The risk association of plasma total homocysteine with acute myocardial infarction is modified by serum vitamin A

Abstract

Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the potential interaction between plasma tHcy and serum Vit-A in relation to incident acute myocardial infarction. Methods Cox proportional hazards models were used to assess the prospective relationships between tHcy and acute myocardial infarction in 2205 patients from Western Norway undergoing elective coronary angiography for suspected stable angina pectoris. Results are reported as hazard ratio per standard deviation increase in log-transformed tHcy. An interaction term for tHcy × Vit-A was added to multivariate models including age, sex, smoking, apolipoprotein B fasting, statin and aspirin prescription and estimated glomerular filtration rate. Results Geometric mean (geometric standard deviation) age of the participants (64.3% men) was 62.3 (1.24) years. Plasma tHcy was higher among participants in the upper versus lower Vit-A tertile. During 7 (2.4) years of follow-up, 15.1% suffered an AMI. A significant association of plasma tHcy with AMI in the total study population was observed. When we stratified the population according to Vit-A tertiles, plasma tHcy was associated with acute myocardial infarction only in the upper Vit-A tertile (hazard ratio per SD: 1.25, 95% confidence interval: 1.04-1.53, p = 0.03). Conclusions The risk relationship between plasma tHcy and acute myocardial infarction was modified by serum concentrations of Vit-A in patients with suspected stable angina pectoris. This finding may clarify the relationship between tHcy and cardiovascular disease.

Retinol, Retinoic Acid, and Retinol-Binding Protein 4 are Differentially Associated with Cardiovascular Disease, Type 2 Diabetes, and Obesity: An Overview of Human Studies

“…In addition, one SD increase in apoA1 concentrations was associated with a 13 % risk reduction (20). In a subsequent paper from the same core population, it was shown that patients with circulating concentrations of retinol exceeding 3.20 µmol/L, one SD increase in plasma total homocysteine concentrations was associated with a 25 % increased risk of CVD in 2205 patients with suspected CAD (21). Taken together, although the findings on the relationship between serum retinol and CVD suggest that higher retinol concentrations may be beneficial compared to lower concentrations in terms of risk, elevated concentrations beyond the upper limit of the reference range, may be harmful in itself or in other ways affect CVD risk such as the reported effectmodification on other risk factors.…”

“…In this review we show that both retinol and retinoic acid have been linked to common lifestyle diseases. Briefly, retinol has been both positively and negatively associated with CVD (13,(15)(16)(17)(18)(19), T2DM (39) and the metabolic syndrome (81), and emerging evidence suggest that retinol can modify the relationship of other common risk factors with CVD (20,21). Less work has been done on circulating concentrations of retinoic acid and disease outcomes, but observational data indicate that it is inversely related to CVD in particular (22,23), whereas the association with T2DM is less clear (39).…”

“…Thus, these seemingly discrepant effects of RBP4 and retinol/retinoic acid on adverse health outcomes indicate that the effects associated with RBP4 may not involve retinol delivery to tissues and subsequent retinoic acid signaling. On the other hand, it is not certain that retinol and retinoic acid are mere innocent bystanders in this context as suggested by: 1) the study showing that products of retinol metabolism and signaling were prospectively related to the development T2DM (39), 2) the partly positive association of retinol with incident CVD mortality (19) and metabolic syndrome (81), 3) our recent findings that serum retinol can modify the effects of common risk factors on CVD development (20,21) and finally, 4) that pharmacological treatment with retinoic acid isoforms induce dyslipidemia (24,25) and homocysteinemia (26), which are common risk factors for CVD in particular. Whether these potentially adverse effects of retinol and retinoic acid includes RBP4 is currently not known although it has been proposed that the RBP4-retinol complex is involved in signaling pathways that are implicated in insulin resistance (103).…”

Creatinine, total cysteine and uric acid are associated with serum retinol in patients with cardiovascular disease

“…Serum retinol has generally been considered to be under tight homeostatic control [15], and we have previously shown that retinol in serum of patients hospitalised for suspected coronary artery disease may range beyond what has been observed in other cohorts [4][5][6][7][8][9]. Factors associated with this variation have not been elucidated to a meaningful extent in CVD patients.…”

“…We have recently reported that elevated serum retinol potentiates the risk of incident acute myocardial infarctions associated with traditional risk markers in subjects hospitalised for suspected coronary artery disease, including lipids and total homocysteine [ 4 , 5 ]. The circulating retinol concentrations in these patients exceed those reported from other cohorts [ 6 – 9 ], and retinol concentrations above clinical reference ranges have been associated with the metabolic syndrome [ 10 ] and cardiovascular disease (CVD) [ 11 ].…”