Seminars in vascular medicine最新文献

Many studies conducted over the last two decades have shown that drug treatment for common medical conditions may have an adverse effect on plasma total homocysteine (tHcy) concentrations. The mechanism for the effects of individual drugs on tHcy concentrations is frequently unknown, as the mechanism of action of the drug may not be established, or the drug is typically administered in combination with other drugs. Some drugs are believed to alter tHcy concentrations by interfering in the metabolism of folate or vitamins B (12) or B (6) or by altering renal function, but the underlying mechanisms for the effects on tHcy concentrations of many drugs remains to be discovered. Several widely used drugs, such as lipid-lowering drugs (like fibrates and niacin) or oral hypoglycemic drugs (like metformin), insulin, drugs used in rheumatoid arthritis, and anticonvulsants cause elevated tHcy concentrations. Sex hormones have variable effects on tHcy levels, and N-acetylcysteine lowers tHcy. The mechanisms of action of drugs on tHcy concentrations and strategies to avoid tHcy elevation have been studied. Assuming that the association of tHcy with cardiovascular disease is causal, this article focuses on the adverse effect on tHcy levels of fibrates, statins and niacin, antihypertensive drugs, metformin, methotrexate and sulfasalazine, anticonvulsant drugs, and levodopa and reviews strategies to avoid such effects. The clinical significance, if any, of these adverse effects on plasma tHcy concentrations remains to be determined.

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. During the last decade, considerable progress in delineating the mechanisms that underlie the atherogenic effects of hyperhomocysteinemia has been achieved through the use of experimental animal models. Among the most informative animal models are those that use genetic and dietary approaches to produce hyperhomocysteinemia in mice. Recent findings demonstrate that hyperhomocysteinemia can accelerate the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Hyperhomocysteinemia also is a potent inducer of endothelial dysfunction, particularly in small vessels such as cerebral arterioles. Mechanisms of endothelial dysfunction may include inhibition of endothelial nitric oxide synthase by its endogenous inhibitor, asymmetric dimethylarginine, and oxidative inactivation of nitric oxide mediated by upregulation of prooxidant enzymes and downregulation of antioxidant enzymes. There also is good evidence from animal models that hyperhomocysteinemia produces endoplasmic reticulum stress, which may contribute to atherosclerosis and endothelial dysfunction by activating signal transduction pathways leading to inflammation, oxidative stress, and apoptosis.

The role of folic acid and homocysteine in pregnancy is becoming clearer. The efforts of many countries to prevent neural tube defects through public awareness of folic acid have been disappointing, but evidence is now emerging that the food fortification programs in the United States and Canada are effective in reducing the numbers of neural tube defects, and there may be additional benefits in terms of other congenital defects such as oral-facial clefts and congenital heart disease. Homocysteine has a significant association with vascular disease in later life, is elevated in preeclampsia, and has been associated with other pregnancy complications such as early pregnancy loss. The data from cohorts of women with a history of preeclampsia during pregnancy indicate that they are at increased risk for cardiovascular and cerebrovascular disease in later life. Elevated homocysteine concentrations may be a common link that accounts for these associations.

Renal insufficiency is invariably accompanied by elevated plasma concentrations of the sulfur-containing and potentially vasculotoxic amino acid homocysteine. There is a strong relationship between glomerular filtration rate and plasma homocysteine concentration. Unlike creatinine, however, homocysteine is avidly reabsorbed in the renal tubules, and its urinary excretion is minimal. There is no evidence that homocysteine is actively removed by the human kidney. In renal insufficiency, plasma concentrations of S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, and sulfate are elevated, pointing to a remethylation or distal transsulfuration/oxidation block as the cause of hyperhomocysteinemia in renal failure. Stable isotope techniques have shown that both whole-body homocysteine remethylation and methionine transmethylation are decreased in renal failure, whereas homocysteine transsulfuration seems intact. Metabolic homocysteine clearance (i.e., transsulfuration relative to plasma homocysteine) is decreased to a major extent. These metabolic disturbances in renal failure can only be partially restored with current treatments. Folic acid treatment lowers plasma homocysteine concentration and increases remethylation and transmethylation rates. Plasma homocysteine, however, is not normalized, and metabolic homocysteine clearance by transsulfuration remains impaired. According to the currently available data, effective normalization of plasma homocysteine can only be obtained when its metabolic clearance through transsulfuration is restored.

Elevated plasma total homocysteine concentration is a risk factor for venous thrombosis. The association is well established in patients with homocystinuria irrespective of the genetic etiology and metabolic background. Homocystinuria is a human model of chronic exposure to very high concentrations of plasma homocysteine and reflects an abnormal amino acid metabolism. Elevated homocysteine levels in patients with venous thrombosis have attracted considerable interest because homocysteine is a potentially reversible thrombophilic marker for venous thrombosis. In contrast to homocystinuria, hyperhomocysteinemia is mild and reflects environmental and constitutional factors such as age, intake of B-vitamins, derangements of metabolism, and renal impairment. This review examines the evidence for the relationship of homocysteine with risk of venous thrombosis in homocystinuria and in the general population.

New developments in diagnostic markers and a better understanding of the limitations of traditional diagnostic strategies have allowed diagnosis of earlier stages and atypical forms of cobalamin deficiency. Still, there are no generally accepted guidelines for the definition, diagnosis, treatment, and follow-up of cobalamin deficiency. The new trend toward defining cobalamin deficiency purely on the basis of biochemical test outcomes in the absence of overt clinical signs and symptoms could, however, be problematic and may result in overdiagnosis and overtreatment. Use of metabolic markers for the assessment of cobalamin deficiency allows the demonstration of tissue deficiency, but the establishment of the cause of deficiency should also be part of the diagnostic approach. Four groups of diagnostic tests are currently available and these include total cobalamin and cobalamin fractions (such as holo-transcobalamin), tests of gastrointestinal dysfunction, tests of metabolic function, and different gene tests. Among the available tests, only homocysteine, methylmalonic acid, holo-transcobalamin, and possibly methylcitric acid are considered to be useful in clinical practice to add to cobalamin. Gastrointestinal function tests may identify the cause of cobalamin deficiency, whereas the diagnostic usefulness of genetic testing needs to be evaluated. This article provides an overview of recent developments and a reappraisal of novel and established diagnostic markers for cobalamin deficiency.

Homocysteine is derived from the essential amino acid methionine and plays a vital role in cellular homeostasis in man. Homocysteine levels depend on its synthesis, involving methionine adenosyltransferase, S-adenosylmethionine-dependent methyltransferases such as glycine N-methyltransferase, and S-adenosylhomocysteine hydrolase; its remethylation to methionine by methionine synthase, which requires methionine synthase reductase, vitamin B (12), and 5-methyltetrahydrofolate produced by methylenetetrahydrofolate reductase or betaine methyltransferase; and its degradation by transsulfuration involving cystathionine beta-synthase. The control of homocysteine metabolism involves changes of tissue content or inherent kinetic properties of the enzymes. In particular, S-adenosylmethionine acts as a switch between remethylation and transsulfuration through its allosteric inhibition of methylenetetrahydrofolate reductase and activation of cystathionine beta-synthase. Mutant alleles of genes for these enzymes can lead to severe loss of function and varying severity of disease. Several defects lead to severe hyperhomocysteinemia, the most common form being cystathionine beta-synthase deficiency, with more than a hundred reported mutations. Less severe elevations of plasma homocysteine are caused by folate and vitamin B (12) deficiency, and renal disease and moderate hyperhomocysteinemia are associated with several common disease states such as cardiovascular disease. Homocysteine toxicity is likely direct or caused by disturbed levels of associated metabolites; for example, methylation reactions through elevated S-adenosylhomocysteine.

The prevention and treatment of age-related cognitive impairment and dementia is one of the greatest and most elusive challenges of our time. The prevalence of dementia increases exponentially with age, as does the prevalence of those with micronutrient deficiency. Several studies have shown that elevated homocysteine is correlated with cognitive decline and with cerebral atrophy and that it predicts the subsequent development of dementia in cognitively intact middle-aged and elderly individuals. If elevated homocysteine promotes cognitive dysfunction, then lowering homocysteine by means of B-vitamin supplementation may protect cognitive function by arresting or slowing the disease process.