Diabetic Atherosclerosis - Pathology

Homocysteine - updated: 15 March 2008

Homocysteine and cardiovascular disease: a review of the evidence

Diab Vasc Dis Res. 2007 Jun;4(2):143-50

Wierzbicki AS.

Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence, as well as data from retrospective and prospective studies, supports an association between elevated HCY levels and increased risk of cardiovascular disease (CVD). However, whether lowering HCY levels by administration of folate and vitamins B6 and B12 is associated with any significant decrease in vascular risk remains the subject of ongoing debate. Although the major studies that have reported to date show that vitamin supplementation was associated with a decrease in HCY levels, this failed to have any significant effect on cardiovascular risk. Furthermore, although some lipid-modifying treatments have been shown to increase HCY levels, there is no evidence that this attenuates or compromises the beneficial effects of such treatments on cardiovascular risk. Taken together, these data suggest that HCY is a marker, rather than a cause, of CVD and therefore do not provide support for routine screening for and treatment of elevated HCY to prevent CVD. Data from ongoing clinical trials are awaited to clarify this issue.

Publication Types:

• Review

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Cell Death Differ. 2004 Jul;11 Suppl 1:S56-64

Austin RC, Lentz SR, Werstuck GH.

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine beta-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic- and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

Publication Types:

• Review

Homocysteine and diabetic macroangiopathy

Nippon Rinsho. 2006 Nov;64(11):2153-8

Araki A.

Moderate hyperhomocysteinemia is one of risk factors for arteriosclerotic disease. In diabetic patients, hyperhomocysteinemia is an independent risk factor for macroangiopathy and mortality. Homocysteinemia is also associated with diabetic microangiopathy, silent stroke, and cognitive impairment. However, excluding those with nephropathy or microangiopathy, plasma homocysteine is lower in diabetic patients than non-diabetic controls. Oral treatment with folic acid, vitamin B12 and B6 reduces plasma homocysteine concentration about by 30%. The vitamin treatment for reduction of hyperhomocysteinemia improves endothelial dysfunction and retards carotid atherosclerosis. Few randomized control trials have showed a positive effect of the vitamin treatment on prevention from stroke and ischemic heart disease. Further prospective intervention studies are necessary to address the issue whether lowering homocysteine does prevent the development and progression of diabetic macroangiopathy.

Publication Types:

• Review

Hyperhomocysteinemia and cardiovascular risk in diabetes mellitus

Ann Ist Super Sanita. 2003;39(2):153-63

Russo GT, Cucinotta D.

Cardiovascular disease is a major cause of death in diabetic subjects. Hyperglycaemia per se cannot explain this excess of risk. Several lines of evidence indicate that mild hyperhomocysteinemia is an independent atherosclerotic risk factor in general population. Hyperhomocysteinemia is not linked with diabetic disease per se, rather fasting homocysteine plasma levels largely depend on glomerular filtration rate (GFR). There is a great dial of controversy on the association between high homocysteine plasma levels and diabetic retinopathy and neuropathy. On the contrary, most of the studies confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular disease associated with diabetes.

Publication Types:

• Review

Clinical relevance of homocysteine monitoring in the diabetic patient

Diabetes Metab. 2002 Dec;28(6 Pt 1):510-5

Benmerabet S, Fredenrich A, Robillon JF, Canivet B, Candito M, Van Obberghen E.

Accelerated atherosclerosis is common in diabetes mellitus, although its extent is not always related to its strong association with classical cardiovascular risk factors. Diabetic patients, especially with type 2 diabetes, are prone to cardiovascular disease which is the leading cause of death in this population. Recent clinical studies among general population have shown that an even mild increase of homocysteinemia play an important role in the progression of atherosclerosis, either in coronary or peripheral arteries. An increasing amount of in vitro data is providing evidence that excess of homocysteine has a toxic effect on the arterial wall. This aminoacid thus appears to be not only a risk marker but also an emerging cardiovascular risk factor. The measurement of plasma homocysteine contributes to the identification, among the diabetic population, of patients at high cardio-vascular risk, with the aim of improving their global management. Moreover the addition of group B vitamins provides an easy and low-cost treatment to lower hyperhomocysteinemia.

Publication Types:

• Review

Publication Types:

• Review