Effects of dietary supplementation with creatine on homocysteinemia and systemic microvascular endothelial function in individuals adhering to vegan diets

Abstract

Since McCully [1] first described the relationship between hyperhomocysteinemia (HHcy), atherosclerosis, and arterial thrombosis in homocystinuria patients, several studies have demonstrated HHcy as an independent risk factor in cardiovascular disease, dementia development, and increasing the risk of mortality [2]. In fact, a total Hcy level of 14.3 lmol/L or greater was independently associated with a relative risk of mortality (54% for all-cause mortality and 52% for cardiovascular mortality) [3]. Humphrey et al. [4] demonstrated that each increase of 5 lmol/L in Hcy levels increased the risk of cardiovascular events by approximately 20%. Vegetarian diets have been demonstrated to decrease cardiovascular disease (CVD) risk factors such as serum lipid profile, serum glucose concentration, and systolic and diastolic blood pressure. Indeed, vegetarians have been shown as presenting less hyperlipidemia, hyperglycemia, and hypertension and obesity compared with nonvegetarians [5]. It is interesting that studies have demonstrated a modest decrease in CVD prevalence and non-decreased mortality from circulatory diseases and cerebrovascular disease in vegetarians compared with nonvegetarians [6]. The counterpoint to this fact is that vegetarian diets provide deficient amounts of vitamin B12, an important co-factor for Hcy removal that leads to HHcy. Indeed, several studies comparing Hcy blood levels among vegetarians and nonvegetarians reported higher levels of Hcy in vegetarians [7]. In addition to that, ovo-lacto vegetarians receive little dietary creatine, while vegans (who do not consume any animal food or animal dairy products) receive no dietary creatine at all [8]. Thus, vegetarians and vegans may synthesize most of their creatine (~90%) [9]. This is particularly relevant since creatine synthesis from Hcy as a subproduct and an elevated creatine synthesis demand may increase Hcy formation. Hcy is an amino acid formed exclusively by demethylation of methionine. In Hcy synthesis, methionine is activated by ATP to form S-adenosylmethionine (SAM). SAM acts primarily as a universal methyl donor in the synthesis of methylated compounds such as neurotransmitters (adrenaline, noradrenaline), DNA, RNA, phosphatidylcholine, and creatine. A subproduct of these methylation reactions is S-adenosylhomocysteine, which is hydrolyzed to adenosine and Hcy (for a more detailed approach, see reviews [8] and [10]). Thus, Cr synthesis and Hcy formation are metabolically linked by methyl metabolism. Previous studies have shown that Cr supplementation downregulates creatine endogenous synthesis [11]. Because Cr synthesis is responsible for a considerable consumption of SAM (at least 40%) and Hcy formation, Cr supplementation leads to reduced Hcys formation in rats [12,13]. There have been only a small number of studies regarding the effect of Cr supplementation in humans, and the results from these studies were quite inconsistent [10]. Van Bavel et al. [14] elegantly studied 56 strict vegetarians who received creatine or placebo supplementation for 3 weeks in a randomized single-blind manner. These authors demonstrated that 42% of the vegan subjects studied presented HHcy (Hcy > 15 lmol/L); three weeks of creatine supplementation significantly (P < 0.05) reduced plasma Hcy concentration. The decreasing-Hcy effects of creatine supplementation were more evident in hyperhomocysteinemic compared to non-hyperhomocysteinemic vegetarian subjects. No HHcy was detected after creatine supplementation. In addition, creatine supplementation enhanced skin