Hyperhomocysteinemia and Cardiovascular Disease

Reacts with NO S-nitrosohomocysteine - this reacts with O2 homocysteine + NOs + 

Causes desquamation of vascular endothelium and impairs regeneration 

Increases platelet coagulability and so activates platelet aggregation Connective tissue abnormalities 

Inhibition of lysyl oxidase disturbance of collagen and elastin cross-linking (see Section 13.3.3) 

In the presence of homocysteine, fibroblasts produce excessively sulfated proteoglycans 

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M. E. Suliman, A. R. Qureshi, P. Barany, P. Stenvinkel, J. C. Filho, B. Anderstam, O. Heimburger, B. Lindholm, and J. Bergstrom, Hyperhomocysteinemia, Nutritional Status, and Cardiovascular Diseases in Hemodialysis Patients, Kidney International 57 (2000) 1727-1735. 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Morgan SL, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm,low dose methotrexate therapy for rheumatoid arthritis implications for cardiovascular disease prevention. J Rheumatol 1998 25(3) 44l-446. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

The data are compatible with the dopamine, glutamate and neurodevelopmental hypotheses as well as with schizophrenia comorbidities, including cardiovascular diseases, diabetes, viral infections, neonatal complications and hyperhomocysteinemia. 

Although, as shown in Table 10.1, there are plausible mechanisms to suggest that homocysteine is a causative factor in cardiovascular disease, it is possible that hyperhomocysteinemia is a result of the renal damage that is an early event in cardiovascular disease, thus a proxy marker of disease rather than a causative factor (Jacobsen, 1998 hangman and Cole, 1999 Kircher and Sinzinger, 2000). in chronic renal failure, hyperhomocysteinemia is associated with cardiovascular disease, probably because of both impaired excretion of homocysteine and impaired activity of betaine homocysteine methyl-transferase elevated plasma dimethylglycine predicts plasma homocysteine (McGregor et al., 2001). 

C. Kitiyakara, J. Gonin, Z. Massy and C. S. Wilcox, Non-Traditional Cardiovascular Disease Risk Factors in End-Stage Renal Disease Oxidative Stress and Hyperhomocysteinemia, Current Opinion in Nephrology and Hypertension 9 (2000) 477-487. 

Vitamin B-6 is also required for the conversion of homocysteine to cysteine and hyperhomocysteinemia appears to be a risk factor for cardiovascular disease. 

Folic acid/cobalamin/pyridoxine hydrochloride are nutritional combinations. Folic acid and cobalamin reduce homocysteine by metabolizing it to methionine. Pyridox-ine facilitates breakdown of homocysteine to cysteine and other by-products. They are indicated for nutritional requirement of patients with end-stage renal failure, dialysis, hyperhomocysteinemia, homocystinuria, nutrient malabsorption or inadequate dietary intake, particularly for patients with or at risk for cardiovascular disease, cerebrovascular disease, peripheral vascular disease, arteriosclerotic... 

Hyperhomocysteinemia high homocysteine concentrations mostly due to genetic mutation, deficiency in B group vitamins and/or renal insufficiency an independent risk factor for cardiovascular disease. 

Mild hyperhomocysteinemia due to inadequate intake of folate and vitamin Bi2 is associated with an increased risk of cardiovascular disease [7]. The number of persons at risk vastly exceeds the number of patients with inborn errors of metabolism, and public health policy recommendations for screening and intervention in patients with mild hyperhomocysteinemia await ongoing clinical trials. 

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