Homocysteine in adult patients with cardiovascular disease: is it clinically relevant in 2025? A tribute to Hieronim Jakubowski (1946-2025)

A history of persistently elevated plasma total homocysteine (tHcy) concentrations, that is, hyperhomocysteinemia, as a risk factor and / or biomarker of increased risk for cardiovascular disease (CVD) is largely based on multiple observational studies with robust evidence only for detrimental effects of homocystinuria. In most adult individuals, fasting plasma tHcy concentrations ranged from 8–30 µmol/l. Evidence for proatherogenic effects of mild tHcy elevation is weak given conflicting data, especially in the presence and treatment of strong risk factors, for example, hypercholesterolemia or diabetes. This statement was supported by randomized controlled trials which failed to show that reduction in tHcy following vitamin interventions improves clinical outcomes in CVD. On the other hand, some studies indicated lower risk of cerebrovascular ischemic events, which, however, is not reflected in clinical guidelines. It has been reported that other Hcy metabolites, including Hcy-thiolactone, Nε-homocysteinyllysine isopeptide, or homocysteinylated proteins, are weakly correlated with tHcy levels and are largely resistant to vitamin interventions, which can in part explain inconsistent data linking disturbed methionine metabolism with CVD. However, high-quality, large-scale clinical research on Hcy metabolites has not been conducted yet. The late Professor Hieronim Jakubowski (passed away on February 22, 2025), an eminent Polish biochemist, devoted his scientific career to exploring complex biochemical and clinical interactions between Hcy and human pathology, as reflected by more than 130 papers on this topic. The present overview summarizes evidence for the current approach to tHcy measurements in individuals at risk of CVD. Based on recent data, with emphasis on the work of H. Jakubowski, we may conclude that the Hcy controversy still exists, and further research is warranted to elucidate a role of this amino acid and its metabolites in CVD.