Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials

Abstract

Plasma total homocysteine (Hcy) has been associated with cardiovascular risk in multiple large-scale epidemiological studies, and it has been considered as an independent risk factor for atherosclerosis. Homocysteine lowering, achieved after the introduction of the folate food fortification programme in North America, was accompanied by an accelerated decline of cardiovascular risk and especially of stroke. Although the initial clinical trials suggested that homocysteine-lowering treatment with folates and B vitamins induces coronary plaque regression, this finding was not confirmed by more recent clinical studies. Under the light of the findings from the recent large randomized clinical trials that failed to document a benefit of Hcy lowering on clinical outcome of patients with atherosclerosis, the role of Hcy as a risk factor and the efficacy of Hcy lowering against atherosclerosis have been questioned. Therefore, better understanding of the mechanisms relating Hcy and Hcy-lowering treatment with vascular function and atherogenesis is crucial, to help us understand why clinical trials failed to show a benefit from Hcy-lowering treatment. Are these therapeutic strategies ineffective because they fail to reduce intracellular Hcy levels and vascular redox state or should Hcy stop being considered as an independent risk factor for atherosclerosis from now on? In this review article, we provide a global approach of the molecular mechanisms relating Hcy with cardiovascular risk and introduce possible mechanistic explanations regarding the inability of clinical trials to detect any clinical benefit from Hcy-lowering treatment in secondary prevention. Finally, we provide clinical recommendations regarding the therapeutic strategies targeting homocysteine in the general population.

Determinants of Hyperhomocysteinemia After Gastric Bypass Surgery in Obese Subjects

“…Plasma homocysteine concentrations were measured by a competitive chemiluminescent enzyme immunoassay on Immulite 2500® (Siemens Healthcare Diagnostics, Puteaux, France) and plasma insulin by BIinsuline IRMA-kit (Gif sur Yvette, France). High homocysteine level was defined as a result >12 μmol/l, corresponding to the high normal value of the laboratory and to the threshold of normal values previously described in healthy subjects without vitamin deficiencies [10]. Low vitamin B12 was <190 ng/l and low folate <3 μg/l, corresponding to the low normal values of the laboratory, respectively.…”

“…Among the most frequently described [7][8][9], deficiencies in vitamin B12 and folate may increase homocysteine levels, now well recognized as an independent cardiovascular risk factor. [10][11][12]. Hyperhomocysteinemia accounts for 10% of the population's risk of coronary artery disease and is also associated with increased risk of peripheral vascular disease, stroke, dementia and osteoporosis [12].…”

“…Homocysteine alters vascular function by enhancing oxidative stress and inflammation in the vascular wall. Homocysteine also enhances thrombogenicity and alters endothelial functions and angiogenesis [10,12,13].…”

AMP-Activated Protein Kinase Inhibits Homocysteine-Induced Dysfunction and Apoptosis in Endothelial Progenitor Cells

“…Obviously, the concentration of Hcy we use is clearly supraphysiological. According to fasting plasma Hcy levels in human, HHcy is classified as moderate (15-30 μmol/L), intermediate (30-100 μmol/ L), or severe (>100 μmol/L) [1]. Considering such a high Hcy concentration we use, this work might be helpful to investigate the pharmacological treatment of severe HHcy.…”

“…Elevated levels of plasma homocysteine (Hcy) are recognized to be an independent risk factor for the development of atherosclerosis and thrombosis [1,2]. By far, the pathogenic mechanisms have not been fully elucidated.…”