In addition to these mechanisms, we suggest that hyperhomocysteinemia (HHcy) may represent a relevant pathogenic factor in the development of perioperative stroke, especially in specific cardiac surgical procedures [2,3].

High homocysteine levels can lead to an ischemic stroke through multiple mechanisms and are associated with the occurrence of atrial fibrillation (AF) and a prothrombotic state [3]. HHcy has an acute and direct effect on atrial ionic channels (inhibition of the transient outward potassium current and ultra-rapid delayed-rectifier K⁺ currents, increase of inward-rectifier K⁺-current, increased Na⁺ currents) that produce early after depolarization and cause focal ectopic/triggered activity [3]. Moreover, HHcy may promote atrial fibrosis (atrial structural remodeling) that causes slow and heterogeneous atrial conduction (with increased P wave dispersion on the electrocardiogram), favoring the appearance of a vulnerable reentrant substrate [4]. These atrial electrical and structural alterations represent a wellknown substrate for AF, resulting in an increased risk of cardioembolic stroke. HHcy may also contribute to a prothrombotic state through different mechanisms (increased tissue factor expression, attenuated anticoagulant processes, enhanced platelet reactivity, increased thrombin generation, augmented Factor V activity, impaired fibrinolytic potential), resulting in increased risk of atrial thrombosis and possible subsequent ischemic embolic stroke [3].

In patients undergoing cardiac surgery who develop HHcy, an appropriate homocysteine-lowering treatment [5] could represent a preventive strategy to prevent the occurrence of AF and reduce the risk of ischemic stroke.