Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases.

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and becoming larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B(12), and vitamin B(6) deficiency and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10 percent of total risk. Elevated plasma homocysteine levels (> 12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence overproportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and life style factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of < 10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25 percent of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of hyperhomocysteinemia can be recommended for the apparently healthy general population.

[Transpupillary thermotherapy in exudative, age-related macular degeneration]. / Transpupilläre Thermotherapie bei exsudativer altersabhängiger Makuladegeneration.

OBJECTIVE: To assess the effectiveness of a single transpupillary thermotherapy (TTT) in patients with exudative, age-related macular degeneration (AMD). METHODS: In a prospective pilot study, 14 patients with a mean age of 78 years (range: 70-92 years) with subfoveal choroidal neovascularisation (CNV) due to exudative, age-related macular degeneration were treated with a single TTT using a diode laser (810 nm). Seven patients had a classic and seven an occult CNV. Laser beam size was 4.5 mm,the power setting was 800 mW and the exposure lasted 60 s. RESULTS: Twelve out of 14 patients could be followed for a period of 18 months. Stabilisation of the visual acuity was achieved in two patients, ten patients lost three or more Snellen lines. In none of the patients a regression of the CNV could be observed immediately after TTT. Inactive fibrotic scars developed in six patients at the end of the study. CONCLUSION: Our results suggest that TTT, according to our protocol, has no beneficial effect on the spontaneous course of the CNV in patients with AMD.

Vascular dysfunction in hyperhomocyst(e)inemia. Implications for atherothrombotic disease.

Elevated plasma homocyst(e)ine is currently accepted as a major, independent risk factor for atherosclerosis and venous thrombosis. Even moderate hyperhomocyst(e)inemia is prospectively associated with increased risk of mortality in patients with cardiovascular disease. However, the underlying mechanisms resulting in vascular damage are not clearly defined. The endothelium exerts fundamental control on the vascular tone, coagulation and fibrinolysis. Injury to the endothelium followed by dysfunction is an early key event preceding manifestation of vessel pathology. Acute and chronic exposure of endothelium to homocyst(e)ine induces impairment of endothelial function associated with altered homeostasis and morphologic changes of the vessel wall. Investigations of the role of homocyst(e)ine in the endothelium-dependent function in healthy subjects and cardiovascular patients have recently added important clinical insight with implications for the treatment of cardiovascular disease. Importantly, the damaging effects of hyperhomocyst(e)inemia on endothelial function are, at least in part, reversible in patients with established vascular disease, supporting further the hypothesis that homocyst(e)ine-lowering through vitamin supplementation may have vasoprotective effects.