Heart is a particularly sensitive organ to iron overload and cardiomyopathy due to
the excessive cardiac iron deposition causes most deaths in disorders such as beta-thalassemia
major. Free or loosely bound iron ions readily cycle between ferrous and ferric states and
catalyze Haber-Weiss reaction that yields highly reactive and toxic hydroxyl radicals. Treatment
with iron chelators (desferrioxamine, deferiprone, and deferasirox) substantially improved
cardiovascular morbidity and mortality in iron overloaded patients. Furthermore, iron
chelators have been studied in various cardiovascular disorders with known or presumed oxidative
stress roles (e.g., ischemia/reperfusion injury) also in patients with normal body iron
contents. The pharmacodynamic and pharmacokinetic properties of these chelators are critical
for effective therapy. For example, the widely clinically used but hydrophilic chelator desferrioxamine
suffers from poor plasma membrane permeability, which means that high and
clinically unachievable concentrations/doses must be employed to obtain cardioprotection.
Therefore, small-molecular and lipophilic chelators with oral availability are more suitable for
this purpose, particularly in states without systemic iron overload. Apart from agents that are
already used in clinical practice, aroylhydrazone iron chelators, namely salicylaldehyde isonicotinoyl
hydrazone (SIH), have provided promising results. However, the use of classical
iron-chelating agents is associated with a risk of toxicity due to indiscriminate iron depletion.
Recent studies have therefore focused on "masked" prochelators that have little or no affinity
for iron until site-specific activation by reactive oxygen species.
Keywords: Cardioprotection, iron chelators, iron prochelators, oxidative stress, anthracyclines, cardiotoxicity.
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