deficiency
• iron therapy
• major adverse cardiovascular events
• sucrosomial iron

Iron deficiency (ID) is one of the most common comorbidities in cardiovascular diseases. Beyond its role in erythropoiesis, iron is essential for mitochondrial function, oxidative metabolism, and the maintenance of cellular energy homeostasis. Cells with high energy demand, such as cardiomyocytes, are particularly vulnerable to the detrimental effects of ID. In patients with heart failure, ID is an independent determinant of adverse outcomes, and growing evidence indicates that it may also adversely affect patients with myocardial ischaemic syndromes.
In study I, we discussed experimental evidence linking myocardial iron deficiency with worsening ischaemia–reperfusion injury and adverse post-ischaemic left ventricular remodelling. We proposed a mechanistic framework linking intracellular iron depletion to cardiomyocyte necrosis during both acute and chronic ischaemia. We hypothesised that such relationship is mediated by chronic hyperactivation of HIF1-α, exacerbation of cytosolic and mitochondrial calcium overload, amplified increase of mitochondrial [NADH]/[NAD+] ratio, and depletion of NAD+ content with inhibition of sirtuin 1–3 activity. The study provides a biochemical rationale for the cardioprotective effect of restoring myocardial iron content. Furthermore, the study underscores the need for markers—either biochemical or imaging-based—that accurately reflect myocardial iron content.
In study II, we evaluated the clinical relevance of ID in patients with acute coronary syndromes. In a prospective cohort of 152 consecutive patients, we evaluated various definitions of ID, based on serum iron, transferrin saturation (TSAT), and ferritin, and explored their associations with left ventricular systolic function, infarct size, and clinical outcomes. ID was frequent, with prevalence ranging from 21% to 62% depending on the definition. ID, defined by serum iron or TSAT, was associated with lower left ventricular ejection fraction and higher high-sensitivity C-reactive protein. Only serum iron <6 µmol/L independently predicted adverse post-discharge events—including myocardial infarction, stroke, or death—after adjustment for the Global Registry of Acute Coronary Events score and left ventricular ejection fraction, but this association was no longer significant after accounting for inflammation. These findings suggest that systemic iron biomarkers are modulated by inflammatory activity, which may obscure their prognostic value. The accompanying reply to this study emphasized that ID definitions based on serum iron or transferrin saturation, rather than ferritin, appear more prognostically relevant.
In study III, we presented the design of the RISE-HF trial, a study testing oral sucrosomial iron in patients with heart failure and ID. Intravenous iron improves symptoms and reduces heart-failure hospitalisations, yet its use is limited by cost, logistics, and safety concerns regarding repeated dosing. Sucrosomial iron (SI) is less expensive and safer, offering a practical alternative for long-term therapy. SI therapy improved six-minute walk distance and quality-of-life scores in a small case-control study, prompting randomised evaluation. The RISE-HF is a randomised, double-blind, placebo-controlled study designed to test whether oral SI (Sideral Forte®) can improve functional capacity and health status in patients with heart failure with reduced or mildly reduced ejection fraction and TSAT<20%. Secondary endpoints include changes in iron status, biomarkers, cardiac function, and oxidative stress. The study will clarify whether long-term oral supplementation can safely and effectively complement intravenous iron therapy, potentially paving the way for larger trials.