Nɛ-homocysteinyl-lysine isopeptide is associated with progression of peripheral artery disease in patients treated with folic acid

Abstract

Objective: Folic acid (FA) administration can reduce plasma total homocysteine (tHcy); however, it fails to decrease cardiovascular events and progression of peripheral artery disease (PAD). Nɛ-homocysteinyl-lysine isopeptide (Nɛ-Hcy-Lys) is formed during catabolism of homocysteinylated proteins. We sought to investigate factors that determine the presence of Nɛ-Hcy-Lys in PAD patients with hyperhomocysteinemia receiving FA.

Patients and methods: We studied 131 consecutive PAD patients with tHcy > 15 μmol l(-1) taking FA 0.4 mg d(-1) for 12 months. Serum Nɛ-Hcy-Lys was determined by high-performance liquid chromatography (HPLC). We also measured interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), asymmetric dimethylarginine (ADMA) and 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)).

Results: FA administration resulted in a 70.5% decrease in tHcy (p < 0.0001). However, serum Nɛ-Hcy-Lys was detectable in 28 (21.4%) patients on FA who were more frequently current smokers and survivors of ischaemic stroke (p < 0.001). They had higher tHcy by 46.0%, PAI-1 by 51.7%, 8-iso-PGF(2α) by 59.1% and ADMA by 26.4% (all, p < 0.0001). The presence of Nɛ-Hcy-Lys was associated with lower ankle-brachial index (ABI) values (p < 0.001) and higher prevalence of cardiovascular events (p < 0.001) following therapy.

Conclusion: The presence of Nɛ-Hcy-Lys in one-fifth of hyperhomocysteinemic individuals with PAD despite FA treatment is associated with progression of PAD and with increased ADMA formation, oxidative stress and hypofibrinolysis.