Hyperhomocysteinemia Is Associated With an Increased Risk of Cardiovascular Disease, Especially in Non–Insulin-Dependent Diabetes Mellitus

Hoogeveen, Ellen K.; Kostense, Pieter J.; Beks, P.J.; Mackaay, A. J. C.; Jakobs, Cornelis; Bouter, Lex M.; Heine, Robert J.; Stehouwer, Coen D.A.

doi:10.1161/01.atv.18.1.133

Cited by 338 publications

(229 citation statements)

References 34 publications

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“…39,40 Several studies also showed a significant association between Hcy and BP, [4][5][6][41][42][43][44][45] or HTN; 1,46 however, no association was found in other studies 47,48 (Table 6). Recently, a randomized, placebo-controlled, Hcy-lowering trial reported a decrease in BP in response to treatment.…”

Section: Discussionmentioning

confidence: 97%

Plasma homocysteine concentration and blood pressure in healthy Iranian adults: the Tehran Homocysteine Survey (2003–2004)

et al. 2005

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Section: Discussionmentioning

confidence: 97%

Plasma homocysteine concentration and blood pressure in healthy Iranian adults: the Tehran Homocysteine Survey (2003–2004)

et al. 2005

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“…These interactions were further strengthened when postmethionine-load homocysteine levels were taken into account. Moreover, the hyperhomocysteinemia associated with an increased cardiovascular risk is stronger in non-insulin-dependent diabetes mellitus than in normal subjects (Hoogeveen et al, 1998). Thus, there are pronounced interactive effects with classic risk factors, suggesting that homocysteine might further increase the cardiovascular risk in patients bearing these risk factors.…”

Section: Interactions Between Hyperhomocysteinemia and The Usual Riskmentioning

confidence: 99%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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“…Even though elevated homocysteine levels contribute to the development of atherosclerosis independently of classical cardiovascular risk factors in diabetic subjects [25,26], the relationship between Hcy and diabetes is still debated. Plasma homocysteine levels have been reported to be normal, reduced or elevated in patients with diabetes [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

et al. 2006

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Aims/hypothesis Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. Materials and methods In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. Results Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-κB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. Conclusions/interpretation Homocysteine upregulates the MMP-TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control.

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Hyperhomocysteinemia Is Associated With an Increased Risk of Cardiovascular Disease, Especially in Non–Insulin-Dependent Diabetes Mellitus

Cited by 338 publications

References 34 publications

Plasma homocysteine concentration and blood pressure in healthy Iranian adults: the Tehran Homocysteine Survey (2003–2004)

Plasma homocysteine concentration and blood pressure in healthy Iranian adults: the Tehran Homocysteine Survey (2003–2004)

Impaired Homocysteine Metabolism and Atherothrombotic Disease

High glucose and homocysteine synergistically affect the metalloproteinases–tissue inhibitors of metalloproteinases pattern, but not TGFB expression, in human fibroblasts

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